(12) STANDARD PATENT APPLICATION (11) Application No. AU 2008202217 A9(19) AUSTRALIAN PATENT OFFICE

(54) TitleNucleic acids and corresponding proteins entitled 191PAD12(b) useful in treatment anddetection of cancer

(51) International Patent Classification(s)C07K 14/00 (2006.01) G01N 33/574 (2006.01)A61K 47/48 (2006.01) A61K 38/00 (2006.01)C07K 14/47 (2006.01)

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Application No: 2008202217 (22) Date of Filing: 2008.05.20

Publication Date:Publication Journal Date:Corrigenda Journal Date:

2008.06.052008.06.052008.06.12

Divisional of:2003228717

Applicant(s)Agensys, Inc.

Inventor(s)Jakobovits, Aya;Ge, Wangmao;Faris, Mary;Raitano, Arthur B.;Challita-Eid, Pia M.

Agent AttorneyFB Rice Co, Level 23 200 Queen Street, Melbourne, VIC, 3000

ABSTRACT00O A novel gene 191 P4D 12(b) and its encoded protein, and variants thereof, are

described wherein 191P4D12(b) exhibits tissue specific expression in normal adulttissue, and is aberrantly expressed in the cancers listed in Table I. Consequently,

191 P4D 12(b) provides a diagnostic, prognostic, prophylactic and/or therapeutic targetfor cancer. The 191P4D12(b) gene or fragment thereof, or its encoded protein, or

CI variants thereof, or a fragment thereof, can be used to elicit a humoral or cellular

immune response; antibodies or T cells reactive with 191P4D12(b) can be used in

active or passive immunization.'

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AUSTRALIA

FB RICE COPatent and Trade Mark Attorneys

Patents Act 1990

AGENSYS, INC.

COMPLETE SPECIFICATION

STANDARD PATENT

Invention Title.

Nucelic acids and corresponding proteins entitled 191PAD12(b)

useful in treatment and detection of cancer

The following statement is a full description of this invention including

the best method of performing it known to us:-

I

NUCLEIC ACIDS AND CORRESPONDING PROTEINS ENTITLED 191o00

0 P4D12(b) USEFUL IN TREATMENT AND DETECTION OF CANCER

This is a divisional of AU 2003228717, the entire contents of which are

incorporated herein by reference.

FIELD OF THE INVENTION

The invention described herein relates to genes and their encoded proteins,

termed 191P4D 12(b), expressed in certain cancers, and to diagnostic and therapeutic

methods and compositions useful in the management of cancers that express 191

SP4D12(b).

BACKGROUND OF THE INVENTION

00 Cancer is the second leading cause of human death next to coronary disease.

Worldwide, millions of people die from cancer every year. In the United States alone,

as reported by the American Cancer Society, cancer causes the death of well over a

half-million people annually, with over 1.2 million new cases diagnosed per year.While deaths from heart disease have been declining significantly, those resulting from

cancer generally are on the rise. In the early part of the next century, cancer is predicted

to become the leading cause of death.

Worldwide, several cancers stand out as the leading killers. In particular,

carcinomas of the lung, prostate, breast, colon, pancreas, and ovary represent the

primary causes of cancer death. These and virtually all other carcinomas share a

common lethal feature. With very few exceptions, metastatic disease from a carcinoma

is fatal. Moreover, even for those cancer patients who initially survive their primary

cancers, common experience has shown that their lives are dramatically altered. Many

cancer patients experience strong anxieties driven by the awareness of the potential for

recurrence or treatment failure. Many cancer patents experience physical debilitations

following treatment. Furthermore, many cancer patients experience a recurrence.

Worldwide, prostate cancer is the fourth most prevalent cancer in men. In North

America and Northern Europe, it is by far the most common cancer in males and is the

second leading cause of cancer death in men. In the United States alone, well over

30,000 men die annually of this disease-second only to lung cancer. Despite the

magnitude of these figures, there is still no effective treatment for metastatic prostate

cancer. Surgical prostatectomy, radiation therapy, hormone ablation therapy, surgical

castration and chemotherapy continue to be the main treatment modalities.

Unfortunately, these treatments are ineffective for many and are often associated with

undesirable consequences.

On the diagnostic front, the lack of a prostate tumor marker that can accurately00

detect early-stage, localized tumors remains a significant limitation in the diagnosis and

N, management of this disease. Although the serum prostate specific antigen (PSA) assay

has been a very useful tool, however its specificity and general utility is widely

regarded as lacking in several important respects.

00

Progress in identifying additional specific markers for prostate cancer has been improved by the generation ofprostate cancer xenografts that can recapitulate different stages of the disease In mice. The LAPC (Los Angeles Prostate

00 Cancer) xenografts are prostate cancer xenografts that have survived passage in severe combined immune deficient (SCID)mice and have exhibited the capacity to mimic the transition from androgen dependence to androgen independence (Klein etal., 1997, Nat. Med. 3:402). More recently Identified prostate cancer markers include PCTA-1 (Su et al., 1996, Proc. Natl.Acad. Sci. USA 93: 7252), prostate-specific membrane (PSM) antigen (Pinto et al., Clin Cancer Res 1996 Sep 2 1445-51), STEAP (Hubert, et al., Proc Natl Acad Sci U S A. 1999 Dec 7; 96(25): 14523-8) and prostate stem cell antigen (PSCA)

S (Reiter et al, 1998, Proc. Natl. Acad. Sci. USA 95: 1735).While previously identified markers such as PSA, PSM, PCTA and PSCA have facilitated efforts to diagnose and

treat prostate cancer, there is need for the identification of additional markers and therapeutic targets for prostate and relatedcancers in order to further improve diagnosis and therapy.Renal cell carcinoma (RCC) accounts for approximately 3 percent of adult malignancies. Once adenomas reach a diameterof 2 to 3 cm, malignant potential exists. In the adult, the two principal malignant renal tumors are renal cell adenocarcinoma

C0 and transitional cell carcinoma of the renal pelvis or ureter. The incidence of renal cell adenocarcinoma is estimated at morethan 29,000 cases In the United States, and more than 11,600 patients died of this disease in 1998. Transitional cell

C"1 carcinoma is less frequent, with an incidence of approximately 500 cases per year in the United States.Surgery has been the primary therapy for renal cell adenocarcinoma for many decades. Until recently, metastatic

disease has been refractory to any systemic therapy. With recent developments in systemic therapies, particularlyimmunotherapies, metastatic renal cell carcinoma may be approached aggressively in appropriate patients with a possibilityof durable responses. Nevertheless, there is a remaining need for effective therapies for these.patients.

Of all new cases of cancer in the United States, bladder cancer represents approximately 5 percent in men (fifthmost common neoplasm) and 3 percent in women (eighth most common neoplasm). The incidence is increasing slowly,.concurrent with an increasing older population. In 1998, there was an estimated 54,500 cases, including 39,500 in men and15,000 in women. The age-adjusted incidence in the United States is 32 per 100,000 for men and eight per 100,000 inwomen. The historic male/female ratio of 3:1 may be decreasing related to smoking patterns in women. There were anestimated 11,000 deaths from bladder cancer in 1998 (7,800 in men and 3,900 in women). Bladder cancer incidence andmortality strongly increase with age and will be an increasing problem as the population becomes more elderly.

Most bladder cancers recur in the bladder. Bladder cancer is managed with a combination of transurethralresection of the bladder (TUR) and intravesical chemotherapy or immunotherapy. The multifocal and recurrent nature ofbladder cancer points out the limitations of TUR. Most muscle-invasive cancers are not cured by TUR alone. Radicalcystectomy and urinary diversion is the most effective means to eliminate the cancer but carry an undeniable impact onurinary and sexual function. There continues to be a significant need for treatment modalities that are beneficial for bladdercancer patients.

An estimated 130,200 cases of colorectal cancer occurred in 2000 in the United States, including 93,800 cases ofcolon cancer and 36,400 of rectal cancer. Colorectal cancers are the third most common cancers in men and women.Incidence rates declined significantly during 1992-1996 per year). Research suggests that these declines have beendue to increased screening and polyp removal, preventing progression of polyps to invasive cancers. There were anestimated 56,300 deaths (47,700 from colon cancer, 8,600 from rectal cancer) in 2000, accounting for about 11% of all U.S.cancer deaths.

At present, surgery is the most common form of therapy for colorectal cancer, and for cancers that have notspread, it is frequently curative. Chemotherapy, or chemotherapy plus radiation, is given before or after surgery to mostpatients whose cancer has deeply perforated the bowel wall or has spread to the lymph nodes. A permanent colostomy

(creation of an abdominal opening for elimination of body wastes) is occasionally needed for colon cancer and is infrequently

required for rectal cancer. There continues to be a need for effective diagnostic and treatment modalities for colorectal

00cancer.

There were an estimated 164,100 new cases of lung and bronchial cancer in 2000, accounting for 14% of all U.S.

cancer diagnoses. The incidence rate of lung and bronchial cancer is declining significantly in men, from a high of 86.5 per

c 100,000 in 1984 to 70.0 in 1996. In the 1990s, the rate of increase among women began to slow. In 1996, the incidence

S rate in women was 42.3 per 100,000.

SLung and bronchial cancer caused an estimated 156,900 deaths in 2000, accounting for 28% of all cancer deaths.

During 1992-1996, mortality from lung cancer declined significantly among men per year) while rates for women were

still significantly increasing per year). Since 1987, more women have died each year of lung cancer than breast

cancer, which, for over 40 years, was the major cause of cancer death in women. Decreasing lung cancer incidence and

c.i mortality rates most likely resulted from decreased smoking rates over the previous 30 years; however, decreasing smoking

patterns among women lag behind those of men. Of concern, although the declines in adult tobacco use have slowed,

00 tobacco use in youth is increasing again.

Treatment options for lung and bronchial cancer are determined by the type and stage of the cancer and include

LC surgery, radiation therapy, and chemotherapy. For many localized cancers, surgery is usually the treatment of choice.

Because the disease has usually spread by the time it is discovered, radiation therapy and chemotherapy are often needed

in combination with surgery. Chemotherapy alone or combined with radiation is the treatment of choice for small cell lung

cancer; on this regimen, a large percentage of patients experience remission, which in some cases is long lasting. There is

however, an ongoing need for effective treatment and diagnostic approaches for lung and bronchial cancers.

An estimated 182,800 new invasive cases of breast cancer were expected to occur among women in the United

States during 2000. Additionally, about 1,400 new cases of breast cancer were expected to be diagnosed in men in 2000.

After increasing about 4% per year in the 1980s, breast cancer incidence rates in women have leveled off in the 1990s to

about 110.6 cases per 100,000.

In the U.S. alone, there were an estimated 41,200 deaths (40,800 women, 400 men) in 2000 due to breast cancer.

Breast cancer ranks second among cancer deaths in women. According to the most recent data, mortality rates declined

significantly during 1992-1996 with the largest decreases in younger women, both white and black. These decreases were

probably the result of earlier detection and improved treatment.

Taking into account the medical circumstances and the patient's preferences, treatment of breast cancer may

involve lumpectomy (local removal of the tumor) and removal of the lymph nodes under the arm; mastectomy (surgical

removal of the breast) and removal of the lymph nodes under the arm; radiation therapy; chemotherapy; or hormone therapy.

Often, two or more methods are used in combination. Numerous studies have shown that, for early stage disease, long-term

survival rates after lumpectomy plus radiotherapy are similar to survival rates after modified radical mastectomy. Significant

advances in reconstruction techniques provide several options for breast reconstruction after mastectomy. Recently, such

reconstruction has been done at the same time as the mastectomy.

Local excision of ductal carcinoma in situ (DCIS) with adequate amounts of surrounding normal breast tissue may

prevent the local recurrence of the DCIS. Radiation to the breast and/or tamoxifen may reduce the chance of DCIS occurring

in the remaining breast tissue. This is important because DCIS, if left untreated, may develop into invasive breast cancer.

Nevertheless, there are serious-side effects or sequelae to these treatments. There is, therefore, a need for efficacious

breast cancer treatments.

There were an estimated 23,100 new cases of ovarian cancer in the United States in 2000. It accounts for 4% of

all cancers among women and ranks second among gynecologic cancers. During 1992-1996, ovan'an cancer incidence

rates were significantly declining. Consequent to ovarian cancer, there were an estimated 14,000 deaths in 2000. Ovarian

cancer causes more deaths than any other cancer of the female reproductive system.

0 Surgery, radiation therapy, and chemotherapy are treatment options for ovarian cancer. Surgery usually includes

the removal of one or both ovaries, the fallopian tubes (salpingo-oophorectomy), and the uterus (hysterectomy). In some

S very early tumors, only the involved ovary will be removed, especially in young women who wish to have children. InS advanced disease, an attempt is made to remove all intra-abdomlnal disease to enhance the effect of chemotherapy. There

continues to be an important need for effective treatment options for ovarian cancer.

SThere were an estimated 28,300 new cases of pancreatic cancer in the United States in 2000. Over the past

years, rates of pancreatic cancer have declined in men. Rates among women have remained approximately constant but

S may be beginning to decline. Pancreatic cancer caused an estimated 28,200 deaths in 2000 in the United States. Over the

past 20 years, there has been a slight but significant decrease In mortality rates among men (about-0.9% per year) while

L| rates have increased slightly among women.

SSurgery, radiation therapy, and chemotherapy are treatment options for pancreatic cancer. These treatment

00 options can extend survival and/or relieve symptoms In many patients but are not likely to produce a cure for most. There is

a significant need for additional therapeutic and diagnostic options for pancreatic cancer.

SUMMARY OF THE INVENTION

The present invention relates to a gene, designated 191P4D12(b), that has now been found to be over-expressed

in the cancer(s) listed in Table I. Northern blot expression analysis of 191P4D12(b) gene expression in normal tissues

shows a restricted expression pattern in adult tissues. The nucleotide (Figure 2) and amino acid (Figure 2, and Figure 3)

sequences of 191P4D12(b) are provided. The tissue-related profile of 191P4D12(b) in normal adult tissues, combined with

the over-expression observed in the tissues listed in Table I, shows that 191P4D12(b) is aberrantly over-expressed in at least

some cancers, and thus serves as a useful diagnostic, prophylactic, prognostic, and/or therapeutic target for cancers of the

tissue(s) such as those listed in Table I.

The invention provides polynucleotides corresponding or complementary to all or part of the 191P4D12(b) genes,

mRNAs, and/or coding sequences, preferably in isolated form, including polynucleotides encoding 191P4D12(b)-related

proteins and fragments of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more than

contiguous amino acids; at least 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 85, 90, 95, 100 or more than 100 contiguous amino

acids of a 191P4D12(b)-related protein, as well as the peptides/proteins themselves; DNA, RNA, DNA/RNA hybrids, and

related molecules, polynucleotides or oligonucleotides complementary or having at least a 90% homology to the

191 P4D12(b) genes or mRNA sequences or parts thereof, and polynucleotides or oligonucleotides that hybridize to the

191P4D12(b) genes, mRNAs, or to 191P4D12(b)-encoding polynucleotides. Also provided are means for isolating cDNAs and

the genes encoding 191P4D12(b). Recombinant DNA molecules containing 191P4D12(b) polynudeotides, cells transformed or

transduced with such molecules, and host-vector systems for the expression of 191P4D12(b) gene products are also provided.

The invention further provides antibodies that bind to 191P4D12(b) proteins and polypeptide fragments thereof, including

polyclonal and monoclonal antibodies, murine and other mammalian antibodies, chimeric antibodies, humanized and fully

human antibodies, and antibodies labeled with a detectable marker or therapeutic agent. In certain embodiments, there is a

proviso that the entire nucleic acid sequence of Figure 2 is not encoded and/or the entire amino acid sequence of Figure 2 is

not prepared. In certain embodimenls, the entire nucleic acid sequence of Figure 2 is encoded and/or the entire amino acid

sequence of Figure 2 is prepared, either of which are in respective human unit dose forms.

The invention further provides methods for detecting the presence and status of 191 P4D12(b) polynucleotides and

proteins in various biological samples, as well as methods for identifying cells that express 191P4D12(b). A typical embodiment of

this invention provides methods for monitoring 191P4012(b) gene products in a tissue or hematology sample having or suspected

of having some form of growth dysregulation such as cancer.0 0 The invention further provides various immunogenic or therapeutic compositions and strategies for treating cancers

that express 191P4D12(b) such as cancers of tissues listed in Table I, including therapies aimed at inhibiting the

transcription, translation, processing or function of 191P4D12(b) as well as cancer vaccines. In one aspect, the invention

provides compositions, and methods comprising them, for treating a cancer that expresses 191P4D12(b) in a human subject

wherein the composition comprises a carrier suitable for human use and a human unit dose of one or more than one agent

that inhibits the production or function of 191P4D12(b). Preferably, the carrier is a uniquely human carrier. In another aspect

of the invention, the agent Is a moiety that is immunoreactive with 191P4D12(b) protein. Non-limiting examples of such

moieties include, but are not limited to, antibodies (such as single chain, monoclonal, polyclonal, humanized, chimeric, or

human antibodies), functional equivalents thereof (whether naturally occurring or synthetic), and combinations thereof. The

S antibodies can be conjugated to a diagnostic or therapeutic moiety. In another aspect, the agent is a small molecule as

defined herein.

00 In another aspect, the agent comprises one or more than one peptide which comprises a cytotoxic T lymphocyte

(CTL) epitope that binds an HLA class I molecule in a human to elicit a CTL response to 191P4D12(b) and/or one or more

ri than one peptide which comprises a helper T lymphocyte (HTL) epitope which binds an HLA class II molecule in a human to

elicit an HTL response. The peptides of the invention may be on the same or on one or more separate polypeptide

molecules. In a further aspect of the invention, the agent comprises one or more than one nucleic acid molecule that

expresses one or more than one of the CTL or HTL response stimulating peptides as described above. In yet another

aspect of the invention, the one or more than one nucleic acid molecule may express a moiety that is immunologically

reactive with 191P4D12(b) as described above. The one or more than one nucleic acid molecule may also be, or encodes, a

molecule that inhibits production of 191P4D12(b). Non-limiting examples of such molecules include, but are not limited to,

those complementary to a nucleotide sequence essential for production of 191P4D12(b) antisense sequences or

molecules that form a triple helix with a nucleotide double helix essential for 191P4D12(b) production) or a ribozyme effective

to lyse 191P4D12(b) mRNA.

Note that to determine the starting position of any peptide set forth in Tables VIII-XXI and XXII to XLIX (collectively

HLA Peptide Tables) respective to its parental protein, variant 1, variant 2, etc., reference is made to three factors: the

particular variant, the length of the peptide in an HLA Peptide Table, and the Search Peptides in Table VII. Generally, a

unique Search Peptide is used to obtain HLA peptides of a particular for a particular variant The position of each Search

Peptide relative to its respective parent molecule is listed in Table VII. Accordingly, if a Search Peptide begins at position

one must add the value "X 1" to each position in Tables VIII-XXI and XXII to XLIX to obtain the actual position of the

HLA peptides in their parental molecule. For example, if a particular Search Peptide begins at position 150 of its parental

molecule, one must add 150 1, 149 to each HLA peptide amino acid position to calculate the position of that amino acid

in the parent molecule.

One embodiment of the invention comprises an HLA peptide, that occurs at least twice in Tables VIII-XXI and XXII

to XLIX collectively, or an oligonucleotide that encodes the HLA peptide. Another embodiment of the invention comprises an

HLA peptide that occurs at least once in Tables VIII-XXI and at least once in tables XXII to XLIX, or an oligonucleotide that

encodes the HLA peptide.

Another embodiment of the invention is antibody epitopes, which comprise a peptide regions, or an oligonucleotide

encoding the peptide region, that has one two, three, four, or five of the following characteristics:

i) a peptide region of at least 5 amino acids of a particular peptide of Figure 3, in any whole number increment upto the full length of that protein in Figure 3, that Includes an amino acid position having a value equal to or greater than

00 0.6, 0.7, 0.8, 0.9, or having a value equal to 1.0, in the Hydrophilicity profile of Figure

0 ii) a peptide region of at least 5 amino acids of a particular peptide of Figure 3, in any whole number increment upto the full length of that protein in Figure 3, that includes an amino acid position having a value equal to or less than 0.5, 0.4,

c 0.3, 0.2, 0.1, or having a value equal to 0.0, in the Hydropathicity profile of Figure 6;

iii) a peptide region of at least 5 amino acids of a particular peptide of Figure 3, in any whole number Increment upto the full length of that protein in Figure 3, that includes an amino acid position having a value equal to or greater than 0.6, 0.7, 0.8, 0.9, or having a value equal to 1.0, in the Percent Accessible Residues profile of Figure 7;

iv) a peptide region of at least 5 amino acids of a particular peptide of Figure 3, in any whole number increment upto the full length of that protein in Figure 3, that includes an amino acid position having a value equal to or greater than

0.6, 0.7, 0.8, 0.9, or having a value equal to 1.0, in the Average Flexibility profile of Figure 8; orSv) a peptide region of at least 5 amino acids of a particular peptide of Figure 3, in any whole number increment up

00 to the full length of that protein in Figure 3, that includes an amino acid position having a value equal to or greater than 0.6, 0.7, 0.8, 0.9, or having a value equal to 1.0, in the Beta-turn profile of Figure 9.

BRIEF DESCRIPTION OF THE FIGURESFigure 1. The 191P4D12(b) SSH sequence of 223 nucleotides.

Figure 2. A) The cDNA and amino acid sequence of 191P4D12(b) variant 1 (also called "191P4012(b) v.1" or

"191P4D12(b) variant is shown in Figure 2A. The start methionine is underlined. The open reading frame extends from

nucleic acid 264-1796 including the stop codon.

B) The cDNA and amino acid sequence of 191P4D12(b) variant 2 (also called "191P4D12(b) is shown in

Figure 28. The codon for the start methionine is underlined. The open reading frame extends from nucleic acid 264-1796

including the stop codon.

C) The cDNA and amino acid sequence of 191P4D12(b) variant 3 (also called "191P4D12(b) is shown in

Figure 2C. The codon for the start methionine is underlined. The open reading frame extends from nucleic acid 264-1796

including the stop codon.

D) The cDNA and amino acid sequence of 191P4D12(b) variant 4 (also called "191P4D12(b) is shown in

Figure 2D. The codon for the start methionine Is underlined. The open reading frame extends from nucleic acid 264-1796

including the stop codon.

E) The cDNA and amino acid sequence of 191P4D12(b) variant5 (also called "191P4D12(b) is shown in

Figure 2E. The codon for the start methionine is underlined. The open reading frame extends from nucleic acid 264-1796

including the stop codon.

F) The cDNA and amino acid sequence of 191P4D12(b) variant 6 (also called "191P4D12(b) is shown in

Figure 2F. The codon for the start methlonine is underlined. The open reading frame extends from nucleic acid 789-1676

including the stop codon.

G) The cDNA and amino acid sequence of 191P4D12(b) variant 7 (also called "191P4D12(b) is shown in

Figure 2G. The codon for the start methionine is underlined. The open reading frame extends from nucleic acid 264-1721

including the stop codon.

H) The cDNA and amino acid sequence of 191P4D12(b) variant8 (also called "191P4D12(b) Is shown in

Figure 2H. The codon for the start methionine is underlined. The open reading frame extends from nucleic acid 264-1796

including the stop codon.

I) The cDNA and amino acid sequence of 191P4D12(b) variant 9 (also called "191P4D12(b) is shown in

Figure 21. The codon for the start methionine is underlined. The open reading frame extends from nucleic acid 708-1121

including the stop codon.

O J) The cDNA and amino acid sequence of 191P4D12(b) variant 10 (also called "191P4D12(b) v.10") is shown in

Figure 2J. The codon for the start methionine is underlined. The open reading frame extends from nucleic acid 264-1796

including the stop codon.

K) The cDNA and amino acid sequence of 191P4012(b) variant 11 (also called "191P4D12(b) v.11") is shown in

Figure 2K. The codon for the start methionine is underlined. The open reading frame extends from nucleic acid 264-1796

including the stop codon.

L) The cDNA and amino acid sequence of 191P4D12(b) variant 12 (also called "191P4D12(b) v.12") is shown in

Figure 2L. The codon for the start methionine is underlined. The open reading frame extends from nucleic acid 264-1796

including the stop codon.

M) The cDNA and amino acid sequence of 191P4D12(b) variant 13 (also called "191P4D12(b) v.13") is shown in

00 Figure 2M. The codon for the start methionine is underlined. The open reading frame extends from nucleic acid 264-1799

including the stop codon.

0i N) The cDNA and amino acid sequence of 191P4D12(b) variant 14 (also called "191P4D12(b) v.14") is shown in

Figure 2N. The codon for the start methionine is underlined. The open reading frame extends from nucleic acid 708-1121

including the stop codon.

Figure 3.

A) The amino acid sequence of 191P4D12(b) v.1 is shown in Figure 3A; it has 510 amino acids.

B) The amino acid sequence of 191P4D12(b) v.2 is shown in Figure 3B; it has 510 amino acids.

C) The amino acid sequence of 191P4D12(b) v.6 is shown in Figure 3C; it has 295 amino acids.

D) The amino acid sequence of 191P4D12(b) v.7 is shown in Figure 3D; it has 485 amino acids.

E) The amino acid sequence of 191P4D12(b) v.10 is shown in Figure 3E; it has 510 amino acids.

F) The amino acid sequence of 191P4D12(b) v.11 is shown in Figure 3F; it has 510 amino acids.

G) The amino acid sequence of 191P4D12(b) v.12 is shown in Figure 3G; it has 510 amino acids.

H) The amino acid sequence of 191P4D12(b) v.13 is shown in Figure 3H; it has 511 amino acids.

I) The amino acid sequence of 191P4D12(b) v.9 is shown in Figure 31; it has 137 amino acids.

J) The amino acid sequence of 191P4D12(b) v.14 is shown in Figure 3J; it has 137 amino acids.

As used herein, a reference to 191P4D12(b) includes all variants thereof, including those shown in Figures 2, 3,

and 11, unless the context clearly indicates otherwise.

Figure 4. Alignment of 191P4D12(b) with known homologs. Figure 4(A) Alignment of 191P4D12(b)with human Ig

superfamily receptor LNIR (gi 14714574). Figure 4(B) Alignment of 191P4D12(b) with mouse nectin 4 (gi 18874521).

Figure 5. Hydrophilicity amino acid profile of 191P4012(b)v.1, v.7, and v.9 determined by computer algorithm

sequence analysis using the method of Hopp and Woods (Hopp Woods 1981. Proc. Natl. Acad. Sci. U.S.A.

78:3824-3828) accessed on the Protscale website located on the World Wide Web at (expasy.ch/cgi-bin/protscale.pl)

through the ExPasy molecular biology server.

Figure 6. Hydropathicity amino acid profile of 191P4D12(b)v.1, v.7, and v.9 determined by computer algorithm

sequence analysis using the method of Kyte and Doolittle (Kyte Doolittle 1982. J. Mol. Biol. 157:105-132) accessed

on the ProtScale website located on the World Wide Web at (.expasy.ch/cgi-bin/protscale.pl) through the ExPasy molecular

biology server.

Figure 7. Percent accessible residues amino acid profile of 191P4D12(b)v.1, v.7, and v.9 determined by computeralgorithm sequence analysis using the method of Janin (Janin 1979 Nature 277:491-492) accessed on the ProtScalewebsite located on the World Wide Web at (.expasy.ch/cgi-bln/protscale.pl) through the ExPasy molecular biology server.

Figure 8. Average flexibility amino acid profile of 191P4012(b)v.1, v.7, and v.9 determined by computer algorithmsequence analysis using the method of Bhaskaran and Ponnuswamy (Bhaskaran and Ponnuswamy 1988. Int. J.Pept. Protein Res. 32:242-255) accessed on the ProtScale website located on the World Wide Web at (.expasy.ch/cgi-bin/protscale.pl) through the ExPasy molecular biology server.

Figure 9. Beta-turn amino acid profile of 191P4D12(b)v.1, v.7, and v.9 determined by computer algorithmsequence analysis using the method of Deleage and Roux (Deleage, Roux B. 1987 Protein Engineering 1:289-294)

S accessed on the ProtScale website located on the World Wide Web at (.expasy.ch/cgi-bin/protscale.pl) through the ExPasymolecular biology server.

Figure 10. Schematic alignment of SNP variants of 191P4D12(b). Variants 191P4D12(b) v.2 through v.5 and C(1 through v.12 are variants with single nucleotlde differences. Compared with v.1, v.13 had an insertion of three bases (GCA)00 between 1262 and1263 and added one amino acid to the protein. Variant v.14 was a SNP variant of transcript variant

v.9, corresponding to the SNP at 2688 of v.1. Though these SNP variants were shown separately, they could also occur inany combinations and in any transcript variants, as shown in Fig. 12, that contained the base pairs. Numbers correspond tothose of 191P4D12(b) v.1. Black box shows the same sequence as 191P4D12(b) v.1. SNPs are indicated above the box.

Figure 11. Schematic alignment of protein variants of 191P4D12(b). Protein variants correspond to nucleotidevariants. Nucleotide variants 191P4D12(b) v.3, v.4, v.5 and v.8 coded for the same protein as v.1. Nucleotide variants191P4D12(b) v.6, v.7, v.8 and v.9 were splice variants of v.1, as shown in Figure 12. Variant v.9 translated to a totallydifferent protein than other variants, with two isoforms that different from each other by one amino acid at 64: A or D. Variantv.13 had an insertion of one amino acid at 334. Single amino acid differences were indicated above the boxes. Blackboxes represent the same sequence as 191P4D12(b) v.1. Numbers underneath the box correspond to 191P4D12(b) v.1.

Figure 12. Exon compositions of transcript variants of 191P4D12(b). Variant 191P4D12(b) v.6, v.7, v.8 and v.9 aretranscript variants of v.1. Variants v.6, v.7 and v.8 spliced out 202-321, 1497-1571 and 2951-3013 of v.1, respectively.Variant v.9 was part of the last exon of v.1. The order of the potential exons on the human genome is shown at the bottom.Poly A tails were not shown in the figure. Ends of exons are shown above the boxes. Numbers in undemeath the boxescorrespond to those of 191P4D12(b) v.1. Lengths of introns and exons are not proportional.

Figure 13. Secondary structure and transmembrane domains prediction for 191P4D12(b) protein variants.The secondary structure of 191P4D12(b) protein variants 1 (SEQ ID NO: 127), v6 (SEQ ID NO: 128), v7 (SEQ ID NO:129), and v9 (SEQ ID NO: 130) (Figures 13A-D respectively) were predicted using the HNN Hierarchical Neural Networkmethod (Guermeur, 1997, http:l/pbil.ibcp.fr/cgi-bin/npsa_automat.pl?page=npsa n.html), accessed from the ExPasymolecular biology server located on the World Wide Web at (.expasy.ch/tools/). This method predicts the presence andlocation of alpha helices, extended strands, and random coils from the primary protein sequence.

The percent of the protein in a given secondary structure is also listed. Figures 13E, 13G, 131,13K: Schematicrepresentations of the probability of existence of transmembrane regions and orientation of 191P4D12(b) variants 1, 6, 7,and 9, respectively, based on the TMpred algorithm of Hofmann and Stoffel which utilizes TMBASE Hofmann, W. Stoffel.TMBASE A database of membrane spanning protein segments Biol. Chem. Hoppe-Seyler 374:166, 1993). Figures 13F,13H, 13J, 13L. Schematic representations of the probability of the existence of transmembrane regions and the extracellularand intracellular orientation of 191P4D12(b) variants 1, 6, 7, and 9, respectively, based on the TMHMM algorithm ofSonnhammer, von Heijne, and Krogh (Erik L.L. Sonnhammer, Gunnar von Heijne, and Anders Krogh: A hidden Markbvmodel for predicting transmembrane helices in protein sequences. In Proc. of Sixth Int. Conf. on Intelligent Systems for

Molecular Biology, p 175-182 Ed J. Glasgow, T. Littlejohn, F. Major, R. Lathrop, D. Sankoff, and C. Sensen Menlo Park, CA:

AAAI Press, 1998). The TMpred and TMHMM algorithms are accessed from the ExPasy molecular biology server located on000 the World Wide Web at (.expasy.ch/tools/).

Figure 14. 191P4D12(b) Expression by RT-PCR. First strand cDNA was prepared from vital pool 1 (liver, lung

and kidney), vital pool 2 (pancreas, colon and stomach), normal kidney, prostate cancer pool, bladder cancer pool, colon

cancer pool, lung cancer pool, breast cancer pool and cancer metastasis pool; prostate cancer metastasis to lymph node,

prostate cancer pool, bladder cancer pool, kidney cancer pool, colon cancer pool, lung cancer pool, ovary cancer pool,

breast cancer pool, cancer metastasis pool, pancreas cancer pool, and LAPC prostate xenograft pool. Normalization was

performed by PCR using primers to actin and GAPDH. Semi-quantitative PCR, using primers to 191P4D12(b), was

S performed at 26 and 30 cycles of amplification. In results show strong expression of 191P4D12(b) in bladder cancer

pool. Expression of 191P4D12(b) was also detected in prostate cancer pool, colon cancer pool, lung cancer pool, breast

CN cancer pool and cancer metastasis pool but very weakly in vital pool 1 and vital pool 2. In results show strong expression

of 191P4D12(b) in prostate, bladder, kidney, colon, lung, ovary, breast, cancer metastasis, and pancreas cancer specimens.0 0 Figure 15. Expression of 191P4D12(b) in normal tissues. Two multiple tissue northern blots (Clontech) both with

2 ug of mRNA/Iane were probed with the 191P4D12(b) sequence. Size standards in kilobases (kb) are indicated on the side.

Results show expression of an approximately 4kb transcript In placenta and very weakly in prostate but not in any other

normal tissue tested. A smaller 191P4D12(b) transcript of approximately 2.5kb was detected in heart and skeletal muscle.

Figure 16. Expression of 191P4D12(b) In Patient Cancer Specimens and Normal Tissues. RNA was extracted

from a pool of 3 bladder cancer patient specimens, as well as from normal prostate normal bladder normal kidney

normal colon normal lung normal breast (NBr), normal ovary and normal pancreas (NPa). Northern

blot with 10 ug of total RNA/lane was probed with 191P4D12(b) SSH sequence. Size standards in kilobases (kb) are

indicated on the side. The 191P4D12(b) transcript was detected in the bladder cancer specimens, but not in the normal

tissues tested.

Figure 17. Expression of 191P4D12(b) in Bladder Cancer Patient Specimens. RNA was extracted from bladder

cancer cell lines normal bladder and bladder cancer patient tumors Northern blots with 10 ug of total RNA

were probed with the 191P4D12(b) SSH fragment. Size standards in kilobases are on the side. Results show expression of

the approximately 4kb 191P4012(b) transcript in the bladder tumor tissues but not in normal bladder. A smaller transcript

was detected in the HT1197 cell line but not in the other cancer cell lines tested.

Figure 18. Expression of 191P4D12(b) in Prostate Cancer Xenografts. RNA was extracted from normal prostate,

and from the prostate cancer xenografts LAPC-4AD, LAPC-4AI, LAPC-9AD, and LAPC-9AI. Northern blots with 10 ug of

total RNA were probed with the 191P4D12(b) SSH fragment. Size standards in kilobases are on the side. Results show

expression of the approximately 4kb 191P4D12(b) transcript in all the LAPC xenograft tissues but not in normal prostate.

Figure 19. Expression of 191P4D12(b) in Cervical Cancer Patient Specimens. RNA was extracted from normal

cervix, Hela cancer cell line, and 3 cervix cancer patient tumors Northern blots with 10 ug of total RNA were probed with

the 191P4D12(b) SSH fragment. Size standards in kilobases are on the side. Results show expression of the approximately

4kb 191P4D12(b) transcript in 2 out of 3 cervix tumors but not in normal cervix nor in the Hela cell line.

Figure 20. Expression of 191P4D12(b) in Lung Cancer Patient Specimens. RNA was extracted from lung cancer

cell lines normal lung bladder cancer patient tumors and normal adjacent tissue (Nat). Northern blots with

ug of total RNA were probed with the 191P4D12(b). Size standards in kilobases are on the side. Results show expression

of the approximately 4kb 191P4D12(b) transcript in the lung tumor tissues but not in normal lung nor in the cell lines tested.

Figure 21. Figure 21A. 191P4D12(b) Expression In Lung Cancer. First strand cDNA was prepared from a panel

of lung cancer specimens. Normalization was performed by PCR using primers to actin. Semi-quantitative PCR, using

primers to 191P4D12(b) SSH fragment, was performed at 26 and 30 cycles of amplification. Expression level was recorded

as 0 no expression detected; 1 weak expression, 2 moderate expression; 3 strong expression. Results show00C expression of 191P4D12(b) in 97% of the 31 lung cancer patient specimens tested. Figure 21B. 191P4D12(b) Expression

in Bladder Cancer. First strand cDNA was prepared from a panel of bladder cancer specimens. Normalization was

Sperformed by PCR using primers to actin. Semi-quantitative PCR, using primers to 191P4D12(b) SSH fragment, was

performed at 26 and 30 cycles of amplification. Expression level was recorded as 0 no expression detected; 1 weak

expression, 2 moderate expression; 3 strong expression. Results show expression of 191P4D12(b) in 94% of the 18

Sbladder cancer patient specimens tested. Figure 21C. 191P4012(b) Expression in Prostate Cancer. First strand cDNA was

prepared from a panel of prostate cancer specimens, and four LAPC prostate cancer xenografts. Normalization was

performed by PCR using primers to actin. Semi-quantitative PCR, using primers to 191P4D12(b) SSH fragment, was

performed at 26 and 30 cycles of amplification. Expression level was recorded as 0 no expression detected; 1 weak

CK1 expression, 2 moderate expression; 3 strong expression. Results show expression of 191P4D12(b) in 100% of the

S'prostate cancer patient specimens tested, and in all 4 prostate cancer xenografts. Figure 21D. 191P4D12(b) Expression in

00 Colon Cancer. First strand cDNA was prepared from a panel of colon cancer specimens. Normalization was performed by

0 PCR using primers to actin. Semi-quantitative PCR, using primers to 191P4D12(b) SSH fragment, was performed at 26 and

cycles of amplification. Expression level was recorded as 0 no expression detected; 1 weak expression, 2

moderate expression; 3 strong expression. Results show expression of 191P4D12(b) in 100% of the 22 colon cancer

patient specimens tested. Figure 21E. 191P4D12(b) Expression in Uterus Cancer. First strand cDNA was prepared from a

panel of uterus cancer specimens. Normalization was performed by PCR using primers to actin. Semi-quantitative PCR,

using primers to 191P4D12(b) SSH fragment, was performed at 26 and 30 cycles of amplification. Expression level was

recorded as 0 no expression detected; 1 weak expression, 2 moderate expression; 3 strong expression. Results

show expression of 191P4D12(b) in 100% of the 12 uterus cancer patient specimens tested. Figure 21F. 191P4D12(b)

Expression in Cervical Cancer. First strand cDNA was prepared from a panel of cervix cancer specimens. Normalization

was performed by PCR using primers to actin. Semi-quantitative PCR, using primers to 191P4D12(b) SSH fragment, was

performed at 26 and 30 cycles of amplification. Expression level was recorded as 0 no expression detected; 1 weak

expression, 2 moderate expression; 3 strong expression. Results show expression of 191P4D12(b) in 100% of the 14

cervix cancer patient specimens tested.

Figure 22. Transient Expression of 191P4D12(b) in Transfected 293T Cells. 293T cells were transfected with

either 191P4D12(b) .pTag5, 191P4D12(b).pcDNA3.1/mychis or pcDNA3.1/mychis vector control. Forty hours later, cell

lysates and supernatant were collected. Samples were run on an SDS-PAGE acrylamide gel, blotted and stained with anti-

his antibody. The blot was developed using the ECL chemiluminescence kit and visualized by autoradiography. Results

show expression from 191P4D12(b).pTag5 plasmid of 191P4D12(b) extracellular domain in the lysate (Lane 2) and secretion

in the culture supernatant (Lane Also, expression of 191P4D12(b) was detected from in the lysates of

191P4D12(b).pcDNA3.1/mychis transfected cells (Lane but not from the control pcDNA3.1/mychis (Lane 4).

Figure 23. Expression of 191P4012(b) in Transduced Cells Following Retroviral Gene Transfer. 3T3 cells were

transduced with the pSRa retroviral vector encoding the 191P4D12(b) gene. Following selection with neomycin, the cells

were expanded and RNA was extracted. Northern blot with 10 ug of total RNA/lane was probed with the 191P4D12(b) SSH

sequence. Size standards in kilobases (kb) are indicated on the side. Results show expression of the 191P4D12(b)

transcript driven from the retroviral LTR, which migrates slower than the endogenous 4 kb 191P4D12(b) transcript detected

in the positive control LAPC-4AD.

DETAILED DESCRIPTION OF THE INVENTIONOutline of Sections

Definitions

II.) 191P4D12(b) Polynucleotides

00 II.A.) Uses of 191P4D12(b) Polynucleotides

II.A.1.) Monitoring of Genetic Abnormalities

ll.A.2.) Antisense Embodiments

II.A.3.) Primers and Primer Pairs

II.A.4.) Isolation of 191P4D12(b)-Encoding Nucleic Acid Molecules

Recombinant Nucleic Acid Molecules and Host-Vector Systems

II1.) 191P4D12(b)-related Proteins

III.A.) Motif-bearing Protein Embodiments

III.B.) Expression of 191P4D12(b)-related Proteins

SIII.C.) Modifications of 191P4D12(b)-related Proteins

III.D.) Uses of 191P4D12(b)-related Proteins

00 IV.) 191P4D12(b) Antibodies

191P4D12(b) Cellular Immune Responses

C VI.) 191P4D12(b) Transgenic Animals

VII.) Methods for the Detection of 191P4D12(b)

VIII.) Methods for Monitoring the Status of 191P4D12(b)-related Genes and Their Products

IX.) Identification of Molecules That Interact With 191P4D12(b)

Therapeutic Methods and Compositions

Anti-Cancer Vaccines

XB.) 191P4D12(b) as a Target for Antibody-Based Therapy

XC.) 191P4D12(b) as a Target for Cellular Immune Responses

X.C.1. Minigene Vaccines

X.C.2. Combinations of CTL Peptides with Helper Peptides

X.C.3. Combinations of CTL Peptides with T Cell Priming Agents

X.C.4. Vaccine Compositions Comprising DC Pulsed with CTL and/or HTL Peptides

Adoptive Immunotherapy

Administration of Vaccines for Therapeutic or Prophylactic Purposes

XI.) Diagnostic and Prognostic Embodiments of 191P4D12(b).

XII.) Inhibition of 191P4D12(b) Protein Function

XII.A.) Inhibition of 191P4D12(b) With Intracellular Antibodies

XII.B.) Inhibition of 191P4D12(b) with Recombinant Proteins

XII.C.) Inhibition of 191P4D12(b) Transcription or Translation

XII.D.) General Considerations for Therapeutic Strategies

XIII.) Identification, Characterization and Use of Modulators of 191P4D12(b)

XIV.) KITSIArticles of Manufacture

Definitions:

Unless otherwise defined, all terms of art, notations and other scientific terms or terminology used herein are

intended to have the meanings commonly understood by those of skill in the art to which this invention pertains. In some

cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion

of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally

understood in the art. Many of the techniques and procedures described or referenced herein are well understood and0 0 commonly employed using conventional methodology by those skilled in the art, such as, for example, the widely utilized

0 molecular cloning methodologies described in Sambrook et Molecular Cloning: A Laboratory Manual 2nd. edition (1989)

SCold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. As appropriate, procedures involving the use of

S commercially available kits and reagents are generally carried out in accordance with manufacturer defined protocols and/or

parameters unless otherwise noted.S The terms "advanced prostate cancer", "locally advanced prostate cancer", "advanced disease" and "locally

advanced disease" mean prostate cancers that have extended through the prostate capsule, and are meant to Include stage

C disease under the American Urological Association (AUA) system, stage C1 C2 disease under the Whitmore-Jewett

system, and stage T3 T4 and N+ disease under the TNM (tumor, node, metastasis) system. In general, surgery is not

recommended for patients with locally advanced disease, and these patients have substantially less favorable outcomes

0 compared to patients having clinically localized (organ-confined) prostate cancer. Locally advanced disease is clinically

00 identified by palpable evidence of induration beyond the lateral border of the prostate, or asymmetry or Induration above the

Sprostate base. Locally advanced prostate cancer is presently diagnosed pathologically following radical prostatectomy if thetumor invades or penetrates the prostatic capsule, extends into the surgical margin, or invades the seminal vesicles.

"Altering the native glycosylation pattern" is intended for purposes herein to mean deleting one or more

carbohydrate moieties found in native sequence 191P4D12(b) (either by removing the underlying glycosylation site or by

deleting the glycosylation by chemical and/or enzymatic means), and/or adding one or more glycosylation sites that are not

present in the native sequence 191P4D12(b). In addition, the phrase includes qualitative changes in the glycosylation of the

native proteins, involving a change in the nature and proportions of the various carbohydrate moieties present.

The term "analog" refers to a molecule which is structurally similar or shares similar or corresponding attributes with

another molecule a 191 P4D12(b)-related protein). For example, an analog of a 191 P4D12(b) protein can be specifically

bound by an antibody or T cell that specifically binds to 191 P4D12(b).

The term "antibody" is used in the broadest sense. Therefore, an "antibody" can be naturally occurring or man-made

such as monoclonal antibodies produced by conventional hybridoma technology. Anti-191P4D12(b) antibodies comprise

monoclonal and polyclonal antibodies as well as fragments containing the antigen-binding domain and/or one or more

complementarity determining regions of these antibodies.

An 'antibody fragment" Is defined as at least a portion of the variable region of the immunoglobulin molecule that

binds to its target, the antigen-binding region. In one embodiment it specifically covers single anti-191P4D12(b) antibodies

and clones thereof (including agonist, antagonist and neutralizing antibodies) and anti-191 P4D12(b) antibody compositions with

polyepitopic specificity.

The term "codon optimized sequences" refers to nucleotide sequences that have been optimized for a particular

host species by replacing any codons having a usage frequency of less than about 20%. Nucleotide sequences that have

been optimized for expression in a given host species by elimination of spurious polyadenylation sequences, elimination of

exon/intron splicing signals, elimination of transposon-like repeats and/or optimization of GC content in addition to codon

optimization are referred to herein as an "expression enhanced sequences."

A "combinatorial library" is a collection of diverse chemical compounds generated by either chemical synthesis or

biological synthesis by combining a number of chemical "building blocks" such as reagents. For example, a linear

combinatorial chemical library, such as a polypeptide mutein) library, is formed by combining a set of chemical building

blocks called amino acids in every possible way for a given compound length the number of amino acids in a

polypeptide compound). Numerous chemical compounds are synthesized through such combinatorial mixing of chemical

building blocks (Gallop et al., J. Med. Chem. 37(9): 1233-1251 (1994)).

O Preparation and screening of combinatorial libraries is well known to those of skill in the art. Such combinatorial

chemical libraries include, but are not limited to, peptide libraries (see, U.S. Patent No. 5,010,175, Furka, Pept. Prot.

Res. 37:487-493 (1991), Houghton et al., Nature, 354:84-88 (1991)), peptolds (PCT Publication No WO 91/19735), encoded

t peptides (PCT Publication WO 93/20242), random bio- oligomers (PCT Publication WO 92/00091), benzodiazepines (U.S.

Pat. No. 5,288,514), diversomers such as hydantoins, benzodiazepines and dipeptides (Hobbs et al., Proc. Nat. Acad. Sci.

USA 90:6909-6913 (1993)), vinylogous polypeptides (Hagihara et al., J. Amer. Chem. Soc. 114:6568 (1992)), nonpeptidal

peptidomimetics with a Beta-D-Glucose scaffolding (Hirschmann et al., J. Amer. Chem. Soc. 114:9217-9218 (1992)),

analogous organic syntheses of small compound libraries (Chen et al., J. Amer. Chem. Soc. 116:2661 (1994)),

oligocarbamates (Cho, et al., Science 261:1303 (1993)), and/or peptidyl phosphonates (Campbell et al., J. Org. Chem.

59:658 (1994)). See, generally, Gordon et al., J. Med. Chem. 37:1385 (1994), nucleic acid libraries (see, Stratagene,

Corp.), peptide nucleic acid libraries (see, U.S. Patent 5,539,083), antibody libraries (see, Vaughn et al., Nature

00 Biotechnology 14(3): 309-314 (1996), and PCT/US96/10287), carbohydrate libraries (see, Uang et al., Science

274:1520-1522 (1996), and U.S. Patent No. 5,593,853), and small organic molecule libraries (see, benzodiazepines,

Baum, C&EN, Jan 18, page 33 (1993); isoprenoids, U.S. Patent No. 5,569,588; thlazolidinones and metathiazanones, U.S.

Patent No. 5,549,974; pyrrolidines, U.S. Patent Nos. 5,525,735 and 5,519,134; morpholino compounds, U.S. Patent No.

5,506, 337; benzodiazepines, U.S. Patent No. 5,288,514; and the like).

Devices for the preparation of combinatorial libraries are commercially available (see, 357 NIPS, 390 NIPS,

Advanced Chem Tech, Louisville KY; Symphony, Rainin, Wobum, MA; 433A, Applied Biosystems, Foster City, CA; 9050,

Plus, Millipore, Bedford, NIA). A number of well-known robotic systems have also been developed for solution phase

chemistries. These systems Include automated workstations such as the automated synthesis apparatus developed by

Takeda Chemical Industries, LTD. (Osaka, Japan) and many robotic systems utilizing robotic arms (Zymate H, Zymark

Corporation, Hopkinton, Mass.; Orca, Hewlett-Packard, Palo Alto, Calif.), which mimic the manual synthetic operations

performed by a chemist. Any of the above devices are suitable for use with the present invention. The nature and

implementation of modifications to these devices (if any) so that they can operate as discussed herein will be apparent to

persons skilled in the relevant art. In addition, numerous combinatorial libraries are themselves commercially available (see,

ComGenex, Princeton, NJ; Asinex, Moscow, RU; Tripos, Inc., St. Louis, MO; ChemStar, Ltd, Moscow, RU; 3D

Pharmaceuticals, Exton, PA; Martek Biosciences, Columbia, MD; etc.).

The term "cytotoxic agent" refers to a substance that inhibits or prevents the expression activity of cells, function of

cells and/or causes destruction of cells. The term is intended to include radioactive isotopes chemotherapeutic agents, and

toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including

fragments and/or variants thereof. Examples of cytotoxic agents include, but are not limited to auristatins, auromycins,

maytansinolds, yttrium, bismuth, ricin, ricin A-chain, combrestatin, duocarmycins, dolostatins, doxorubicin, daunorubicin,

taxol, cisplatin, cc1065, ethidium bromide, mitomycin, etoposide, tenoposlde, vincristine, vinblastine, colchicine, dihydroxy

anthracin dione, actinomycin, diphtheria toxin, Pseudomonas exotoxin (PE) A, PE40, abrin, abrin A chain, modeccin A chain,

alpha-sarcin, gelonin, mitogellin, retstrictocin, phenomycin, enomycin, curicin, crotin, calicheamicin, Sapaonaria officinalis

inhibitor, and glucocorticoid and other chemotherapeutic agents, as well as radioisotopes such as At211 1131, 1125, Y90, Re' 86

Re' 88 Sm' 53 Bi212o213, P32 and radioactive isotopes of Lu including Lu' 7 Antibodies may also be conjugated to an anti-

cancer pro-drug activating enzyme capable of converting the pro-drug to its active form.

The "gene product" is sometimes referred to herein as a protein or mRNA. For example, a "gene product of the

invention" is sometimes referred to herein as a "cancer amino acid sequence", "cancer protein", "protein of a cancer listed in

Table a "cancer mRNA", "mRNA of a cancer listed in Table etc. In one embodiment, the cancer protein is encoded by anucleic acid of Figure 2. The cancer protein can be a fragment, or alternatively, be the full-length protein to the fragment

00 encoded by the nucleic acids of Figure 2. In one embodiment, a cancer amino acid sequence is used to determine

0 sequence identity or similarity. In another embodiment, the sequences are naturally occurring allelic variants of a proteinencoded by a nucleic acid of Figure 2. In another embodiment, the sequences are sequence variants as further described

ct herein.

"High throughput screening" assays for the presence, absence, quantification, or other properties of particularnucleic acids or protein products are well known to those of skill in the art. Similarly, binding assays and reporter gene

assays are similarly well known. Thus, U.S. Patent No. 5,559,410 discloses high throughput screening methods for

proteins; U.S. Patent No. 5,585,639 discloses high throughput screening methods for nucleic acid binding in arrays);while U.S. Patent Nos. 5,576,220 and 5,541,061 disclose high throughput methods of screening for ligand/antibody binding.

In addition, high throughput screening systems are commercially available (see, Amersham Biosciences,

Piscataway, NJ; Zymark Corp., Hopkinton, MA; Air Technical Industries, Mentor, OH; Beckman Instruments, Inc. Fullerton,

00 CA; Precision Systems, Inc., Natick, MA; etc.). These systems typically automate entire procedures, including all sample

and reagent pipetting, liquid dispensing, timed incubations, and final readings of the microplate in detector(s) appropriate for

the assay. These configurable systems provide high throughput and rapid start up as well as a high degree of flexibility and

customization. The manufacturers of such systems provide detailed protocols for various high throughput systems. Thus,

Zymark Corp. provides technical bulletins describing screening systems for detecting the modulation of gene

transcription, ligand binding, and the like.

The term "homolog" refers to a molecule which exhibits homology to another molecule, by for example, having

sequences of chemical residues that are the same or similar at corresponding positions.

"Human Leukocyte Antigen" or "HLA" is a human class I or class II Major Histocompatibility Complex (MHC) protein

(see, Stites, et al., IMMUNOLOGY, 8Tm ED., Lange Publishing, Los Altos, CA (1994).

The terms "hybridize', "hybridizing", "hybridizes" and the like, used in the context of polynucleotides, are meant to

refer to conventional hybridization conditions, preferably such as hybridization in 50% formamide/6XSSC/0.1% SDS/100

pig/ml ssDNA, in which temperatures for hybridization are above 37 degrees C and temperatures for washing in

0.1XSSC/0.1% SDS are above 55 degrees C.

The phrases "isolated" or "biologically pure" refer to material which is substantially or essentially free from

components which normally accompany the material as it is found in its native state. Thus, isolated peptides in accordance

with the invention preferably do not contain materials normally associated with the peptides in their in situ environment. For

example, a polynucleotide is said to be "isolated" when it is substantially separated from contaminant polynuceotides that

correspond or are complementary to genes other than the 191P4D12(b) genes or that encode polypeptides other than

191P4D12(b) gene product or fragments thereof. A skilled artisan can readily employ nucleic acid isolation procedures to obtain

an isolated 191P4D12(b) polynucleotide. A protein is said to be "solated," for example, when physical, mechanical or chemical

methods are employed to remove the 191P4D12(b) proteins from cellular constituents that are normally associated with the

protein. A skilled artisan can readily employ standard purification methods to obtain an isolated 191P4D12(b) protein.

Altematively, an isolated protein can be prepared by chemical means.

The term "mammal" refers to any organism classified as a mammal, including mice, rats, rabbits, dogs, cats, cows,

horses and humans. In one embodiment of the invention, the mammal is a mouse. In another embodiment of the invention, the

mammal is a human.

The terms "metastatic prostate cancer" and "metastatic disease" mean prostate cancers that have spread to

regional lymph nodes or to distant sites, and are meant to include stage D disease under the AUA system and stage

TxNxM+ under the TNM system. As is the case with locally advanced prostate cancer, surgery is generally not indicated for

patients with metastatic disease, and hormonal (androgen ablation) therapy is a preferred treatment modality. Patients with

0C metastatic prostate cancer eventually develop an androgen-refractory state within 12 to 18 months of treatment initiation.

0 Approximately half of these androgen-refractory patients die within 6 months after developing that status. The most common

site for prostate cancer metastasis is bone. Prostate cancer bone metastases are often osteoblastic rather than osteolytic

resulting in net bone formation). Bone metastases are found most frequently in the spine, followed by the femur, pelvis,

rib cage, skull and humerus. Other common sites for metastasis include lymph nodes, lung, liver and brain. Metastatic

C^ prostate cancer is typically diagnosed by open or laparoscopic pelvic lymphadenectomy, whole body radionuclide scans,

skeletal radiography, and/or bone lesion biopsy.

The term "modulator" or "test compound" or "drug candidate" or grammatical equivalents as used herein describe

any molecule, protein, oligopeptide, small organic molecule, polysaccharide, polynucleotide, etc., to be tested for the

C=K capacity to directly or indirectly alter the cancer phenotype or the expression of a cancer sequence, a nucleic acid or

Sprotein sequences, or effects of cancer sequences signaling, gene expression, protein interaction, etc.) In one aspect,

00 a modulator will neutralize the effect of a cancer protein of the Invention. By "neutralize" is meant that an activity of a protein

is inhibited or blocked, along with the consequent effect on the cell. In another aspect, a modulator will neutralize the effect

of a gene, and its corresponding protein, of the invention by normalizing levels of said protein. In preferred embodiments,

modulators alter expression profiles, or expression profile nucleic acids or proteins provided herein, or downstream effector

pathways. In one embodiment, the modulator suppresses a cancer phenotype, e.g. to a normal tissue fingerprint. In another

embodiment, a modulator induced a cancer phenotype. Generally, a plurality of assay mixtures is run in parallel with

different agent concentrations to obtain a differential response to the various concentrations. Typically, one of these

concentrations serves as a negative control, at zero concentration or below the level of detection.

Modulators, drug candidates or test compounds encompass numerous chemical classes, though typically they are

organic molecules, preferably small organic compounds having a molecular weight of more than 100 and less than about

2,500 Daltons. Preferred small molecules are less than 2000, or less than 1500 or less than 1000 or less than 500 D.

Candidate agents comprise functional groups necessary for structural interaction with proteins, particularly hydrogen

bonding, and typically include at least an amine, carbonyl, hydroxyl or carboxyl group, preferably at least two of the functional

chemical groups. The candidate agents often comprise cyclical carbon or heterocyclic structures andlor aromatic or

polyaromatic structures substituted with one or more of the above functional groups. Modulators also comprise biomolecules

such as peptides, saccharides, fatty acids, steroids, purines, pyrimidines, derivatives, structural analogs or combinations

thereof. Particularly preferred are peptides. One class of modulators are peptides, for example of from about five to about

amino adds, with from about five to about 20 amino acids being preferred, and from about 7 to about 15 being particularly

preferred. Preferably, the cancer modulatory protein is soluble, includes a non-transmembrane region, and/or, has an N-

terminal Cys to aid in solubility. In one embodiment, the C-terminus of the fragment is kept as a free acid and the N-terminus

is a free amine to aid in coupling, to cysteine. In one embodiment, a cancer protein of the invention is conjugated to an

immunogenic agent as discussed herein. In one embodiment, the cancer protein is conjugated to BSA. The peptides of the

invention, of preferred lengths, can be linked to each other or to other amino acids to create a longer peptide/protein.

The modulatory peplides can be digests of naturally occurring proteins as is outlined above, random peptides, or "biased"

random peptides. In a preferred embodiment, peptide/protein-based modulators are antibodies, and fragments thereof, as

defined herein.

Modulators of cancer can also be nucleic acids. Nucleic acid modulating agents can be naturally occurring nucleic

acids, random nucleic acids, or "biased" random nucleic acids. For example, digests of prokaryotic or eukaryotic genomes

can be used In an approach analogous to that outlined above for proteins.

The term "monodonal antibody" refers to an antibody obtained from a population of substantially homogeneous

00 antibodies, the antibodies comprising the population are identical except for possible naturally occuning mutations that are

O present in minor amounts.

CK1 A "motif", as in biological motif of a 191P4D12(b)-related protein, refers to any pattern of amino acids forming part

Sof the primary sequence of a protein, that is associated with a particular function protein-protein interaction, protein-DNA

S interaction, etc) or modification that is phosphorylated, glycosylated or amidated), or localization secretory

sequence, nuclear localization sequence, etc.) or a sequence that is correlated with being immunogenic, either humorally or

ri cellularly. A motif can be either contiguous or capable of being aligned to certain positions that are generally correlated with

a certain function or property. In the context of HLA motifs, "motif refers to the pattern of residues in a peptide of defined

S length, usually a peptide of from about 8 to about 13 amino acids for a class I HLA motif and from about 6 to about 25 amino

acids for a class II HLA motif, which is recognized by a particular HLA molecule. Peptide motifs for HLA binding are typically

different for each protein encoded by each human HLA allele and differ in the pattern of the primary and secondary anchor

CK residues.00

0A "pharmaceutical excipient" comprises a material such as an adjuvant, a carrer, pH-adjusting and buffering

agents, tonicity adjusting agents, wetting agents, preservative, and the like.

"Pharmaceutically acceptable" refers to a non-toxic, inert, and/or composition that is physiologically compatible with

humans or other mammals.

The term "polynucleotide" means a polymeric form of nucleotides of at least 10 bases or base pairs in length, either

ribonucleotides or deoxynucleotides or a modified form of either type of nucleotide, and is meant to include single and double

stranded forms of DNA and/or RNA. In the art, this term if often used interchangeably with "oligonucleotide". A

polynucleotide can comprise a nucleotide sequence disclosed herein wherein thymidine as shown for example in Figure

2, can also be uracil this definition pertains to the differences between the chemical structures of DNA and RNA, in

particular the observation that one of the four major bases in RNA is uracil instead of thymidine

The term "polypeptide" means a polymer of at least about 4, 5, 6, 7, or 8 amino acids. Throughout the

specification, standard three letter or single letter designations for amino acids are used. In the art, this term is often used

interchangeably with "peptide" or "protein".

An HLA "primary anchor residue" is an amino acid at a specific position along a peptide sequence which is

understood to provide a contact point between the immunogenic peptide and the HLA molecule. One to three, usually two,

primary anchor residues within a peptide of defined length generally defines a "motif for an immunogenic peptide. These

residues are understood to fit in close contact with peptide binding groove of an HLA molecule, with their side chains buried

in specific pockets of the binding groove. In one embodiment, for example, the primary anchor residues for an HLA class I

molecule are located at position 2 (from the amino terminal position) and at the carboxyl terminal position of a 8, 9, 10, 11, or

12 residue peptide epitope in accordance with the invention. Alternatively, in another embodiment, the primary anchor

residues of a peptide binds an HLA class II molecule are spaced relative to each other, rather than to the termini of a

peptide, where the peptide is generally of at least 9 amino acids in length. The primary anchor positions for each motif and

supermotif are set forth in Table IV. For example, analog peptides can be created by altering the presence or absence of

particular residues in the primary and/or secondary anchor positions shown in Table IV. Such analogs are used to modulate

the binding affinity and/or population coverage of a peptide comprising a particular HLA motif or supermotif.

"Radioisotopes" include, but are not limited to the following (non-limiting exemplary uses are also set forth):

Examples of Medical Isotopes:

Isotope Description of use

Actinium-225 See Thorium-229 (Th-229)

(AC-225)

7 Parent of Radium-223 (Ra-223) which is an alpha emitter used to treat metastases in the

S Actinium-227 skeleton resulting from cancer breast and prostate cancers), and cancer

(AC-227) radioimmunotherapy

Bismuth-212 See Thorium-228 (Th-228)(81-212)

Bismuth-213 See Thorium-229 (Th-229)(Bi-213)

Cadmium-109Cadm1 09 Cancer detection(Cd-109)

Radiation source for radiotherapy of cancer, for food Irradiators, and for sterilization of

medical supplies\Copper-64

Copper-64 A positron emitter used for cancer therapy and SPECT imagingcN (Cu-64)

Copper-67 Beta/gamma emitter used in cancer radioimmunotherapy and diagnostic studies breast

1 (Cu-67) and colon cancers, and lymphoma)00

Dysprosium-166 Cancer radioimmunotherapy(Dy-166)

S Erbium-169 Rheumatoid arthritis treatment, particularly for the small joints associated with fingers and

(Er-169) toes

Europium-152 Radiation source for food irradiation and for sterilization of medical supplies(Eu-152)

Europium-154 Radiation source for food irradiation and for sterilization of medical supplies(Eu-154)

Gadolinium-153 Osteoporosis detection and nuclear medical quality assurance devices(Gd-153)

Gold-198 Implant and Intracavity therapy of ovarian, prostate, and brain cancers(Au-198)Holmium-166 Multiple myeloma treatment in targeted skeletal therapy, cancer radioimmunotherapy, bone

(Ho-166) marrow ablation, and rheumatoid arthritis treatment

Osteoporosis detection, diagnostic imaging, tracer drugs, brain cancer treatment,lodine-125 radiolabeling, tumor imaging, mapping of receptors in the brain, interstitial radiation therapy,

(1-125) brachytherapy for treatment of prostate cancer, determination of glomerular filtration rate

(GFR), determination of plasma volume, detection of deep vein, thrombosis of the legs

Thyroid function evaluation, thyroid disease detection, treatment of thyroid cancer as well as

Iodine-131 other non-malignant thyroid diseases Graves disease, goiters, and hyperthyroidism),(1-131) treatment of leukemia, lymphoma, and other forms of cancer breast cancer) using

radiolmmunotherapy

Iridium-192 Brachytherapy, brain and spinal cord tumor treatment, treatment of blocked arteries (lr-192) arteriosclerosis and restenosis), and implants for breast and prostate tumors

Lutetium-177 Cancer radiolmmunotherapy and treatment of blocked arteries arteriosclerosis and

(Lu-177) restenosis)

Parent of Technetium-99m (Tc-99m) which is used for imaging the brain, liver, lungs, heart,

Molybdenum-99 and other organs. Currently, Tc-99m is the most widely used radioisotope used for diagnostic

(Mo-99) imaging of various cancers and diseases involving the brain, heart, liver, lungs; also used indetection of deep vein thrombosis of the legs

Osmium-194 Cancer radioimmunotherapy(Os-194)

Palladium-103 Prostate cancer treatment(Pd-103)

Platinum-195m Studies on biodistribution and metabolism of cisplatin, a chemotherapeutic drug(Pt-195m)

Phosphorus-32 Polycythemia rubra vera (blood cell disease) and leukemia treatment, bone cancer

00(P-32) diagnosis/treatment; colon, pancreatic, and liver cancer treatment; radiolabeling nucleic acids

for in vitro research, diagnosis of superficial tumors, treatment of blocked arteries arteriosclerosis and restenosis), and intracavity therapy

Phosphorus-33 Leukemia treatment, bone disease diagnosis/treatment, radiolabeling, and treatment of

(P-33) blocked arteries arteriosclerosis and restenosis)

Radium-223(Ra-223)

Rhenium-186(Re-186)

See Actinium-227 (Ac-227)

Bone cancer pain relief, rheumatoid arthritis treatment, and diagnosis and treatment oflymphoma and bone, breast, colon, and liver cancers using radioimmunotherapy

Rhenium-188 Cancer diagnosis and treatment using radioimmunotherapy, bone cancer pain relief,(Re-188) treatment of rheumatoid arthritis, and treatment of prostate cancer

Rhodium-105(Rh-105)

Samarium-145(Sm-145)

Samarium-153(Sm-153)

Cancer radioimmunotherapy

Ocular cancer treatment

Cancer radioimmunotherapy and bone cancer pain relief

Scandium-47 Cancer radioimmunotherapy and bone cancer pain relief(Sc-47)

Strontium-89(Sr-89)

Radiotracer used in brain studies, imaging of adrenal cortex by gamma-scintigraphy, laterallocations of steroid secreting tumors, pancreatic scanning, detection of hyperactiveparathyroid glands, measure rate of bile acid loss from the endogenous pool

Bone cancer detection and brain scans

Bone cancer pain relief, multiple myeloma treatment, and osteoblastic therapy

Technetium-99mSee Molybdenum-99 (Mo-99)(Tc-99m)

Thorium-228(Th-228)

Thorium-229(Th-229)

Thulium-170(Tm-170)

Tin-117m(Sn-117m)

Tungsten-188(W-188)

Parent of Bismuth-212 (Bi-212) which is an alpha emitter used in cancer radioimmunotherapy

Parent of Actinium-225 (Ac-225) and grandparent of Bismuth-213 (Bi-213) which are alpha

emitters used in cancer radioimmunotherapy

Gamma source for blood irradiators, energy source for implanted medical devices

Cancer immunotherapy and bone cancer pain relief

Parent for Rhenium-188 (Re-188) which is used for cancer diagnostics/treatment, bone

cancer pain relief, rheumatoid arthritis treatment, and treatment of blocked arteries

arteriosclerosis and restenosis)

Xenon-127 Neurolmaging of brain disorders, high resolution SPECT studies, pulmonary function tests,

(Xe-127) and cerebral blood flow studies

Ytterblum-175(Yb-175)

Yttrium-91(Y-91)

Cancer radioimmunotherapy

Microseeds obtained from irradiating Yttrium-89 (Y-89) for liver cancer treatment

A gamma-emitting label for Yttrium-90 (Y-90) which is used for cancer radioimmunotherapylymphoma, breast, colon, kidney, lung, ovarian, prostate, pancreatic, and inoperable

liver cancers)

By "randomized" or grammatical equivalents as herein applied to nucleic acids and proteins is meant that each

nucleic acid and peptide consists of essentially random nucleotides and amino acids, respectively. These random peptides

0 0 (or nucleic acids, discussed herein) can incorporate any nudeotide or amino acid at any position. The synthetic process can

be designed to generate randomized proteins or nucleic acids, to allow the formation of all or most of the possible

combinations over the length of the sequence, thus forming a library of randomized candidate bioactive proteinaceous

C agents.

In one embodiment, a library is "fully randomized," with no sequence preferences or constants at any position. In

another embodiment, the library is a "biased random" library. That is, some positions within the sequence either are held

constant, or are selected from a limited number of possibilities. For example, the nucleotides or amino acid residues are

randomized within a defined class, of hydrophobic amino acids, hydrophilic residues, sterically biased (either small or

large) residues, towards the creation of nucleic acid binding domains, the creation of cysteines, for cross-linking, prolines for

SH-3 domains, serines, threonines, tyrosines or histidines for phosphorylation sites, etc., or to purines, etc.

SA "recombinant" DNA or RNA molecule is a DNA or RNA molecule that has been subjected to molecular manipulation

00 in vitro.

SNon-limiting examples of small molecules include compounds that bind or interact with 191P4D12(b), ligands

C( including hormones, neuropeptides, chemokines, odorants, phospholipids, and functional equivalents thereof that bind and

preferably inhibit 191P4D12(b) protein function. Such non-limiting small molecules preferably have a molecular weight of

less than about 10 kDa, more preferably below about 9, about 8, about 7, about 6, about 5 or about 4 kDa. In certain

embodiments, small molecules physically associate with, or bind, 191P4D12(b) protein; are not found in naturally occurring

metabolic pathways; and/or are more soluble in aqueous than non-aqueous solutions

"Stringency" of hybridization reactions is readily determinable by one of ordinary skill in the art, and generally is an

empirical calculation dependent upon probe length, washing temperature, and salt concentration. In general, longer probes

require higher temperatures for proper annealing, while shorter probes need lower temperatures. Hybridization generally

depends on the ability of denatured nucleic acid sequences to reanneal when complementary strands are present in an

environment below their melting temperature. The higher the degree of desired homology between the probe and

hybridizable sequence, the higher the relative temperature that can be used. As a result, it follows that higher relative

temperatures would tend to make the reaction conditions more stringent, while lower temperatures less so. For additional

details and explanation of stringency of hybridization reactions, see Ausubel et al., Current Protocols in Molecular Biology,

Wiley Interscience Publishers, (1995).

"Stringent conditions" or "high stringency conditions", as defined herein, are identified by, but not limited to, those

that employ low ionic strength and high temperature for washing, for example 0.015 M sodium chloride/0.0015 M sodium

citrate/0.1% sodium dodecyl sulfate at 50°C; employ during hybridization a denaturing agent, such as formamide, for

example, 50% (vfv) formamide with 0.1% bovine serum albumin/0.1% Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium

phosphate buffer at pH 6.5 with 750 mM sodium chloride, 75 mM sodium citrate at 42 oC; or employ 50% formamide, 5 x

SSC (0.75 M NaCI, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 0.1% sodium pyrophosphate, 5 x

Denhardt's solution, sonicated salmon sperm DNA (50 p.g/ml), 0.1% SDS, and 10% dextran sulfate at 42 oC, with washes at

42oC in 0.2 x SSC (sodium chloride/sodium, citrate) and 50%.formamide at 55 followed by a high-stringency wash

consisting of 0.1 x SSC containing EDTA at 55 oC. "Moderately stringent conditions" are described by, but not limited to,

those in Sambrook et al., Molecular Cloning: A Laboratory Manual, New York: Cold Spring Harbor Press, 1989, and include

the use of washing solution and hybridization conditions temperature, ionic strength and %SDS) less stringent than

those described above. An example of moderately stringent conditions is overnight incubation at 370C in a solution

comprising: 20% formamide, 5 x SSC (150 mM NaCI, 15 mM trisodium citrate), 50 mM sodium phosphate (pH 5 x

Denhardt's solution, 10% dextran sulfate, and 20 mg/mL denatured sheared salmon sperm DNA, followed by washing the

00 filters in 1 x SSC at about 37-500C. The skilled artisan will recognize how to adjust the temperature, ionic strength, etc. as

0 necessary to accommodate factors such as probe length and the like.

C< An HLA "supermotif is a peptide binding specificity shared by HLA molecules encoded by two or more HLA alleles.

Overall phenotypic frequences of HLA-supertypes in different ethnic populations are set forth in Table IV The non-

limiting constituents of various supetypes are as follows:

A2: A*0201, A*0202, A*0203, A*0204, A* 0205, A*0206, A*6802, A*6901, A*0207

SA3 A3, All, A31, A*3301, A*6801, A*0301, A*1101, A'3101

B7: B7, 8*3501-03, B*51, 8*5301, 8*5401, 8*5501, B*5502, B'5601, B'6701, B*7801, B*0702, B*5101, B*5602

I B44: B*3701, B*4402, 8*4403, B*60 (B*4001), B61 (B*4006)

C Al: A*0102, A*2604, A*3601, A*4301, A*8001C A24: A*24, A*30, A*2403, A*2404, A*3002, A*3003

C 827: B*1401-02, 8*1503, B*1509, 8*1510, 8*1518, B*3801-02, B*3901, 8*3902, B*3903-04, 8*4801-02, B*7301,000 B'2701-08

858: B*1516, B*1517, 8*5701, B*5702, B58

B62: 8*4601, 852, B*1501 (B62), B*1502 (B75), B*1513 (B77)

Calculated population coverage afforded by different HLA-supertype combinations are set forth in Table IV

As used herein "to treat" or "therapeutic" and grammatically related terms, refer to any improvement of any

consequence of disease, such as prolonged survival, less morbidity, and/or a lessening of side effects which are the

byproducts of an alternative therapeutic modality; full eradication of disease is not required.

A "transgenic animal" a mouse or rat) is an animal having cells that contain a transgene, which transgene

was introduced into the animal or an ancestor of the animal at a prenatal, an embryonic stage. A "transgene" is a DNA

that is integrated into the genome of a cell from which a transgenic animal develops.

As used herein, an HLA or cellular immune response "vaccine" is a composition that contains or encodes one or

more peptides of the invention. There are numerous embodiments of such vaccines, such as a cocktail of one or more

individual peptides; one or more peptides of the invention comprised by a polyepitopic peptide; or nucleic acids that encode

such individual peptides or polypeptides, a minigene that encodes a polyepitopic peptide. The "one or more peptides"

can Include any whole unit integer from 1-150 or more, at least 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12,13, 14,15,16,17, 18,

19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30,31,32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,45,46,47,48,49,50,

65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, or 150 or more peptides of the invention.

The peptides or polypeptides can optionally be modified, such as by lipidation, addition of targeting or other sequences. HLA

class I peptides of the invention can be admixed with, or linked to, HLA class II peptides, to facilitate activation of both

cytotoxic T lymphocytes and helper T lymphocytes. HLA vaccines can also comprise peptide-pulsed antigen presenting

cells, dendritic cells.

The term "variant refers to a molecule that exhibits a variation from a described type or norm, such as a protein that has

one or more different amino acid residues in the corresponding position(s) of a specifically described protein the

191P4D12(b) protein shown in Figure 2 or Figure 3. An analog is an example of a variant protein. Splice isoforms and single

nucleotides polymorphisms (SNPs) are further examples of variants.

The "191P4D12(b)-related proteins" of the invention include those specifically identified herein, as well as allelic

variants, conservative substitution variants, analogs and homologs that can be isolated/generated and characterized without

undue experimentation following the methods outlined herein or readily available in the art. Fusion proteins that combine parts of

Sdifferent 191P4D12(b) proteins or fragments thereof, as well as fusion proteins of a 191P4012(b) protein and a heterologous

polypeptide are also included. Such 191P4D12(b) proteins are collectively referred to as the 191P4D12(b)-related proteins, the

00 proteins of the invention, or 191P4D12(b). The term "191P4D12(b)-related protein" refers to a polypeptide fragment or a0 191P4D12(b) protein sequence of 4, 5, 6, 7, 8, 9,10,11,12,13,14,15,16,17,18,19, 20, 21, 22, 23, 24, 25, or more than C-i amino acids; or, at least 30, 35, 40, 45, 50, 55, 60, 65, 70,80, 85, 90, 95,100,105, 110,115,120,125,130,135, 140,145,

150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525,550, 575, or 576 or more amino acids.

II.) 191P4D12(b) PolynucleotidesOne aspect of the invention provides polynucleotides corresponding or complementary to all or part of a

191P4D12(b) gene, mRNA, and/or coding sequence, preferably in isolated form, including polynucleotides encoding a191P4D12(b)-related protein and fragments thereof, DNA, RNA, DNA/RNA hybrid, and related molecules, polynucleotides or

C ollgonucleotides complementary to a 191P4D12(b) gene or mRNA sequence or a part thereof, and polynucleotides or

oligonucleotides that hybridize to a 191P4D12(b) gene, mRNA, or to a 191P4012(b) encoding polynudeotide (collectively,0 191P4D12(b) polynucleotides"). In all instances when referred to in this section, T can also be U in Figure 2.SEmbodiments of a 191P4D12(b) polynucleotide include: a 191P4012(b) polynucleotide having the sequence

C= shown in Figure 2, the nucleotide sequence of 191P4D12(b) as shown in Figure 2 wherein T is U; at least 10 contiguousnucleotides of a polynucleotide having the sequence as shown in Figure 2; or, at least 10 contiguous nudeotides of apolynucleotide having the sequence as shown in Figure 2 where T is U. For example, embodiments of 191P4D12(b)nucleotides comprise, without limitation:

a polynucleotide comprising, consisting essentially of, or consisting of a sequence as shown in Figure 2,wherein T can also be U;

(II) a polynucleotide comprising, consisting essentially of, or consisting of the sequence as shown in Figure2A, from nudeotide residue number 264 through nucleotide residue number 1796, including the stop codon,wherein T can also be U;

(II) a polynucleotide comprising, consisting essentially of, or consisting of the sequence as shown in Figure2B, from nucleotide residue number 264 through nucleotide residue number 1796, including the stop codon,wherein T can also be U;

(IV) a polynucleotide comprising, consisting essentially of, or consisting of the sequence as shown in Figure2C, from nucleotide residue number 264 through nucleotide residue number 1796, including the a stop codon,wherein T can also be U;

a polynucleotide comprising, consisting essentially of, or consisting of the sequence as shown in Figure2D, from nucleotide residue number 264 through nuceotide residue number 1796, including the stop codon,wherein T can also be U;

(VI) a polynucleotide comprising, consisting essentially of, or consisting of the sequence as shown in Figure2E, from nucleotide residue number 264 through nucleotide residue number 1796, including the stop codon,wherein T can also be U;

(VII) a polynucleotide comprising, consisting essentially of, or consisting of the sequence as shown in Figure2F, from nucleotide residue number 789 through nucleotide residue number 1676, including the stop codon,wherein T can also be U;

(VIII) a polynucleotide comprising, consisting essentially of, or consisting of the sequence as shown in Figure

0 2G, from nucleotide residue number 264 through nucleotide residue number 1721, including the stop codon,

0 wherein T can also be U;

[c (IX) a polynucleotide comprising, consisting essentially of, or consisting of the sequence as shown in Figure

2H, from nucleotide residue number 264 through nucleotide residue number 1796, including the stop codon,

wherein T can also be U;

a polynucleotide comprising, consisting essentially of, or consisting of the sequence as shown in Figure

21, from nucleotide residue number 708 through nucleotide residue number 1121, including the stop codon,

wherein T can also be U;

Ci (XI) a polynucleotide comprising, consisting essentially of, or consisting of the sequence as shown in Figure

C 2J, from nucleotide residue number 264 through nucleotide residue number 1796, including the stop codon,

C] wherein T can also be U;00

S(XII) a polynucleotide comprising, consisting essentially of, or consisting of the sequence as shown in Figure

CK1 2K, from nucleotide residue number 264 through nucleotide residue number 1796, including the stop codon,

wherein T can also be U;

(XIII) a polynucleotide comprising, consisting essentially of, or consisting of the sequence as shown in Figure

2L, from nucleotide residue number 264 through nucleotide residue number 1796, including the stop codon,

wherein T can also be U;

(XIV) a polynucleotide comprising, consisting essentially of, or consisting of the sequence as shown in Figure

2M, from nucleotide residue number 264 through nucleotide residue number 1799, including the stop codon,

wherein T can also be U;

(XV) a polynucleotide comprising, consisting essentially of, or consisting of the sequence as shown in Figure

2N, from nucleotide residue number 708 through nucleotide residue number 1121, including the stop codon,

wherein T can also be U;

(XVI) a polynucleotide that encodes a 191P4D12(b)-related protein that is at least 90, 91, 92, 93, 94, 95, 96,

97, 98, 99 or 100% homologous to an entire amino acid sequence shown in Figure 2A-N;

(XVII) a polynucleotide that encodes a 191P4D12(b)-related protein that is at least 90, 91, 92, 93, 94, 95, 96,

97, 98, 99 or 100% identical to an entire amino acid sequence shown in Figure 2A-N;

(XVIII) a polynucleotide that encodes at least one peptide set forth in Tables VIII-XXI and XXII-XLIX;

(XIX) a polynucleotide that encodes a peptide region of at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of Figures 3A-B and 3E-G

in any whole number increment up to 510 that includes at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16,

17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value

greater than 0.5 in the Hydrophilicity profile of Figure

(XX) a polynucleotide that encodes a peptide region of at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of Figure 3A-B and 3E-G

In any whole number increment up to 510 that includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,34., 35 amino acid position(s) having a value less than

in the Hydropathicity profile of Figure 6;00O (XXI) a polynudeotide that encodes a peptide region of at least 5, 6,7,8,9,10,11,12,13,14,15,16,17,18,

S19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33,34,35 amino acids of a peptide of Figure 3A-B and 3E-G

in any whole number increment up to 510 that includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value greater than

in the Percent Accessible Residues profile of Figure 7;

c (XXII) a polynucleotide that encodes a peptide region of at least 5, 6, 7, 8,9,10,11,12,13,14,15,16,17,18,

19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35 amino acids of a peptide of Figure 3A-B and 3E-G

in any whole number increment up to 510 that includes 1, 2,3,4, 5,6,7,8, 9,10,11,12,13,14,15,16,17,18,

S19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35 amino acid position(s) having a value greater than

in the Average Flexibility profile of Figure 8;

C0 (XXIII) a polynudeotde that encodes a peptide region of at least 5, 6,7, 8, 9, 10,11, 12,13,14,15,16,17,18,

0 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of Figure 3A-B and 3E-G

CNI in any whole number increment up to 510 that includes 1, 2,3,4, 5,6, 7,8,9,10,11,12,13,14,15,16,17,18,

19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30,31, 32, 33, 34, 35 amino acid position(s) having a value greater than

in the Beta-turn profile of Figure 9;

(XXIV) a polynucleoude that encodes a peptide region of at least 5, 6,7,8,9,10,11,12,13,14,15,16,17,18,

19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of Figure 3C in any whole

number increment up to 295 that includes 1, 2, 3,4,5,6, 7, 8, 9, 10,11,12,13,14,15,16, 17,18, 19, 20, 21, 22,

23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 in the

Hydrophilidty profile of Figure

(XXV) a polynudeotide that encodes a peptide region of at least 5,6, 7, 8, 9,10,11,12,13,14,15,16, 17,18,

19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35 amino acids of a peptide of Figure 3C in any whole

number increment up to 295 that includes 1,2,3, 4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,

23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value less than 0.5 in the

Hydropathicity profile of Figure 6;

(XXVI) a polynudeotide that encodes apeptide region of at least 5, 6,7,8,9,10,11,12,13,14,15,16,17,18,

19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of Figure 3C in any whole

number incrementup to 295 that includes 1,2,3,4,5,6,7,8, 9,10,11,12,13,14,15,16,17,18,19, 20, 21, 22,

23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 in the

Percent Accessible Residues profile of Figure 7;

(XXVII) a polynucleotide that encodes a peptide region of at least 5,6,7, 8, 9,10,11,12,13,14,15,16,17,18,

19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of Figure 3C in any whole

number increment up to 295 that includes 1,2, 3,4, 5,6,7, 8,9,10,11,12,13,14,15,16,17,18,19, 20, 21,22,

23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 in the

Average Flexibility profile of Figure 8;

(XXVIII) a polynucleotide that encodes a peptide region of at least 5,6, 7, 8, 9,10,11,12,13,14,15,16,17,18,

19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of Figure 3C in any whole

number incrementup to 295 thatincludes 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17, 18,19, 20,21,22,

00 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35 amino acid positon(s) having a value greater than 0.5 in the Beta-

O turn profile of Figure 9

cl (XXIX) a polynucleotide that encodes a peptide region of at least 5, 6, 7, 8, 9,10,11,12,13,14,15,16,17, 18,

19, 20, 21, 22,23,24, 25,26, 27,28,29,30,31,32, 33,34,35 amino acids ofa peptide of Figure 3D in any whole

number increment up to 485 that includes 1, 2,3,4,5, 6,7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,

S23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 in the

Hydrophilicity profile of Figure

(XXX) a polynucleotide that encodes a peptide region of at least 5, 6,7, 8,9,10,11,12,13,14,15, 16, 17,18,

S19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35 amino acids of a peptide of Figure 3D in any whole

C number increment up to 485 that includes 1,2, 3,4, 5, 6,7, 8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,

S23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35 amino acid position(s) having a value less than 0.5 in the

00 Hydropathicity profile of Figure 6;

S(XXXI) a polynucleotide that encodes a peptide region of at least 5, 6, 7, 8, 9,10,11,12,13,14,15,16,17,18,

19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of Figure 3D in any whole

number increment up to 485 that includes 1, 2, 3,4,5, 6,7,8,9,10,11,12,13,14,15,16,17,18,19, 20, 21,22,

23, 24, 25, 26, 27, 28, 29, 30, 31,32,33, 34,35 amino acid position(s) having a value greater than 0.5 in the

Percent Accessible Residues profile of Figure 7;

(XXXII) a polynucleotide that encodes a peptide region of at least 5, 6,7,8,9,10,11,12,13,14,15,16,17,18,

19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of Figure 3D in any whole

number increment up to 485 that includes 1, 2, 3,4, 5,6,7,8, 9,10,11,12,13,14,15,16, 17,18,19, 20, 21,22,

23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 in the

Average Flexibility profile of Figure 8;

(XXXIII) a polynucleotide that encodes a peptide region of at least 5, 6, 7, 8, 9,10,11,12,13,14,15, 16,17, 18,

19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of Figure 3D in any whole

number increment up to 485 that includes 1, 2,3,4, 5,6,7,8,9,10, 11, 12,13,14,15,16,17,18,19,20, 21,22,

23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 in the Beta-

turn profile of Figure 9

(XXXIV) a polynucleotide that encodes a peptide region of at least 5, 6, 7, 8, 9,10,11,12, 13,14,15,16,17, 18,

19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35 amino acids of a peptide of Figure 3H in any whole

number Increment up to 511 that includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,

23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 in the

Hydrophilicity profile of Figure

(XXXV) a polynucleotide that encodes a peptide region of at least 5, 6, 7,8, 9,10, 11, 12, 13, 14, 15, 16,17,18,

19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35 amino acids of a peptide of Figure 3H in any whole

number increment up to 511 that includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14,15,16, 17, 18, 19, 20, 21, 22,

23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value less than 0.5 in the

Hydropathicity profile of Figure 6;

(XXXVI) a polynucleotide that encodes a peptide region of at least 5,6, 7 9,10,11,12,13,14,15,16,17,18,

19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35 amino acids of a peptide of Figure 3H in any whole

00 numberincrementupto511 thatincludes 1,2,3,4,5,6,7, 8, 9,10,11,12,13,14,15,16,17, 18,19,20,21, 22,

S23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 in the

Percent Accessible Residues profile of Figure 7;

(XXXVII) a polynucleotide that encodes a peptide region of at least 5, 6,7,8,9,10,11,12,13,14,15,16,17,18,

19,20,21, 22, 23, 24, 25, 26, 27, 28, 29,30,31, 32, 33, 34, 35 amino acids of a peptide of Figure 3H in any whole

number increment up to 511 that includes 1,2,3, 4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19, 20,21,22,

23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 in the

Average Flexibility profile of Figure 8;

(XXXVIII) a polynucleotide that encodes a peptide region of at least 5, 6,7,8,9,10,11,12,13,14,15,16,17,18,

S19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of Figure 3H in any whole

(N number increment up to 511 that includes 1,2, 3,4, 5, 6,7, 8, 9,10,11,12,13,14,15,16,17,18,19,20, 21, 22,00

S23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 in the Beta-

q turn profile of Figure 9

(XXXIX) a polynucleotide that encodes a peptide region of at least 5, 6,7, 8, 9,10,11,12,13,14,15,16,17,18,

19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34, 35 amino acids of a peptide of Figure 31-J in any

whole number increment up to 137 that includes 1, 2, 3,4, 5, 6,7,8, 9,10,11, 12,13,14,15,16,17,18,19,20,

21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 in

the Hydrophilicity profile of Figure

(XL) a polynucleotide that encodes a peptide region of at least 5, 6, 7, 8,9,10,11,12,13,14,15,16,17,18,

19, 20, 21, 22, 23, 24, 25, 26, 27; 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of Figure 31-J in any

whole number increment up to 137 that includes 1, 2,3,4,5,6,7,8, 9,10,11,12,13,14,15,16,17,18,19,20,

21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31,32, 33, 34, 35 amino acid position(s) having a value less than 0.5 in the

Hydropathicity profile of Figure 6;

(XLI) a polynudeotide that encodes a peptide region of at least 5, 6,7,8, 9,10,11,12,13,14,15,16,17,18,

19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of Figure 31-J in any

whole number increment up to 137 that Indudes 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,

21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31,32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 in

the Percent Accessible Residues profile of Figure 7;

(XLII) a polynucleotide that encodes a peptide region of at least 5, 6,7,8,9,10,11,12,13,14,15,16,17,18,

19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35 amino acids of a peptide of Figure 31-J in any

whole number increment up to 137 that includes 1, 2, 3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,

21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 in

the Average Flexibility profile of Figure 8;

(XLIII) a polynucleotide that encodes a peptide region of at least 5, 6, 7, 8, 9, 10,11, 12,13,14, 15, 16, 17,18,

19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of Figure 31-J in any

whole number increment up to 137 that includes 1,2, 3,4,5,6,7, 8,9,10,11,12,13,14,15,16,17,18,19,20,

21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 in

the Beta-turn profile of Figure 9

(XLIV) a polynucleotide that is fully complementary to a polynucleotide of any one of (I)-(XLIII).

00 (XLV) a peptide that is encoded by any of to (XLIV); and

OS(XLVI) a composition comprising a polynucleotide of any of (I)-(XLIII) or peptide of (XLV) together with a

pharmaceutical excipient and/or in a human unit dose form.

(XLVII) a method of using a polynucleotide of any (I)-(XLIV) or peptide of (XLV) or a composition of (XLVI) in a

method to modulate a cell expressing 191P4D12(b),

Lc (XLVIII) a method of using a polynuceotide of any (I)-(XLIV) or peptide of (XLV) or a composition of (XLVI) in a

method to diagnose, prophylax, prognose, or treat an individual who bears a cell expressing 191P4D12(b)

(XLIX) a method of using a polynucleotide of any (I)-(XLIV) or peptide of (XLV) or a composition of (XLVI) in a

method to diagnose, prophylax, prognose, or treat an individual who bears a cell expressing 191P4D12(b), said

cell from a cancer of a tissue listed In Table I;<00

00(L) a method of using a polynucleotide of any (I)-(XLIV) or peptide of (XLV) or a composition of (XLVI) in a

Smethod to diagnose, prophylax, prognose, or treat a a cancer;

(LI) a method of using a polynucleotide of any (I)-(XLIV) or peptide of (XLV) or a composition of (XLVI) in a

method to diagnose, prophylax, prognose, or treat a a cancer of a tissue listed in Table I; and,

(LII) a method of using a polynucleotide of any (I)-(XLIV) or peptide of (XLV) or a composition of (XLVI) in a

method to identify or characterize a modulator of a cell expressing 191P4D12(b).

As used herein, a range is understood to disclose specifically all whole unit positions thereof.

Typical embodiments of the invention disclosed herein include 191P4D12(b) polynucleotides that encode specific

portions of 191P4D12(b) mRNA sequences (and those which are complementary to such sequences) such as those that

encode the proteins and/or fragments thereof, for example:

4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65,

80, 85, 90, 95, 100, 105,110,115, 120, 125, 130,135,140, 145, 150, 155,160,165, 170, 175, 180, 185,190,195, 200,

225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 505 or 510 more contiguous amino acids of 191P4D12(b)

variant 1; the maximal lengths relevant for other variants are: variant 2, 510 amino acids; variant 6, 295 amino acids, variant

7, 485 amino acids, variant 10, 510 amino acids, variant 11,510 amoni adds, variant 12, 510 amoni acids, variant 13, 511

amino acids, variant 9, 137 amino acids, and variant 14, 137 amino acids.

For example, representative embodiments of the invention disclosed herein include: polynucleotides and their

encoded peptides themselves encoding about amino acid 1 to about amino acid 10 of the 191P4D12(b) protein shown in

Figure 2 or Figure 3, polynucleotides encoding about amino acid 10 to about amino acid 20 of the 191P4D12(b) protein

shown in Figure 2 or Figure 3, polynucleotides encoding about amino acid 20 to about amino acid 30 of the 191P4D12(b)

protein shown in Figure 2 or Figure 3, polynucleotides encoding about amino acid 30 to about amino acid 40 of the

191P4D12(b) protein shown in Figure 2 or Figure 3, polynucleotides encoding about amino acid 40 to about amino acid 50 of

the 191P4D12(b) protein shown in Figure 2 or Figure 3, polynucleotides encoding about amino acid 50 to about amino acid

of the 191P4D12(b) protein shown in Figure 2 or Figure 3, polynucleotides encoding about amino acid 60 to about amino

acid 70 of the 191P4D12(b) protein shown in Figure 2 or Figure 3, polynucleotides encoding about amino acid 70 to about

amino acid 80 of the 191P4D12(b) protein shown in Figure 2 or Figure 3, polynucleotides encoding about amino acid 80 to

about amino acid 90 of the 191P4D12(b) protein shown in Figure 2 or Figure 3, polynudeotides encoding about amino acid

to about amino acid 100 of the 191P4D12(b) protein shown in Figure 2 or Figure 3, in increments of about 10 amino

acids, ending at the carboxyl terminal amino acid set forth in Figure 2 or Figure 3. Accordingly, polynucleotides encoding

portions of the amino acid sequence (of about 10 amino acids), of amino acids, 100 through the carboxyl terminal amino acid

00 of the 191P4D12(b) protein are embodiments of the invention. Wherein it is understood that each particular amino acid

0 position discloses that position plus or minus five amino acid residues.

l Polynucleotides encoding relatively long portions of a 191P4D12(b) protein are also within the scope of the

invention. For example, polynucleotides encoding from about amino acid 1 (or 20 or 30 or 40 etc.) to about amino acid

(or 30, or 40 or 50 etc.) of the 191P4012(b) protein "or variant shown in Figure 2 or Figure 3 can be generated by a variety

of techniques well known in the art. These polynudeotide fragments can include any portion of the 191P4D12(b) sequence

r as shown in Figure 2.

Additional illustrative embodiments of the invention disclosed herein include 191P4D12(b) polynucleotide

fragments encoding one or more of the biological motifs contained within a 191P4D12(b) protein "or variant" sequence,

C- including one or more of the motif-bearing subsequences of a 191P4D12(b) protein "or varianf' set forth in Tables VIII-XXI

and XXII-XLIX. In another embodiment, typical polynucleotide fragments of the invention encode one or more of the regions

ri of 191P4D12(b) protein or variant that exhibit homology to a known molecule. In another embodiment of the invention,00

typical polynucleotide fragments can encode one or more of the 191P4D12(b) protein or variant N-glycosylation sites, cAMP

and cGMP-dependent protein kinase phosphorylation sites, casein kinase II phosphorylation sites or N-myristoylation site

and amidation sites.

Note that to determine the starting position of any peptide set forth in Tables VIII-XXI and Tables XXII to XLIX

(collectively HLA Peptide Tables) respective to its parental protein, variant 1, variant 2, etc., reference is made to three

factors: the particular variant, the length of the peptide in an HLA Peptide Table, and the Search Peptides listed in Table VII.

Generally, a unique Search Peptide is used to obtain HLA peptides for a particular variant. The position of each Search

Peptide relative to its respective parent molecule is listed in Table VII. Accordingly, if a Search Peptide begins at position

one must add the value "X minus 1" to each position in Tables VIII-XXI and Tables XXII-IL to obtain the actual position of

the HLA peptides in their parental molecule. For example if a particular Search Peptide begins at position 150 of its parental

molecule, one must add 150 1, 149 to each HLA peptide amino acid position to calculate the position of that amino acid

in the parent molecule.

II.A.) Uses of 191P4D12(b) Polynucleotides

II.A.1.) Monitoring of Genetic Abnormalities

The polynucleotides of the preceding paragraphs have a number of different specific uses. The human

191P4D12(b) gene maps to the chromosomal location set forth in the Example entitled "Chromosomal Mapping of

191P4D12(b)." For example, because the 191P4D12(b) gene maps to this chromosome, polynucleotides that encode

different regions of the 191P4D12(b) proteins are used to characterize cytogenetic abnormalities of this chromosomal locale,

such as abnormalities that are identified as being associated with various cancers. In certain genes, a variety of

chromosomal abnormalities including rearrangements have been identified as frequent cytogenetic abnormalities in a

number of different cancers (see e.g. Krajinovic et al., Mutat. Res. 382(3-4): 81-83 (1998); Johansson et al., Blood 86(10):

3905-3914 (1995) and Finger et al., P.N.A.S. 85(23): 9158-9162 (1988)). Thus, polynucleotides encoding specific regions of

the 191P4D12(b) proteins provide new tools that can be used to delineate, with greater precision than previously possible,

cytogenetic abnormalities in the chromosomal region that encodes 191P4D12(b) that may contribute to the malignant

phenotype. In this context, these polynucleotides satisfy a need in the art for expanding the sensitivity of chromosomal

screening in order to identify more subtle and less common chromosomal abnormalities (see e.g. Evans et al., Am. J. Obstet.

Gynecol 171(4): 1055-1057 (1994)).

Furthermore, as 191P4D12(b) was shown to be highly expressed in prostate and other cancers, 191P4D12(b)

polynucleotides are used in methods assessing the status of 191P4D12(b) gene products in normal versus cancerous

0 tissues. Typically, polynucleotides that encode specific regions of the 191P4D12(b) proteins are used to assess the

S presence of perturbations (such as deletions, insertions, point mutations, or alterations resulting in a loss of an antigen etc.)

in specific regions of the 191P4D12(b) gene, such as regions containing one or more motifs. Exemplary assays include both

RT-PCR assays as well as single-strand conformation polymorphism (SSCP) analysis (see, Marrogi et al., J. Cutan.

Pathol. 26(8): 369-378 (1999), both of which utilize polynucleotides encoding specific regions of a protein to examine these

C regions within the protein.

II.A.2.) Antisense Embodiments

Other specifically contemplated nucleic acid related embodiments of the invention disclosed herein are genomic DNA,

cDNAs, ribozymes, and antisense molecules, as well as nucleic acid molecules based on an alternative backbone, or including

C alternative bases, whether derived from natural sources or synthesized, and include molecules capable of inhibiting the RNA or

00C protein expression of 191P4D12(b). For example, antisense molecules can be RNAs or other molecules, including peptide

nucleic acids (PNAs) or non-nucleic acid molecules such as phosphorothioate derivatives that specifically bind DNA or RNA

0 in a base pair-dependent manner. A skilled artisan can readily obtain these classes of nucleic acid molecules using the

191P4D12(b) polynucleotides and polynucleotide sequences disclosed herein.

Antisense technology entails the administration of exogenous oligonucleotides that bind to a target polynucleotide

located within the cells. The term "antisense" refers to the fact that such oligonucleotides are complementary to their

intracellular targets, 191P4D12(b). See for example, Jack Cohen, Oligodeoxynucleotides, Antisense Inhibitors of Gene

Expression, CRC Press, 1989; and Synthesis 1:1-5 (1988). The 191P4D12(b) antisense oligonucleotides of the present

invention include derivatives such as S-oligonucleotides (phosphorothioate derivatives or S-oligos, see, Jack Cohen, supra),

which exhibit enhanced cancer cell growth inhibitory action. S-oligos (nucleoside phosphorothioates) are isoelectronic

analogs of an oligonucleotide (0-oligo) in which a nonbridging oxygen atom of the phosphate group is replaced by a sulfur

atom. The S-oligos of the present invention can be prepared by treatment of the corresponding O-oligos with 3H-1,2-

benzodithiol-3-one-1,1-dioxide, which is a sulfur transfer reagent. See, lyer, R. P. et al., J. Org. Chem. 55:4693-4698

(1990); and lyer, R. P. et al., J. Am. Chem. Soc. 112:1253-1254 (1990). Additional 191P4D12(b) antisense oligonucleotides

of the present invention include morpholino antisense oligonucleotides known in the art (see, Partridge et al., 1996,

Antisense Nucleic Acid Drug Development 6: 169-175).

The 191P4D12(b) antisense oligonucleotides of the present invention typically can be RNA or DNA that is

complementary to and stably hybridizes with the first 100 5' codons or last 100 3' codons of a 191P4D12(b) genomic

sequence or the corresponding mRNA. Absolute complementarity is not required, although high degrees of complementarity

are preferred. Use of an oligonudeotide complementary to this region allows for the selective hybridization to 191 P4D12(b)

mRNA and not to mRNA specifying other regulatory subunits of protein kinase. In one embodiment, 191P4D12(b) antisense

oligonucleotides of the present invention are 15 to 30-mer fragments of the antisense DNA molecule that have a sequence

that hybridizes to 191P4D12(b) mRNA. Optionally, 191P4D12(b) antisense oligonucleotide is a 30-mer oligonucleotide that

is complementary to a region in the first 10 5' codons or last 10 3' codons of 191P4012(b). Alternatively, the antisense

molecules are modified to employ ribozymes in the inhibition of 191P4D12(b) expression, see, L. A. Couture D. T.

Stinchcomb; Trends Genet 12: 510-515 (1996).

II.A.3.) Primers and Primer Pairs

Further specific embodiments of these nucleotides of the invention include primers and primer pairs, which allow

the specific amplification of polynucleotides of the invention or of any specific parts thereof, and probes that selectively or

specifically hybridize to nucleic acid molecules of the invention or to any part thereof. Probes can be labeled with a

detectable marker, such as, for example, a radioisotope, fluorescent compound, bioluminescent compound, a

chemiluminescent compound, metal chelator or enzyme. Such probes and primers are used to detect the presence of a

00 191P4D12(b) polynucleotide in a sample and as a means for detecting a cell expressing a 191P4D12(b) protein.O

SExamples of such probes include polypeptides comprising all or part of the human 191P4D12(b) cDNA sequence

shown in Figure 2. Examples of primer pairs capable of specifically amplifying 191P4D12(b) mRNAs are also described in the

ct Examples. As will be understood by the skilled artisan, a great many different primers and probes can be prepared based on the

sequences provided herein and used effectively to amplify and/or detect a 191P4D12(b) mRNA.

0 The 191P4D12(b) polynucleotides of the invention are useful for a variety of purposes, including but not limited to

their use as probes and primers for the amplification andlor detection of the 191P4D12(b) gene(s), mRNA(s), or fragments

thereof; as reagents for the diagnosis and/or prognosis of prostate cancer and other cancers; as coding sequences capable

of directing the expression of 191P4D12(b) polypeptides; as tools for modulating or inhibiting the expression of the

191P4D12(b) gene(s) and/or translation of the 191P4D12(b) transcript(s); and as therapeutic agents.

0 The present invention includes the use of any probe as described herein to identify and isolate a 191P4D12(b) or

00 191P4D12(b) related nucleic acid sequence from a naturally occurring source, such as humans or other mammals, as well as the

isolated nucleic acid sequence perse, which would comprise all or most of the sequences found in the probe used.

ll.A.4.) Isolation of 191P4D12(b)-Encoding Nucleic Acid Molecules

The 191P4D12(b) cDNA sequences described herein enable the isolation of other polynucleotides encoding

191P4D12(b) gene product(s), as well as the isolation of polynucleotides encoding 191P4D12(b) gene product homologs,

alternatively spliced isoforms, allelic variants, and mutant forms of a 191P4D12(b) gene product as well as polynucleotides that

encode analogs of 191P4D12(b)-related proteins. Various molecular cloning methods that can be employed to isolate full length

cDNAs encoding a 191P4D12(b) gene are well known (see, for example, Sambrook, J. et al., Molecular Cloning: A Laboratory

Manual, 2d edition, Cold Spring Harbor Press, New York, 1989; Current Protocols in Molecular Biology. Ausubel et al., Eds.,

Wiley and Sons, 1995). For example, lambda phage cloning methodologies can be conveniently employed, using commercially

available cloning systems Lambda ZAP Express, Stratagene). Phage clones containing 191P4D12(b) gene cDNAs can be

identified by probing with a labeled 191P4D12(b) cDNA or a fragment thereof. For example, in one embodiment, a 191P4D12(b)

cDNA Figure 2) or a portion thereof can be synthesized and used as a probe to retrieve overlapping and full-length cDNAs

corresponding to a 191P4D12(b) gene. A 191P4D12(b) gene itself can be isolated by screening genomic DNA libraries, bacterial

artificial chromosome libraries (BACs), yeast artificial chromosome libraries (YACs), and the like, with 191P4D12(b) DNA probes

or primers.

Recombinant Nucleic Acid Molecules and Host-Vector Systems

The invention also provides recombinant DNA or RNA molecules containing a 191P4D12(b) polynudeotide, a fragment,

analog or homologue thereof, including but not limited to phages, plasmids, phagemids, cosmids, YACs, BACs, as well as various

viral and non-viral vectors well known in the art, and cells transformed or transfected with such recombinant DNA or RNA

molecules. Methods for generating such molecules are well known (see, for example, Sambrook et al., 1989, supra).

The Invention further provides a host-vector system comprising a recombinant DNA molecule containing a

191P4D12(b) polynucleotide, fragment, analog or homologue thereof within a suitable prokaryotic or eukaryotic host cell.

Examples of suitable eukaryotic host cells include a yeast cell, a plant cell, or an animal cell, such as a mammalian cell or an

insect cell a baculovirus-infectible cell such as an Sf9 or HighFive cell). Examples of suitable mammalian cells include

various prostate cancer cell lines such as DU145 and TsuPrl, other transfectable or transducible prostate cancer cell lines,

primary cells (PrEC), as well as a number of mammalian cells routinely used for the expression of recombinant proteins

COS, CHO, 293, 293T cells). More particularly, a polynucleotide comprising the coding sequence of 191P4D12(b) or a

fragment, analog or homolog thereof can be used to generate 191P4D12(b) proteins or fragments thereof using any number of

Shost-vector systems routinely used and widely known In the art.

O A wide range of host-vector systems suitable for the expression of 191P4D12(b) proteins or fragments thereof are

C= available, see for example, Sambrook et al., 1989, supra; Current Protocols in Molecular Biology, 1995, supra). Preferred vectors

S for mammalian expression include but are not limited to pcDNA 3.1 myc-His-tag (Invitrogen) and the retroviral vector

pSRatkneo (Muller etal., 1991, MCB 11:1785). Using these expression vectors, 191P4D12(b) can be expressed in several

prostate cancer and non-prostate cell lines, including for example 293, 293T, rat-1, NIH 3T3 and TsuPrl. The host-vector

C' systems of the invention are useful for the production of a 191P4D12(b) protein or fragment thereof. Such host-vector

systems can be employed to study the functional properties of 191P4D12(b) and 191P4D12(b) mutations or analogs.

Recombinant human 191P4D12(b) protein or an analog or homolog or fragment thereof can be produced by

mammalian cells transfected with a construct encoding a 191P4D12(b)-related nucleotide. For example, 293T cells can be

transfected with an expression plasmid encoding 191P4D12(b) or fragment, analog or homolog thereof, a 191P4D12(b)-

1 related protein is expressed in the 293T cells, and the recombinant 191P4D12(b) protein is isolated using standard00C purification methods affinity purification using anti-191P4D12(b) antibodies). In another embodiment, a 191P4D12(b)

o coding sequence is subcloned into the retroviral vector pSRaMSVtkneo and used to infect various mammalian cell lines,

such as NIH 3T3, TsuPrl, 293 and rat-1 in order to establish 191P4D12(b) expressing cell lines. Various other expression

systems well known in the art can also be employed. Expression constructs encoding a leader peptide joined in frame to a

191P4D12(b) coding sequence can be used for the generation of a secreted form of recombinant 191P4D12(b) protein.

As discussed herein, redundancy in the genetic code permits variation in 191P4D12(b) gene sequences. In

particular, it is known in the art that specific host species often have specific codon preferences, and thus one can adapt the

disclosed sequence as preferred for a desired host. For example, preferred analog codon sequences typically have rare

codons codons having a usage frequency of less than about 20% in known sequences of the desired host) replaced

with higher frequency codons. Codon preferences for a specific species are calculated, for example, by utilizing codon

usage tables available on the INTERNET such as at URL dna.affrc.go.jpl-nakamura/codon.html.

Additional sequence modifications are known to enhance protein expression in a cellular host. These include

elimination of sequences encoding spurious polyadenylation signals, exonlintron splice site signals, transposon-like repeats,

and/or other such well-characterized sequences that are deleterious to gene expression. The GC content of the sequence is

adjusted to levels average for a given cellular host, as calculated by reference to known genes expressed in the host cell.

Where possible, the sequence is modified to avoid predicted hairpin secondary mRNA structures. Other useful modifications

include the addition of a translational initiation consensus sequence at the start of the open reading frame, as described in

Kozak, Mol. Cell Biol., 9:5073-5080 (1989). Skilled artisans understand that the general rule that eukaryotic ribosomes

initiate translation exclusively at the 5' proximal AUG codon is abrogated only under rare conditions (see, Kozak PNAS

92(7): 2662-2666, (1995) and Kozak NAR 15(20): 8125-8148 (1987)).

III.) 191P4D12(b)-related Proteins

Another aspect of the present invention provides 191 P4D12(b)-related proteins. Specific embodiments of

191P4D12(b) proteins comprise a polypeptide having all or part of the amino acid sequence of human 191P4D12(b) as

shown in Figure 2 or Figure 3. Alternatively, embodiments of 191P4D12(b) proteins comprise variant, homolog or analog

polypeptides that have alterations in the amino acid sequence of 191 P4D12(b) shown in Figure 2 or Figure 3.

Embodiments of a 191P4D12(b) polypeptide include: a 191P4D12(b) polypeptide having a sequence shown in

Figure 2, a peptide sequence of a 191P4D12(b) as shown in Figure 2 wherein T is U; at least 10 contiguous nucleotides of a

polypeptide having the sequence as shown in Figure 2; or, at least 10 contiguous peptides of a polypeptide having the

sequence as shown in Figure 2 where T is U. For example, embodiments of 191P4D12(b) peptides comprise, without

limitation:00

a protein comprising, consisting essentially of, or consisting of an amino acid sequence as shown in

Figure 2A-N or Figure 3A-J;

(II) a 191P4D12(b)-related protein that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% homologous

to an entire amino acid sequence shown in Figure 2A-N or 3A-J;

(III) a 191P4D12(b)-related protein that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% identical to

an entire amino acid sequence shown in Figure 2A-N or 3A-J;

(IV) a protein that comprises at least one peptide set forth in Tables VIII to XLIX, optionally with a proviso

C that it is not an entire protein of Figure 2;

0000 a protein that comprises at least one peptide set forth in Tables VIII-XXI, collectively, which peptide is

0also set forth in Tables XXII to XLIX, collectively, optionally with a proviso that it is not an entire protein of Figure 2;

C (VI) a protein that comprises at least two peptides selected from the peptides set forth in Tables VIII-XLIX,

optionally with a proviso that it is not an entire protein of Figure 2;

(VII) a protein that comprises at least two peptides selected from the peptides set forth in Tables VIII to XLIX

collectively, with a proviso that the protein is not a contiguous sequence from an amino acid sequence of Figure 2;

(VIII) a protein that comprises at least one peptide selected from the peptides set forth in Tables VIII-XXI; and

at least one peptide selected from the peptides set forth in Tables XXII to XLIX, with a proviso that the protein is

not a contiguous sequence from an amino acid sequence of Figure 2;

(IX) a polypeptide comprising at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,

26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a protein of Figure 3A-B or 3E-G, in any whole number

increment up to 510 respectively that includes at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,

21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35 amino acid position(s) having a value greater than

in the Hydrophilicity profile of Figure

a polypeptide comprising at least 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,

26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a protein of Figure 3A-B or 3E-G, in any whole number

increment up to 510 respectively that includes at least at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17,

18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value less than

in the Hydropathlcity profile of Figure 6;

(XI) a polypeptide comprising at least 5, 6, 7, 8, 9,10, 11, 12,13,14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24,

26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a protein of Figure 3A-B or 3E-G, in any whole number

increment up to 510 respectively that includes at least at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,

18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value greater

than 0.5 in the Percent Accessible Residues profile of Figure 7;

(XII) a polypeptide comprising at least 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,

26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a protein of Figure 3A-B or 3E-G, in any whole number

increment up to 510 respectively that includes at least at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,

18,19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35 amino acid position(s) having a value greater

OO than 0.5 in the Average Flexibility profile of Figure 8;

OS(XIII) a polypeptide comprising at least 5, 6,7,8,9,10,11,12,13,14,15,16,17,18,19, 20,21,22,23,24,

26, 27, 28, 29, 30, 31,32, 33, 34, amino acids of a protein of Figure 3A-B or 3E-G in any whole number

c increment up to 510 respectively that includes at least at least 1,2, 3,4,5,6,7,8, 9,10,11,12,13,14,15,16, 17,

18,19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35 amino acid position(s) having a value greater

Sthan 0.5 in the Beta-turn profile of Figure 9;

(XIV) a polypeptide comprising at least 5,6,7,8, 9,10,11, 12,13,14, 15,16, 17,18,19, 20, 21, 22, 23, 24,

25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a protein of Figure 3C, in any whole number increment up

to 295 respectively that includes at least 1, 2, 3,4, 5,6, 7,8, 9,10,11,12,13,14, 15,16,17,18,19, 20, 21, 22,

C 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 in the

SHydrophilicity profile of Figure 00

0 (XV) a polypeptide comprising at least 5,6,7,8,9,10,11,12,13,14,15,16,17,18,19, 20,21, 22,23, 24,

C 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a protein of Figure 3C, in any whole number increment up

to 295 respectively that includes at least at least 1, 2, 3,4, 5, 6, 7, 8, 9,10,11, 12, 13, 14, 15, 16,17, 18, 19,

21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value less than 0.5 in the

Hydropathicity profile of Figure 6;

(XVI) a polypeptide comprising at least 5,6,7,8, 9,10,11,12,13,14,15,16, 17,18,19, 20,21, 22,23, 24,

26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a protein of Figure 3C, in any whole number increment up

to 295 respectively that includes at least at least 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19,

21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 in

the Percent Accessible Residues profile of Figure 7;

(XVII) a polypeptide comprising at least 5,6,7, 8, 9,10,11,12,13,14,15,16, 17,18,19, 20,21, 22, 23, 24,

26, 27, 28, 29, 30, 31,32, 33, 34, 35 amino acids of a protein of Figure 3C, in any whole number increment up

to 295 respectively that includes at least at least 1,2,3,4,5,6,7,8,9, 10, 11, 12,13, 14,15,16,17,18,19,20,

21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 In

the Average Flexibility profile of Figure 8;

(XVIII) a polypeptide comprising at least 5,6,7,8,9, 10, 11, 12,13,14,15,16,17,18,19,20,21,22,23,24,

26, 27, 28, 29, 30, 31, 32, 33, 34, amino acids of a protein of Figure 3C in any whole number increment up to

295 respectively that includes at least at least 1, 2,3,4, 5, 6, 7,8, 9,10, 11, 12, 13, 14, 15, 16,17,18,19,20, 21,

22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 in the

Beta-turn profile of Figure 9;

(XIX) a polypeptide comprising at least 5, 6, 7, 8, 9,10, 11,12,13,14,15,16,17,18,19, 20, 21, 22, 23, 24,

26, 27, 28, 29, 30, 31,32, 33,34, 35 amino acids of a protein of Figure 3D, In any whole number increment up

to 485 respectively that indudes at least 1, 2,3,4, 5, 6, 7,8, 9,10,11,12,13,14,15,16,17,18,19, 20, 21,22,

23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 in the

Hydrophilicity profile of Figure

(XX) a polypeptide comprising at least 5, 6, 7, 8, 9, 10, 11, 12,13,14,15,16, 17, 18,19,20, 21, 22, 23, 24,

26, 27, 28, 29, 30, 31,32, 33, 34, 35 amino acids of a protein of Figure 3D, in any whole number increment up

to 485respectively that includes at least at least 1, 2, 3, 4,5, 6, 7, 8, 9,10,11,12,13,14,15,16,17,18,19,

21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value less than 0.5 in the

0

(XXI) a polypeptide comprising at least 5, 6, 7.8, 9,10, 11, 12, 13, 14, 15.16, 17, 18, 19, 20. 21, 22, 23, 24,

26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a protein of Figure 31), in any whole number Increment up

to 485 respectively that includes at least at least 1, 2, 3,4, 5, 6,7, 8,9,10,11, 12,13,14, 15, 16, 17,18, 19,20,

21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 In

c-K1 the Percent Accessible Residues profile of Figure 7;

(XXII) a polypeptide comprising at least 5, 6,7, 8, 9,10, 11,12,13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24,

26, 27, 28, 29, 30, 31, 32, 33, 34. 35 amino acids of a protein of Figure 3D, in any whole number increment up

to 485 respectively that includes atleast at least1, 2 3 4 6 7 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,

21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 in

00 the Average Flexibility profile of Figure 8;

(XXIII) a polypeptide comprising at least 5, 6, 7,8, 9,10, 11,12,13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24,

26, 27, 28, 29, 30, 31, 32, 33, 34, amino acids of a protein of Figure 3D in any whole number increment up to

485 respecively that includes at least at leastl1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,

22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 in the

Beta-turn profile of Figure 9;

(XXIV) a polypeptide comprising at least 5, 6,7, 8, 9,10, 11, 12, 13,14,15,16, 17, 18, 19, 20, 21, 22, 23, 24,

26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a protein of Figure 3H, in any whole number increment up

to 611 respectively that includes at leasti1, 2, 3, 4, 5,6, 7, 8,9,10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22,

23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 in the

Hydrophilicity profile of Figure

(XXV) a polypeptide comprising at least 5, 6, 7, 8,9, 10, 11,12,13, 14,15,16, 17, 18, 19, 20, 21, 22, 23, 24,

26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a protein of Figure 3H, in any whole number increment up

to 511 respectively that includes at least at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19,

21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value less than 0.5 in the

Hydropathicity profile of Figure 6;

(XXVI) a polypeptide comprising at least 5, 6,7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,

26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a protein of Figure 3H, in any whole number increment up

to 511 respectively that includes at least at least 1, 2,3, 4,5, 6,7, 8, 9,10,11, 12,13, 14, 15, 16, 17, 18,19,

21, 22, 23, 24, 25, 26, 27, 28,29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 in

the Percent Accessible Residues profile of Figure 7;

(XXVII) a polypeptide comprising at least 5, 6, 7, 8,9,10,11, 12,13, 14,15,16,17, 18,19, 20, 21, 22, 23, 24,

26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a protein of Figure 3H, in any whole number increment up

to 511 respectively that includes atleast atleast, 2, 3,4, 5,6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,

21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 in

the Average Flexibility profile of Figure 8;

(XXVIII) a polypeptide comprising at least 5, 6, 7, 8, 9, 10,11, 12,13,14,15,16,17,18,19, 20, 21, 22, 23, 24,

00 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, amino acids of a protein of Figure 3H in any whole number increment up to

O 511 respectively that includes at least at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16,17, 18, 19, 20, 21,

C22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 in the

Beta-turn profile of Figure 9;

(XXIX) a polypeptide comprising at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,

26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a protein of Figure 31-J, in any whole number increment up

to 137 respectively that includes at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,

23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 in the

Hydrophilicity profile of Figure

S(XXX) a polypeptide comprising at least 5, 6, 7, 8, 9, 10,11,12,13,14,15,16,17,18,19, 20, 21, 22, 23, 24,

26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a protein of Figure 31-J, in any whole number increment0 0 up to 137 respectively that includes at least at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,

21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value less than 0.5 in

the Hydropathicity profile of Figure 6;

(XXXI) a polypeptide comprising at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17,18,19, 20, 21, 22, 23, 24,

26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a protein of Figure 31-J, in any whole number Increment up

to 137 respectively that includes at least at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,

21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 in

the Percent Accessible Residues profile of Figure 7;

(XXXII) a polypeptide comprising at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,

26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a protein of Figure 31-J, in any whole number increment

up to 137 respectively that includes at least at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13,14, 15, 16, 17, 18, 19,

21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value greater than

in the Average Flexibility profile of Figure 8;

(XXXIII) a polypeptide comprising at least 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17,18,19, 20, 21, 22, 23, 24,

26, 27, 28, 29, 30, 31, 32, 33, 34, amino acids of a protein of Figure 31-J in any whole number increment up to

137 respectively that includes at least at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,

22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having a value greater than 0.5 in the

Beta-turn profile of Figure 9;

(XXXIV) a peptide that occurs at least twice in Tables VIII-XXI and XXII to XLIX, collectively;

(XXXV) a peptide that occurs at least three times in Tables VIII-XXI and XXII to XLIX, collectively;

(XXXVI) a peptide that occurs at least four times in Tables VIII-XXI and XXII to XLIX, collectively;

(XXXVII) a peptide that occurs at least five times in Tables VIII-XXI and XXII to XLIX, collectively;

(XXXVIII) a peptide that occurs at least once in Tables VIII-XXI, and at least once in tables XXII to XLIX;

(XXXIX) a peptide that occurs at least once in Tables VIII-XXI, and at least twice in tables XXII to XLIX;

(XL) a peptide that occurs at least twice in Tables VIII-XXI, and at least once in tables XXII to XLIX;

(XLI) a peptide that occurs at least twice in Tables VIII-XXI, and at least twice in tables XXII to XLIX;

(XLII) a peptide which comprises one two, three, four, or five of the following characteristics, or an

oligonucleotide encoding such peptide:0 i) a region of at least 5 amino acids of a particular peptide of Figure 3, in any whole number increment

up to the full length of that protein in Figure 3, that includes an amino acid position having a value equal to or

greater than 0.5, 0.6, 0.7, 0.8, 0.9, or having a value equal to 1.0, in the Hydrophilicity profile of Figure

C ii) a region of at least 5 amino acids of a particular peptide of Figure 3, in any whole number increment

up to the full length of that protein in Figure 3, that includes an amino acid position having a value equal to or less

Sthan 0.5, 0.4, 0.3, 0.2, 0.1, or having a value equal to 0.0, in the Hydropathicity profile of Figure 6;

iii) a region of at least 5 amino acids of a particular peptide of Figure 3, in any whole number increment

up to the full length of that protein in Figure 3, that includes an amino acid position having a value equal to or

greater than 0.5, 0.6, 0.7, 0.8, 0.9, or having a value equal to 1.0, in the Percent Accessible Residues profile of

RFigure 7;

iv) a region of at least 5 amino acids of a particular peptide of Figure 3, in any whole number increment

00 up to the full length of that protein in Figure 3, that Includes an amino acid position having a value equal to or

greater than 0.5, 0.6, 0.7, 0.8, 0.9, or having a value equal to 1.0, in the Average Flexibility profile of Figure 8; or,

C v) a region of at least 5 amino acids of a particular peptide of Figure 3, in any whole number increment

up to the full length of that protein in Figure 3, that includes an amino acid position having a value equal to or

greater than 0.5, 0.6, 0.7, 0.8, 0.9, or having a value equal to 1.0, in the Beta-turn profile of Figure 9;

(XLIII) a composition comprising a peptide of (I)-(XLII) or an antibody or binding region thereof together with a

pharmaceutical excipient andlor in a human unit dose form.

(XLIV) a method of using a peptide of or an antibody or binding region thereof or a composition of

(XLIII) in a method to modulate a cell expressing 191P4D12(b),

(XLV) a method of using a peptide of (I)-(XLII) or an antibody or binding region thereof or a composition of

(XLIII) in a method to diagnose, prophylax, prognose, or treat an individual who bears a cell expressing 191P4D12(b)

(XLVI) a method of using a peptide of (I)-(XLII) or an antibody or binding region thereof or a composition (XIIII)

in a method to diagnose, prophylax, prognose, or treat an individual who bears a cell expressing 191P4D12(b), said cell from

a cancer of a tissue listed in Table I;

(XLVII) a method of using a peptide of (I)-(XLII) or an antibody or binding region thereof or a composition of

(XLIII) in a method to diagnose, prophylax, prognose, or treat a a cancer;

(XLVIII) a method of using a peptide of (I)-(XLII) or an antibody or binding region thereof or a composition of

(XLIII) in a method to diagnose, prophylax, prognose, or treat a a cancer of a tissue listed in Table I; and,

(XLIX) a method of using a a peptide of (I)-(XLII) or an antibody or binding region thereof or a composition

(XLIII) in a method to identify or characterize a modulator of a cell expressing 191P4D12(b).

As used herein, a range is understood to specifically disclose all whole unit positions thereof.

Typical embodiments of the invention disclosed herein include 191P4D12(b) polynucleotides that encode specific

portions of 191P4D12(b) mRNA sequences (and those which are complementary to such sequences) such as those that

encode the proteins and/or fragments thereof, for example:

4, 5, 6, 7, 8, 9, 10,11, 12,13,14,15,16,17,18,19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65,

00 75, 80,85,90, 95,100,105, 110, 115,120,125,130,135,140,145,150,155,160,165,170, 175,180,185,190,195, 200,

O 225, 250, 275, 300, 325, 350, 375, 400,425, 450, 475, 500, 505, or 510 or more contiguous amino acids of 191P4D12(b)

C1 variant 1; the maximal lengths relevant for other variants are: variant 2, 510 amino acids; variant 6, 295 amino acids, variant

7, 485 amino acids, variant 10, 510 amino acids, variant 11, 510 amino acids, variant 12, 510 amino acids, variant 13, 511

amino acids, variant 9, 137 amino acids, and variant 14, 137 amino acids..

In general, naturally occurring allelic variants of human 191P4D12(b) share a high degree of structural identity and

C homology 90% or more homology). Typically, allelic variants of a 191P4D12(b) protein contain conservative amino acid

substitutions within the 191P4D12(b) sequences described herein or contain a substitution of an amino acid from a corresponding

position in a homologue of 191P4D12(b). One class of 191P4D12(b) allelic variants are proteins that share a high degree of

homology with at least a small region of a particular 191P4D12(b) amino add sequence, but further contain a radical departure

from the sequence, such as a non-conservative substitution, truncation, insertion or frame shift. In comparisons of protein

CN sequences, the terms, similarity, identity, and homology each have a distinct meaning as appreciated in the field of genetics.00

Moreover, orthology and paralogy can be important concepts describing the relationship of members of a given protein family In

one organism to the members of the same family in other organisms.

Amino acid abbreviations are provided in Table II. Conservative amino acid substitutions can frequently be made

in a protein without altering either the conformation or the function of the protein. Proteins of the invention can comprise 1, 2,

3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 conservative substitutions. Such changes include substituting any of isoleucine

valine and leucine for any other of these hydrophobic amino acids; aspartic acid for glutamic acid and vice

versa; glutamine for asparagine and vice versa; and serine for threonine and vice versa. Other substitutions

can also be considered conservative, depending on the environment of the particular amino acid and its role in the three-

dimensional structure of the protein. For example, glycine and alanine can frequently be interchangeable, as can

alanine and valine Methionine which is relatively hydrophobic, can frequently be interchanged with leucine and

isoleucine, and sometimes with valine. Lysine and arginine are frequently interchangeable in locations in which the

significant feature of the amino acid residue is its charge and the differing pK's of these two amino acid residues are not

significant. Still other changes can be considered "conservative" in particular environments (see, e.g. Table III herein; pages

13-15 "Biochemistry" 2nd ED. Lubert Stryer ed (Stanford University); Henikoff et al., PNAS 1992 Vol 89 10915-10919; Lei et

al., J Biol Chem 1995 May 19; 270(20):11882-6).

Embodiments of the invention disclosed herein include a wide variety of art-accepted variants or analogs of

191P4D12(b) proteins such as polypeptides having amino acid insertions, deletions and substitutions. 191P4D12(b) variants

can be made using methods known in the art such as site-directed mutagenesis, alanine scanning, and PCR mutagenesis.

Site-directed mutagenesis (Carter et al., Nucl. Acids Res., 13:4331 (1986); Zoller et al., Nucl. Acids Res., 10.6487 (1987)),

cassette mutagenesis (Wells et al., Gene, 34:315 (1985)), restriction selection mutagenesis (Wells et al., Philos. Trans. R.

Soc. London SerA, 317:415 (1986)) or other known techniques can be performed on the cloned DNA to produce the

191P4D12(b) variant DNA.

Scanning amino acid analysis can also be employed to identify one or more amino acids along a contiguous

sequence that is involved in a specific biological activity such as a protein-protein interaction. Among the preferred scanning

amino acids are relatively small, neutral amino acids. Such amino acids include alanine, glycine, serine, and cysteine.

Alanine is typically a preferred scanning amino acid among this group because it eliminates the side-chain beyond the beta-

carbon and is less likely to alter the main-chain conformation of the variant. Alanine is also typically preferred because it is

the most common amino acid. Further, it is frequently found in both buried and exposed positions (Creighton, The Proteins,

Freeman Co., Chothia, J. Mol. Biol., 150:1 (1976)). If alanine substitution does not yield adequate amounts of

variant, an isosteric amino acid can be used.

00 As defined herein, 191P4D12(b) variants, analogs or homologs, have the distinguishing attribute of having at least00 one epitope that is "cross reactive" with a 191P4D12(b) protein having an amino acid sequence of Figure 3. As used in this

sentence, "cross reactive" means that an antibody or T cell that specifically binds to a 191P4D12(b) variant also specifically

c binds to a 191P4D12(b) protein having an amino acid sequence set forth in Figure 3. A polypeptide ceases to be a variant of

a protein shown in Figure 3, when it no longer contains any epitope capable of being recognized by an antibody or T cell that

specifically binds to the starting 191P4D12(b) protein. Those skilled in the art understand that antibodies that recognize

proteins bind to epitopes of varying size, and a grouping of the order of about four or five amino acids, contiguous or not, is

regarded as a typical number of amino acids In a minimal epitope. See, Nair et al., J. Immunol 2000 165(12): 6949-

6955; Hebbes et al., Mol Immunol (1989) 26(9):865-73; Schwartz et al., J Immunol (1985) 135(4):2598-608.

LC Other classes of 191P4D12(b)-related protein variants share 70%, 75%, 80%, 85% or 90% or more similarity with

an amino acid sequence of Figure 3, or a fragment thereof. Another specific class of 191P4D12(b) protein variants or

00 analogs comprises one or more of the 191P4D12(b) biological motifs described herein or presently known in the art. Thus,

encompassed by the present invention are analogs of 191P4D12(b) fragments (nucleic or amino acid) that have altered

Cl functional immunogenic) properties relative to the starting fragment. It is to be appreciated that motifs now or which

become part of the art are to be applied to the nucleic or amino acid sequences of Figure 2 or Figure 3.

As discussed herein, embodiments of the claimed invention include polypeptides containing less-than the full

amino acid sequence of a 191P4D12(b) protein shown in Figure 2 or Figure 3. For example, representative embodiments of

the invention comprise peptides/proteins having any 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more contiguous amino acids of

a 191P4D12(b) protein shown in Figure 2 or Figure 3.

Moreover, representative embodiments of the invention disclosed herein include polypeptides consisting of about

amino acid 1 to about amino acid 10 of a 191P4D12(b) protein shown in Figure 2 or Figure 3, polypeptides consisting of

about amino acid 10 to about amino acid 20 of a 191P4D12(b) protein shown in Figure 2 or Figure 3, polypeptides consisting

of about amino acid 20 to about amino acid 30 of a 191P4D12(b) protein shown in Figure 2 or Figure 3, polypeptides

consisting of about amino acid 30 to about amino acid 40 of a 191P4D12(b) protein shown in Figure 2 or Figure 3,

polypeptides consisting of about amino acid 40 to about amino acid 50 of a 191P4D12(b) protein shown in Figure 2 or Figure

3, polypeptides consisting of about amino acid 50 to about amino acid 60 of a 191P4D12(b) protein shown in Figure 2 or

Figure 3, polypeptides consisting of about amino acid 60 to about amino acid 70 of a 191P4D12(b) protein shown in Figure 2

or Figure 3, polypeptides consisting of about amino acid 70 to about amino acid 80 of a 191P4D12(b) protein shown in

Figure 2 or Figure 3, polypeptides consisting of about amino acid 80 to about amino acid 90 of a 191P4D12(b) protein shown

in Figure 2 or Figure 3, polypeptides consisting of about amino acid 90 to about amino acid 100 of a 191P4D12(b) protein

shown in Figure 2 or Figure 3, etc. throughout the entirety of a 191P4D12(b) amino acid sequence. Moreover, polypeptides

consisting of about amino acid 1 (or 20 or 30 or 40 etc.) to about amino acid 20, (or 130, or 140 or 150 etc.) of a

191P4D12(b) protein shown in Figure 2 or Figure 3 are embodiments of the invention. It is to be appreciated that the starting

and stopping positions in this paragraph refer to the specified position as well as that position plus or minus 5 residues.

191P4D12(b)-related proteins are generated using standard peptide synthesis technology or using chemical cleavage

methods well known in the art. Alternatively, recombinant methods can be used to generate nucleic acid molecules that encode a

191P4D12(b)-related protein. In one embodiment, nucleic acid molecules provide a means to generate defined fragments of a

191P4D12(b) protein (or variants, homologs or analogs thereof).

III.A.) Motif-bearing Protein Embodiments

OO Additional illustrative embodiments of the invention disclosed herein include 191P4D12(b) polypeptides comprising

S the amino acid residues of one or more of the biological motifs contained within a 191P4D12(b) polypeptide sequence set

Cr forth in Figure 2 or Figure 3. Various motifs are known In the art, and a protein can be evaluated for the presence of such

motifs by a number of publicly available Internet sites (see, URL addresses: pfam.wustl.edu/;

searchlauncher.bcm.tmc.edulseq-search/struc-predict.html; psort.ims.u-tokyo.ac.jp/; cbs.dtu.dk/;

O ebi.ac.uk/interpro/scan.html; expasy.ch/tools/scnpsitl .html; EpimatrixTM and EplmerT Brown University,

S brown.edulResearch/TB-HIVLab/epimatrixepimatx.html; and BIMAS, bimas.dcrtnih.gov/.).

Motif bearing subsequences of all 191P4D12(b) variant proteins are set forth and identified in Tables VIII-XXI and

XXII-XLIX.

C Table V sets forth several frequently occurring motifs based on pfam searches (see URL address pfam.wustl.edul).

The columns of Table V list motif name abbreviation, percent Identity found amongst the different member of the motif

C family, motif name or description and most common function; location information is included if the motif is relevant for000 location.

S Polypeptides comprising one or more of the 191P4D12(b) motifs discussed above are useful in elucidating the

specific characteristics of a malignant phenotype in view of the observation that the 191P4D12(b) motifs discussed above

are associated with growth dysregulation and because 191P4D12(b) is overexpressed in certain cancers (See, Table I).

Casein kinase II, cAMP and camp-dependent protein kinase, and Protein Kinase C, for example, are enzymes known to be

associated with the development of the malignant phenotype (see e.g. Chen etal., Lab Invest., 78(2): 165-174 (1998);

Gaiddon et al., Endocrinology 136(10): 4331-4338 (1995); Hall et al., Nucleic Acids Research 24(6): 1119-1126 (1996);

Peterziel et al., Oncogene 18(46): 6322-6329 (1999) and O'Brian, Oncol. Rep. 305-309 (1998)). Moreover, both

glycosylation and myristoylation are protein modifications also associated with cancer and cancer progression (see e.g.

Dennis et al., Biochem. Biophys. Acta 1473(1):21-34 (1999); Raju et al., Exp. Cell Res. 235(1): 145-154 (1997)). Amidation

is another protein modification also associated with cancer and cancer progression (see e.g. Treston et al., J. Natl. Cancer

Inst. Monogr. 169-175 (1992)).

In another embodiment, proteins of the invention comprise one or more of the immunoreactive epitopes identified

in accordance with art-accepted methods, such as the peptides set forth in Tables VIII-XXI and XXII-XLIX. CTL epitopes can

be determined using specific algorithms to identify peptides within a 191P4D12(b) protein that are capable of optimally binding to

specified HLA alleles Table IV; Epimatrix M and EpimerTM Brown University, URL brown.edulResearch/TB-

HIV_Lablepimabix/epimatrix.html; and BIMAS, URL bimas.dcrt.nih.gov/.) Moreover, processes for identifying peptides that have

sufficient binding affinity for HLA molecules and which are correlated with being immunogenic epitopes, are well known in the

art, and are carried out without undue experimentation. In addition, processes for identifying peptides that are immunogenic

epitopes, are well known in the art, and are carried out without undue experimentation either in vitro or in vivo.

Also known in the art are principles for creating analogs of such epitopes in order to modulate immunogenicity. For

example, one begins with an epitope that bears a CTL or HTL motif (see, the HLA Class I and HLA Class II

motifs/supermotifs of Table IV). The epitope is analoged by substituting out an amino acid at one of the specified positions,

and replacing it with another amino acid specified for that position. For example, on the basis of residues defined in Table

IV, one can substitute out a deleterious residue in favor of any other residue, such as a preferred residue; substitute a less-

preferred residue with a preferred residue; or substitute an originally-occurring preferred residue with another preferred

residue. Substitutions can occur at primary anchor positions or at other positions in a peptide; see, Table IV.

A variety of references reflect the art regarding the identification and generation of epitopes In a protein of interest

as well as analogs thereof. See, for example, WO 97/33602 to Chesnut et al.; Sette, Immunogenetics 1999 50(3-4): 201-

212; Sette et al., J. Immunol. 2001 166(2): 1389-1397; Sidney et al., Hum. Immunol. 1997 58(1): 12-20; Kondo et al.,

Immunogenetics 1997 45(4): 249-258; Sidney etal., J. Immunol. 1996 157(8): 3480-90; and Falk et Nature 351: 290-6

00 (1991); Hunt et al., Science 255:1261-3(1992); Parker etal., J. Immunol. 149:3580-7 (1992); Parker etal., J. Immunol.

152:163-75 (1994)); Kast et al., 1994 152(8): 3904-12; Borras-Cuesta et al., Hum. Immunol. 2000 61(3): 266-278; Alexander

et al., J, Immunol. 2000 164(3); 164(3): 1625-1633; Alexander et al., PMID: 7895164, UI: 95202582; O'Sullivan et al., J.

Immunol. 1991 147(8): 2663-2669; Alexander etal., Immunity 1994 751-761 and Alexander et al., Immunol. Res. 1998

18(2): 79-92.

Related embodiments of the invention include polypeptides comprising combinations of the different motifs set forth

in Table VI, and/or, one or more of the predicted CTL epitopes of Tables VIII-XXI and XXII-XLIX, and/or, one or more of the

predicted HTL epitopes of Tables XLVI-XLIX, and/or, one or more of the T cell binding motifs known in the art. Preferred

S embodiments contain no insertions, deletions or substitutions either within the motifs or within the intervening sequences of

Cr the polypeptides. In addition, embodiments which Include a number of either N-terminal and/or C-terminal amino acid

residues on either side of these motifs may be desirable (to, for example, include a greater portion of the polypeptide

00 architecture in which the motif is located). Typically, the number of N-terminal and/or C-terminal amino acid residues on

either side of a motif is between about 1 to about 100 amino acid residues, preferably 5 to about 50 amino acid residues.

C 191P4D12(b)-related proteins are embodied in many forms, preferably in isolated form. A purified 191P4D12(b)

protein molecule will be substantially free of other proteins or molecules that impair the binding of 191P4012(b) to antibody,

T cell or other ligand. The nature and degree of isolation and purification will depend on the intended use. Embodiments of a

191P4D12(b)-related proteins include purified 191P4D12(b)-related proteins and functional, soluble 191P4D12(b)-related

proteins. In one embodiment, a functional, soluble 191P4D12(b) protein or fragment thereof retains the ability to be bound

by antibody, T cell or other ligand.

The invention also provides 191P4D12(b) proteins comprising biologically active fragments of a 191P4D12(b)

amino acid sequence shown in Figure 2 or Figure 3. Such proteins exhibit properties of the starting 191P4D12(b) protein,

such as the ability to elicit the generation of antibodies that specifically bind an epitope associated with the starting

191P4D12(b) protein; to be bound by such antibodies; to elicit the activation of HTL or CTL; and/or, to be recognized by HTL

or CTL that also specifically bind to the starting protein.

191P4D12(b)-related polypeptides that contain particularly interesting structures can be predicted and/or identified using

various analytical techniques well known in the art, including, for example, the methods of Chou-Fasman, Gamier-Robson, Kyte-

Doolittle, Eisenberg, Karplus-Schultz or Jameson-Wolf analysis, or based on immunogenicity. Fragments that contain such

structures are particularly useful in generating subunit-specific anti-191P4D12(b) antibodies or T cells or in identifying cellular

factors that bind to 191P4D12(b). For example, hydrophilicity profiles can be generated, and immunogenic peptide fragments

identified, using the method of Hopp, T.P. and Woods, 1981, Proc. Natl. Acad. Sci. U.S.A. 78:3824-3828.

Hydropathidty profiles can be generated, and immunogenic peptide fragments identified, using the method of Kyte, J. and

Doolittle, 1982, J. Mol. Biol. 157:105-132. Percent Accessible Residues profiles can be generated, and

immunogenic peptide fragments identified, using the method of Janin 1979, Nature 277:491-492. Average Flexibility

profiles can be generated, and immunogenic peptide fragments identified, using the method of Bhaskaran Ponnuswamy

1988, Int. J. Pept. Protein Res. 32:242-255. Beta-turn profiles can be generated, and immunogenic peptide fragments

identified, using the method of Deleage, Roux 1987, Protein Engineering 1:289-294.

CTL epitopes can be determined using specific algorithms to identify peptides within a 191P4D12(b) protein that are

capable of optimally binding to specified HLA alleles by using the SYFPEITHI site at World Wide Web URL syfpeithi.bmi-

heidelberg.com/; the listings in Table EpimatrixTM and Epimer TM Brown University, URL (brown.edu/ResearchTfB-

HIVLab/epimatrixepimatrix.html); and BIMAS, URL bimas.dcrt.nih.gov/). Illustrating this, peptide epitopes from 191P4D12(b)

that are presented in the context of human MHC Class I molecules, HLA-A1, A2, A3, All, A24, 87 and B35 were

0 predicted (see, Tables VIII-XXI, XXII-XLIX). Specifically, the complete amino acid sequence of the 191P4D12(b) protein

0 and relevant portions of other variants, for HLA Class I predictions 9 flanking residues on either side of a point mutation

C- or exon Juction, and for HLA Class II predictions 14 flanking residues on either side of a point mutation or exon junction

Scorresponding to that variant, were entered into the HLA Peptide Motif Search algorithm found in the Bioinformatlcs and

Molecular Analysis Section (BIMAS) web site listed above; in addition to the site SYFPEITHI, at URL syfpeithi.bmi-

heidelberg.com/.

CN The HLA peptide motif search algorithm was developed by Dr. Ken Parker based on binding of specific peptide

sequences In the groove of HLA Class I molecules, in particular HLA-A2 (see, Falk et al., Nature 351: 290-6 (1991);

r- Hunt et al., Science 255:1261-3 (1992); Parker et al., J. Immunol. 149:3580-7 (1992); Parker et al., J. Immunol. 152:163-75

LC (1994)). This algorithm allows location and ranking of 8-mer, 9-mer, and 10-mer peptides from a complete protein sequence

for predicted binding to HLA-A2 as well as numerous other HLA Class I molecules. Many HLA class I binding peplides are 8-

1 10 or 11-mers. For example, for Class I HLA-A2, the epitopes preferably contain a leucine or methionine at00C position 2 and a valine or leucine at the C-terminus (see, Parker et at., J. Immunol. 149:3580-7 (1992)). Selected

S results of 191P4D12(b) predicted binding peptides are shown in Tables VIII-XXI and XXII-XLIX herein. In Tables VIII-XXI and

XXII-XLVII, selected candidates, 9-mers and 10-mers, for each family member are shown along with their location, the amino

acid sequence of each specific peptide, and an estimated binding score. In Tables XLVI-XLIX, selected candidates,

mers, for each family member are shown along with their location, the amino acid sequence of each specific peptide, and an

estimated binding score. The binding score corresponds to the estimated half time of dissociation of complexes containing

the peptide at 37oC at pH 6.5. Peptides with the highest binding score are predicted to be the most tightly bound to HLA

Class I on the cell surface for the greatest period of time and thus represent the best immunogenic targets for T-cell

recognition.

Actual binding of peptides to an HLA allele can be evaluated by stabilization of HLA expression on the antigen-

processing defective cell line T2 (see, Xue et al., Prostate 30:73-8 (1997) and Peshwa et al., Prostate 36:129-38

(1998)). Immunogenicity of specific peptides can be evaluated in vitro by stimulation of CD8+ cytotoxic T lymphocytes (CTL)

in the presence of antigen presenting cells such as dendritic cells.

It is to be appreciated that every epitope predicted by the BIMAS site, EpimerTM and EpimatrixTM sites, or specified

by the HLA class I or class II motifs available in the art or which become part of the art such as set forth In Table IV (or

determined using World Wide Web site URL syfpeithi.bml-heidelberg.com/, or BIMAS, bimas.dcrtnih.gov/) are to be "applied"

to a 191P4D12(b) protein in accordance with the invention. As used in this context "applied" means that a 191P4D12(b)

protein is evaluated, visually or by computer-based patterns finding methods, as appreciated by those of skill in the

relevant art. Every subsequence of a 191P4D12(b) protein of 8, 9, 10, or 11 amino acid residues that bears an HLA Class I

motif, or a subsequence of 9 or more amino acid residues that bear an HLA Class II motif are within the scope of the

invention.

III.B.) Expression of 191P4D12(b)-related Proteins

In an embodiment described in the examples that follow, 191P4D12(b) can be conveniently expressed in cells

(such as 293T cells) transfected with a commercially available expression vector such as a CMV-driven expression vector

encoding 191P4D12(b) with a C-terminal 6XHis and MYC tag (pcDNA3.1/mycHIS, Invitrogen or Tag5, GenHunter

Corporation, Nashville TN). The Tag5 vector provides an IgGK secretion signal that can be used to facilitate the production

.of a secreted 191P4D12(b) protein in transfected cells. The secreted HIS-tagged 191P4D12(b) In the culture media can be

purified, using a nickel column using standard techniques.

III.C.) Modifications of 191P4D12(b)-related Proteins

00 Modifications of 191P4D12(b)-related proteins such as covalent modifications are included within the scope of this

0 invention. One type of covalent modification includes reacting targeted amino acid residues of a 191P4D12(b) polypeptide

with an organic derivatizing agent that is capable of reacting with selected side chains or the N- or C- terminal residues of a

t 191P4D12(b) protein. Another type of covalent modification of a 191P4D12(b) polypeptide included within the scope of this

invention comprises altering the native glycosylation pattern of a protein of the invention. Another type of covalent

0 modification of 191P4D12(b) comprises linking a 191P4D12(b) polypeptide to one of a variety of nonproteinaceous polymers,

polyethylene glycol (PEG), polypropylene glycol, or polyoxyalkylenes, in the manner set forth in U.S. Patent Nos.

4,640,835; 4,496,689; 4,301,144; 4,670,417; 4,791,192 or 4,179,337.

The 191P4D12(b)-related proteins of the present invention can also be modified to form a chimeric molecule

comprising 191P4D12(b) fused to another, heterologous polypeptide or amino acid sequence. Such a chimeric molecule can

be synthesized chemically or recombinantly. A chimeric molecule can have a protein of the invention fused to another tumor-

00 associated antigen or fragment thereof. Alternatively, a protein in accordance with the invention can comprise a fusion of

S fragments of a 191P4D12(b) sequence (amino or nucleic acid) such that a molecule is created that is not, through its length,

CK directly homologous to the amino or nucleic acid sequences shown in Figure 2 or Figure 3. Such a chimeric molecule can

comprise multiples of the same subsequence of 191P4D12(b). A chimeric molecule can comprise a fusion of a

191P4D12(b)-related protein with a polyhistidine epitope tag, which provides an epitope to which immobilized nickel can

selectively bind, with cytokines or with growth factors. The epitope tag is generally placed at the amino- or carboxyl-

terminus of a 191P4D12(b) protein. In an alternative embodiment, the chimeric molecule can comprise a fusion of a

191P4D12(b)-related protein with an immunoglobulin or a particular region of an immunoglobulin. For a bivalent form of the

chimeric molecule (also referred to as an "immunoadhesin"), such a fusion could be to the Fc region of an IgG molecule. The

Ig fusions preferably include the substitution of a soluble (transmembrane domain deleted or inactivated) form of a

191P4012(b) polypeptide in place of at least one variable region within an Ig molecule. In a preferred embodiment, the

immunoglobulin fusion includes the hinge, CH2 and CH3, or the hinge, CHI, CH2 and CH3 regions of an IgGI molecule. For

the production of immunoglobulin fusions see, U.S. Patent No. 5,428,130 issued June 27, 1995.

III.D.) Uses of 191P4D12(b)-related Proteins

The proteins of the invention have a number of different specific uses. As 191P4D12(b) is highly expressed in

prostate and other cancers, 191P4D12(b)-related proteins are used in methods that assess the status of 191P4D12(b) gene

products in normal versus cancerous tissues, thereby elucidating the malignant phenotype. Typically, polypeptides from

specific regions of a 191P4D12(b) protein are used to assess the presence of perturbations (such as deletions, insertions,

point mutations etc.) in those regions (such as regions containing one or more motifs). Exemplary assays utilize antibodies

or T cells targeting 191P4D12(b)-related proteins comprising the amino acid residues of one or more of the biological motifs

contained within a 191P4D12(b) polypeptide sequence in order to evaluate the characteristics of this region in normal versus

cancerous tissues or to elicit an immune response to the epitope. Alternatively, 191P4D12(b)-related proteins that contain

the amino acid residues of one or more of the biological motifs in a 191P4D12(b) protein are used to screen for factors that

interact with that region of 191P4D12(b).

191P4D12(b) protein fragments/subsequences are particularly useful in generating and characterizing domain-specific

antibodies antibodies recognizing an extracellular or intracellular epitope of a 191P4D12(b) protein), for identifying agents or

cellular factors that bind to 191P4D12(b) or a particular structural domain thereof, and in various therapeutic and diagnostic

contexts, including but not limited to diagnostic assays, cancer vaccines and methods of preparing such vaccines.

Proteins encoded by the 191P4D12(b) genes, or by analogs, homologs or fragments thereof, have a variety of

00 uses, including but not limited to generating antibodies and in methods for identifying ligands and other agents and cellular

O constituents that bind to a 191P4D12(b) gene product. Antibodies raised against a 191P4D12(b) protein or fragment thereof

CN are useful in diagnostic and prognostic assays, and imaging methodologies in the management of human cancers

characterized by expression of 191P4D12(b) protein, such as those listed in Table 1. Such antibodies can be expressed

intracellularly and used in methods of treating patients with such cancers. 191P4D12(b)-related nucleic acids or proteins are

also used in generating HTL or CTL responses.

C Various immunological assays useful for the detection of 191P4D12(b) proteins are used, including but not limited to

various types of radioimmunoassays, enzyme-linked immunosorbent assays (ELISA), enzyme-linked immunofluorescent assays

(ELIFA), immunocytochemical methods, and the like. Antibodies can be labeled and used as immunological imaging reagents

si capable of detecting 191P4D12(b)-expressing cells in radioscintigraphic imaging methods). 191P4D12(b) proteins are also

c particularly useful in generating cancer vaccines, as further described herein.

000 IV.) 191P4D12(b) Antibodies

Another aspect of the invention provides antibodies that bind to 191P4D12(b)-related proteins. Preferred antibodies

specifically bind to a 191P4D12(b)-related protein and do not bind (or bind weakly) to peptides or proteins that are not

191P4D12(b)-related proteins under physiological conditions. In this context, examples of physiological conditions include: 1)

phosphate buffered saline; 2) Tris-buffered saline containing 25mM Tris and 150 mM NaCI; or normal saline NaCI); 4)

animal serum such as human serum; or, 5) a combination of any of 1) through these reactions preferably taking place at pH

altematively in a range of pH 7.0 to 8.0, or altematively in a range of pH 6.5 to 8.5; also, these reactions taking place at a

temperature between 4°C to 370C. For example, antibodies that bind 191P4D12(b) can bind 191P4D12(b)-related proteins such

as the homologs or analogs thereof.

191P4D12(b) antibodies of the invention are particularly useful in cancer (see, Table I) diagnostic and

prognostic assays, and imaging methodologies. Similarly, such antibodies are useful in the treatment, diagnosis, and/or

prognosis of other cancers, to the extent 191P4D12(b) is also expressed or overexpressed in these other cancers.

Moreover, intracellularly expressed antibodies single chain antibodies) are therapeutically useful in treating cancers in

which the expression of 191P4D12(b) is involved, such as advanced or metastatic prostate cancers.

The invention also provides various immunological assays useful for the detection and quantification of 191P4D12(b)

and mutant 191P4D12(b)-related proteins. Such assays can comprise one or more 191P4D12(b) antibodies capable of

recognizing and binding a 191P4012(b)-related protein, as appropriate. These assays are performed within various

immunological assay formats well known in the art, including but not limited to various types of radioimmunoassays, enzyme-

linked immunosorbent assays (ELSA), enzyme-linked immunofluorescent assays (ELIFA), and the like.

Immunological non-antibody assays of the invention also comprise T cell immunogenicity assays (inhibitory or

stimulatory) as well as major histocompatibility complex (MHC) binding assays.

In addition, immunological imaging methods capable of detecting prostate cancer and other cancers expressing

191P4012(b) are also provided by the invention, including but not limited to radioscinligraphic imaging methods using labeled

191P4D12(b) antibodies. Such assays are clinically useful in the detection, monitoring, and prognosis of 191P4D12(b) expressing

cancers such as prostate cancer.

191P4D12(b) antibodies are also used in methods for purifying a 191P4D12(b)-related protein and for isolating

191P4D12(b) homologues and related molecules. For example, a method of purifying a 191P4D12(b)-related protein comprises

incubating a 191P4D12(b) antibody, which has been coupled to a solid matrix, with a lysate or other solution containing a

191P4D12(b)-related protein under conditions that permit the 191P4D12(b) antibody to bind to the 191P4D12(b)-related protein;

washing the solid matrix to eliminate impurities; and eluting the 191P4D12(b)-related protein from the coupled antibody. Other

uses of 191P4D12(b) antibodies in accordance with the invention include generating anti-idiotypic antibodies that mimic a

00 191P4D12(b) protein.

SVarious methods for the preparation of antibodies are well known in the art. For example, antibodies can be prepared

by Immunizing a suitable mammalian host using a 191P4D12(b)-related protein, peptide, or fragment, in isolated or

c immunoconjugated form (Antibodies: A Laboratory Manual, CSH Press, Eds., Harlow, and Lane (1988); Harlow, Antibodies, Cold

Spring Harbor Press, NY (1989)). In addition, fusion proteins of 191P4D12(b) can also be used, such as a 191P4D12(b) GST-

0 fusion protein. In a particular embodiment, a GST fusion protein comprising all or most of the amino acid sequence of Figure 2 or

Figure 3 is produced, then used as an immunogen to generate appropriate antibodies. In another embodiment, a 191P4012(b)-

related protein is synthesized and used as an immunogen.

In addition, naked DNA immunization techniques known in the art are used (with or without purified 191P4D12(b)-

related protein or 191P4D12(b) expressing cells) to generate an immune response to the encoded immunogen (for review, see

0 Donnelly et al., 1997, Ann. Rev. Immunol. 15: 617-648).

00 The amino acid sequence of a 191P4D12(b) protein as shown in Figure 2 or Figure 3 can be analyzed to select specific

regions of the 191P4D12(b) protein for generating antibodies. For example, hydrophobicity and hydrophilicity analyses of a

CN 191P4D12(b) amino acid sequence are used to identify hydrophilic regions in the 191P4D12(b) structure. Regions of a

191P4D12(b) protein that show immunogenic structure, as well as other regions and domains, can readily be identified using

various other methods known in the art, such as Chou-Fasman, Gamier-Robson, Kyte-Doolittle, Eisenberg, Karplus-Schultz or

Jameson-Wolf analysis. Hydrophilicity profiles can be generated using the method of Hopp, T.P. and Woods, 1981,

Proc. Natl. Acad. Sci. U.S.A. 78:3824-3828. Hydropathlcity profiles can be generated using the method of Kyte, J. and

Doolittle, 1982, J. Mol. Biol. 157:105-132. Percent Accessible Residues profiles can be generated using the

method of Janin 1979, Nature 277:491-492. Average Flexibility profiles can be generated using the method of Bhaskaran

Ponnuswamy 1988, Int. J. Pept. Protein Res. 32:242-255. Beta-turn profiles can be generated using the method of

Deleage, Roux 1987, Protein Engineering 1:289-294. Thus, each region identified by any of these programs or methods

is within the scope of the present invention. Methods for the generation of 191P4D12(b) antibodies are further illustrated by way

of the examples provided herein. Methods for preparing a protein or polypeptide for use as an immunogen are well known in the

art. Also well known in the art are methods for preparing immunogenic conjugates of a protein with a carrier, such as BSA, KLH or

other carrier protein. In some circumstances, direct conjugation using, for example, carbodiimide reagents are used; in other

instances linking reagents such as those supplied by Pierce Chemical Co., Rockford, IL, are effective. Administration of a

191P4D12(b) immunogen is often conducted by injection over a suitable time period and with use of a suitable adjuvant, as is

understood in the art. During the immunization schedule, titers of antibodies can be taken to determine adequacy of antibody

formation.

191P4D12(b) monoclonal antibodies can be produced by various means well known in the art. For example,

immortalized cell lines that secrete a desired monoclonal antibody are prepared using the standard hybridoma technology of

Kohler and Milstein or modifications that immortalize antibody-producing B cells, as is generally known. Immortalized cell lines

that secrete the desired antibodies are screened by immunoassay in which the antigen is a 191P4D12(b)-related protein. When

the appropriate immortalized cell culture is identified, the cells can be expanded and antibodies produced either from in vitro

cultures or from ascites fluid.

The antibodies or fragments of the invention can also be produced, by recombinant means. Regions that bind

specifically to the desired regions of a 191P4D12(b) protein can also be produced in the context of chimeric or complementarity-

determining region (CDR) grafted antibodies of multiple species origin. Humanized or human 191P4D12(b) antibodies can also

be produced, and are preferred for use in therapeutic contexts. Methods for humanizing murine and other non-human antibodies,

by substituting one or more of the non-human antibody CDRs for corresponding human antibody sequences, are well known (see

00 for example, Jones et al., 1986, Nature 321: 522-525; Riechmann et 1988, Nature 332: 323-327; Verhoeyen et al., 1988,

Science 239: 1534-1536). See also, Carter et 1993, Proc. Natl. Acad. Sd. USA 89: 4285 and Sims et al., 1993, J. Immunol.

CN 151:2296.

Methods for producing fully human monoclonal antibodies include phage display and transgenic methods (for review,

see Vaughan et al., 1998, Nature Biotechnology 16: 535-539). Fully human 191P4D12(b) monoclonal antibodies can be

generated using cloning technologies employing large human Ig gene combinatorial libraries phage display) (Griffiths and

1 Hoogenboom, Building an in vitro immune system: human antibodies from phage display libraries. In: Protein Engineering of

Antibody Molecules for Prophylactic and Therapeutic Applications in Man, Clark, M. Nottingham Academic, pp 45-64 (1993);

I> Burton and Barbas, Human Antibodies from combinatorial libraries. Id., pp 65-82). Fully human 191P4D12(b) monoclonal

K antibodies can also be produced using transgenic mice engineered to contain human Immunoglobulin gene loci as described in

PCT Patent Application W098124893, Kucherlapati and Jakobovits et al., published December 3, 1997 (see also, Jakobovits,

CN 1998, Exp. Opin. Invest. Drugs 607-614; U.S. patents 6,162,963 issued 19 December 2000; 6,150,584 issued 12 November000 2000; and, 6,114598 issued 5 September 2000). This method avoids the in vitro manipulation required with phage display

technology and efficiently produces high affinity authentic human antibodies.

Reactivity of 191P4D12(b) antibodies with a 191P4D12(b)-related protein can be established by a number of well

known means, including Western blot, Immunoprecipitation, ELISA, and FACS analyses using, as appropriate, 191P4D12(b)-

related proteins, 191P4D12(b)-expressing cells or extracts thereof. A 191P4D12(b) antibody or fragment thereof can be

labeled with a detectable marker or conjugated to a second molecule. Suitable detectable markers include, but are not

limited to, a radioisotope, a fluorescent compound, a bioluminescent compound, chemiluminescent compound, a metal

chelator or an enzyme. Further, bi-specific antibodies specific for two or more 191P4D12(b) epitopes are generated using

methods generally known in the art. Homodimeric antibodies can also be generated by cross-linking techniques known in

the art Wolff et al., Cancer Res. 53: 2560-2565).

191P4D12(b) Cellular Immune Responses

The mechanism by which T cells recognize antigens has been delineated. Efficacious peptide epitope vaccine

compositions of the invention induce a therapeutic or prophylactic immune responses in very broad segments of the world-

wide population. For an understanding of the value and efficacy of compositions of the invention that induce cellular immune

responses, a brief review of immunology-related technology is provided.

A complex of an HLA molecule and a peptidic antigen acts as the ligand recognized by HLA-restricted T cells

(Buus, S. etal., Cell 47:1071, 1986; Babbitt, B. P. et al., Nature 317:359, 1985; Townsend, A. and Bodmer, Annu. Rev.

Immunol. 7:601, 1989; Germain, R. Annu. Rev. Immunol. 11:403,1993). Through the study of single amino acid

substituted antigen analogs and the sequencing of endogenously bound, naturally processed peptides, critical residues that

correspond to motifs required for specific binding to HLA antigen molecules have been identified and are set forth in Table IV

(see also, Southwood, et al., J. Immunol. 160:3363,1998; Rammensee, et al., Immunogenetics 41:178, 1995;

Rammensee et al., SYFPEITHI, access via World Wide Web at URL (134.2.96.221/scrpts.hlaserver.dll/home.htm); Sette, A.

and Sidney, J. Curr. Opin. Immunol. 10:478, 1998; Engelhard, V. Curr. Opin. Immunol. 6:13, 1994; Sette, A. and Grey, H.

Curr. Opin. Immunol. 4:79,1992; Sinigaglia, F. and Hammer, J. Curr. Biol. 6:52, 1994; Ruppert et al., Cell 74:929-937,

1993; Kondo et al., J. Immunof. 155:4307-4312, 1995; Sidney et al., J. Immunol. 157:3480-3490, 1996; Sidney et al., Human

Immunol. 45:79-93, 1996; Sette, A. and Sidney, J. Immunogenetics 1999 Nov; 50(3-4):201-12, Review).

Furthermore, x-ray crystallographic analyses of HLA-peptide complexes have revealed pockets within the peptide

binding cleft/groove of HLA molecules which accommodate, in an allele-specific mode, residues borne by peptide ligands;

these residues in turn determine the HLA binding capacity of the peptides in which they are present. (See, Madden,

D.R. Annu. Rev. Immunol. 13:587,1995; Smith, et Immunity 4:203, 1996; Fremont et al., Immunity 8:305,1998; Stem et

00 Structure 2:245, 1994; Jones, E.Y. Curr. Opin. Immunol. 9:75,1997; Brown, J. H. et Nature 364:33, 1993; Guo, H. C.O

et al., Proc. Natl. Acad. Sci. USA 90:8053, 1993; Guo, H. C. et Nature 360:364, 1992; Silver, M. L. et al., Nature 360:367,

S1992; Matsumura, M. et Science 257:927, 1992; Madden et al., Cell 70:1035, 1992; Fremont, D. H. et al., Science

c 257:919, 1992; Saper, M. Bjorkman, P. J. and Wiley, D. J. Mol. Biol. 219:277, 1991.)

Accordingly, the definition of class I and class II allele-specific HLA binding motifs, or class I or class II supermotifs

0 allows identification of regions within a protein that are correlated with binding to particular HLA antigen(s).

Thus, by a process of HLA motif Identification, candidates for epitope-based vaccines have been identified; such

candidates can be further evaluated by HLA-peptide binding assays to determine binding affinity and/or the time period of

association of the epitope and its corresponding HLA molecule. Additional confirmatory work can be performed to select,

S amongst these vaccine candidates, epitopes with preferred characteristics in terms of population coverage, and/or

0 immunogenicity.

00 Various strategies can be utilized to evaluate cellular immunogeniclty, including:

S1) Evaluation of primary T cell cultures from normal individuals (see, Wentworth, P. A. et al., Mol. Immunol.

CN" 32:603, 1995; Celis, E. et al., Proc. Natl. Acad. Sci. USA 91:2105, 1994; Tsai, V. et al., J. Immunol. 158:1796,1997;

Kawashima, I. et al., Human Immunol. 59:1, 1998). This procedure Involves the stimulation of peripheral blood lymphocytes

(PBL) from normal subjects with a test peptide in the presence of antigen presenting cells in vitro over a period of several

weeks. T cells specific for the peptide become activated during this time and are detected using, a lymphokine- or

51Cr-release assay Involving peptide sensitized target cells.

2) Immunization of HLA transgenic mice (see, Wentworth, P. A. et J. Immunol. 26:97, 1996; Wentworth, P.

A. et Int. Immunol. 8:651, 1996; Alexander, J. et J. Immunol. 159:4753, 1997). For example, in such methods

peptides in incomplete Freund's adjuvant are administered subcutaneously to HLA transgenic mice. Several weeks following

immunization, splenocytes are removed and cultured in vitro in the presence of test peptide for approximately one week.

Peptide-specific T cells are detected using, a 51Cr-release assay involving peptide sensitized target cells and target

cells expressing endogenously generated antigen.

3) Demonstration of recall T cell responses from immune individuals who have been either effectively vaccinated

and/or from chronically ill patients (see, Rehermann, B. etal., J. Exp. Med. 181:1047, 1995; Doolan, D. L. e al.,

Immunity 7:97, 1997; Bertoni, R. et J. Clin. Invest. 100:503,1997; Threlkeld, S. C. et J. Immunol. 159:1648, 1997;

Diepolder, H. M. et J. Virol. 71:6011, 1997). Accordingly, recall responses are detected by culturing PBL from subjects

that have been exposed to the antigen due to disease and thus have generated an immune response "naturally", or from

patients who were vaccinated against the antigen. PBL from subjects are cultured in vitro for 1-2 weeks in the presence of

test peptide plus antigen presenting cells (APC) to allow activation of "memory" T cells, as compared to "naive" T cells. At

the end of the culture period, T cell activity is detected using assays including 5 1Cr release involving peptide-sensitized

targets, T cell proliferation, or lymphokine release.

VI.) 191P4D12(b) Transgenic Animals

Nucleic acids that encode a 191P4D12(b)-related protein can also be used to generate either transgenic animals or

"knock out" animals that, in turn, are useful in the development and screening of therapeutically useful reagents. In

accordance with established techniques, cDNA encoding 191P4D12(b) can be used to clone genomic DNA that encodes

191P4D12(b). The cloned genomic sequences can then be used to generate transgenic animals containing cells that

express DNA that encode 191P4D12(b). Methods for generating transgenic animals, particularly animals such as mice or

rats, have become conventional in the art and are described, for example, in U.S. Patent Nos. 4,736,866 issued 12 April

S 1988, and 4,870,009 issued 26 September 1989. Typically, particular cells would be targeted for 191P4D12(b) transgene

0 incorporation with tissue-specific enhancers.

CK Transgenic animals that include a copy of a transgene encoding 191P4D12(b) can be used to examine the effect

of increased expression of DNA that encodes 191P4D12(b). Such animals can be used as tester animals for reagents

thought to confer protection from, for example, pathological conditions associated with Its overexpression. In accordance

with this aspect of the invention, an animal is treated with a reagent and a reduced incidence of a pathological condition,

CN compared to untreated animals that bear the transgene, would indicate a potential therapeutic intervention for the

pathological condition.

Alternatively, non-human homologues of 191P4D12(b) can be used to construct a 191P4D12(b) "knock out" animal

that has a defective or altered gene encoding 191P4D12(b) as a result of homologous recombination between the

C endogenous gene encoding 191P4D12(b) and altered genomic DNA encoding 191P4D12(b) introduced into an embryonic

CK cell of the animal. For example, cDNA that encodes 191P4D12(b) can be used to clone genomic DNA encoding00

191P4012(b) in accordance with established techniques. A portion of the genomic DNA encoding 191P4D12(b) can be

deleted or replaced with another gene, such as a gene encoding a selectable marker that can be used to monitor integration.

Typically, several kilobases of unaltered flanking DNA (both at the 5' and 3' ends) are included in the vector (see, e.g.,

Thomas and Capecchi, Cell, 51:503 (1987) for a description of homologous recombination vectors). The vector is introduced

into an embryonic stem cell line by electroporation) and cells in which the introduced DNA has homologously

recombined with the endogenous DNA are selected (see, Li et al., Cell, 69:915 (1992)). The selected cells are then

injected into a blastocyst of an animal a mouse or rat) to form aggregation chimeras (see, Bradley, in

Teratocarcinomas and Embryonic Stem Cells: A Practical Approach, E. J. Robertson, ed. (IRL, Oxford, 1987), pp. 113-152).

A chimeric embryo can then be implanted into a suitable pseudopregnant female foster animal, and the embryo brought to

term to create a "knock out" animal. Progeny harboring the homologously recombined DNA in their germ cells can be

identified by standard techniques and used to breed animals in which all cells of the animal contain the homologously

recombined DNA. Knock out animals can be characterized, for example, for their ability to defend against certain

pathological conditions or for their development of pathological conditions due to absence of a 191 P4D12(b) polypeptide.

VII.) Methods for the Detection of 191P4D12(b)

Another aspect of the present invention relates to methods for detecting 191P4D12(b) polynucleotides and

191P4D12(b)-related proteins, as well as methods for identifying a cell that expresses 191P4D12(b). The expression profile of

191P4D12(b) makes it a diagnostic marker for metastasized disease. Accordingly, the status of 191P4D12(b) gene products

provides information useful for predicting a variety of factors including susceptibility to advanced stage disease, rate of

progression, and/or tumor aggressiveness. As discussed in detail herein, the status of 191P4D12(b) gene products in patient

samples can be analyzed by a variety protocols that are well known In the art including immunohistochemical analysis, the variety

of Northem blotting techniques including in situ hybridization, RT-PCR analysis (for example on laser capture micro-dissected

samples), Western blot analysis and tissue array analysis.

More particularly, the invention provides assays for the detection of 191P4D12(b) polynudeotides in a biological

sample, such as serum, bone, prostate, and other tissues, urine, semen, cell preparations, and the like. Detectable 191P4D12(b)

polynucleotides include, for example, a 191P4D12(b) gene or fragment thereof, 191P4D12(b) mRNA, alternative splice variant

191P4D12(b) mRNAs, and recombinant DNA or RNA molecules that contain a 191P4D12(b) polynucleotide. A number of

methods for amplifying andlor detecting the presence of 191P4D12(b) polynucleotides are well known in the art and can be

employed in the practice of this aspect of the invention.

In one embodiment, a method for detecting a 191P4D12(b) mRNA in a biological sample comprises producing cDNA

from the sample by reverse transcription using at least one primer; amplifying the cDNA so produced using a 191P4D12(b)

00 polynucleotides as sense and antisense primers to amplify 191P4D12(b) cDNAs therein; and detecting the presence of the

amplified 191P4D12(b) cDNA. Optionally, the sequence of the amplified 191P4D12(b) cDNA can be determined.

In another embodiment, a method of detecting a 191P4D12(b) gene in a biological sample comprises first isolating

c genomic DNA from the sample; amplifying the Isolated genomic DNA using 191P4D12(b) polynucleotides as sense and

antisense primers; and detecting the presence of the amplified 191P4D12(b) gene. Any number of appropriate sense and

S antisense probe combinations can be designed from a 191P4D12(b) nucleolide sequence (see, Figure 2) and used for

this purpose.

The invention also provides assays for detecting the presence of a 191P4D12(b) protein in a tissue or other biological

sample such as serum, semen, bone, prostate, urine, cell preparations, and the like. Methods for detecting a 191P4D12(b)-

CKl related protein are also well known and include, for example, immunoprecipitation, immunohistochemical analysis, Western blot

0 analysis, molecular binding assays, ELISA, ELIFA and the like. For example, a method of detecting the presence of a

00 191P4D12(b)-related protein in a biological sample comprises first contacting the sample with a 191P4D12(b) antibody, a

S 191P4D12(b)-reactive fragment thereof, or a recombinant protein containing an antigen-binding region of a 191P4D12(b)

C1 antibody; and then detecting the binding of 191P4D12(b)-related protein in the sample.

Methods for Identifying a cell that expresses 191P4D12(b) are also within the scope of the invention. In one

embodiment, an assay for identifying a cell that expresses a 191P4D12(b) gene comprises detecting the presence of

191P4D12(b) mRNA in the cell. Methods for the detection of particular mRNAs in cells are well known and include, for example,

hybridization assays using complementary DNA probes (such as in situ hybridization using labeled 191 P4D12(b) riboprobes,

Northern blot and related techniques) and various nucleic acid amplification assays (such as RT-PCR using complementary

primers specific for 191P4D12(b), and other amplification type detection methods, such as, for example, branched DNA, SISBA,

TMA and the like). Alternatively, an assay for identifying a cell that expresses a 191P4D12(b) gene comprises detecting the

presence of 191P4D12(b)-related protein in the cell or secreted by the cell. Various methods for the detection of proteins are well

known in the art and are employed for the detection of 191P4D12(b)-related proteins and cells that express 191P4D12(b)-related

proteins.

191P4D12(b) expression analysis is also useful as a tool for identifying and evaluating agents that modulate

191P4D12(b) gene expression. For example, 191P4D12(b) expression is significantly upregulated in prostate cancer, and is

expressed in cancers of the tissues listed in Table I. Identification of a molecule or biological agent that inhibits 191P4D12(b)

expression or over-expression in cancer cells is of therapeutic value. For example, such an agent can be identified by using

a screen that quantifies 191P4D12(b) expression by RT-PCR, nucleic acid hybridization or antibody binding.

VIII.) Methods for Monitoring the Status of 191P4D12(b)-related Genes and Their Products

Oncogenesis is known to be a multistep process where cellular growth becomes progressively dysregulated and

cells progress from a normal physiological state to precancerous and then cancerous states (see, Alers et al., Lab

Invest. 77(5): 437-438 (1997) and Isaacs et al., Cancer Surv. 23:19-32 (1995)). In this context, examining a biological

sample for evidence of dysregulated cell growth (such as aberrant 191P4D12(b) expression in cancers) allows for early

detection of such aberrant physiology, before a pathologic state such as cancer has progressed to a stage that therapeutic

options are more limited and or the prognosis is worse. In such examinations, the status of 191P4D12(b) in a biological

sample of interest can be compared, for example, to the status of 191P4D12(b) in a corresponding normal sample a

sample from that individual or alternatively another individual that is not affected by a pathology). An alteration in the status

of 191P4D12(b) in the biological sample (as compared to the normal sample) provides evidence of dysregulated cellular

growth. In addition to using a biological sample that is not affected by a pathology as a normal sample, one can also use a

00 predetermined normative value such as a predetermined normal level of mRNA expression (see, Grever et al., J. Comp.

S Neurol. 1996 Dec 9; 376(2): 306-14 and U.S. Patent No. 5,837,501) to compare 191P4D12(b) status in a sample.

CK1 The term "status" in this context Is used according to its art accepted meaning and refers to the condition or state of a

gene and its products. Typically, skilled artisans use a number of parameters to evaluate the condition or state of a gene and Its

products. These include, but are not limited to the location of expressed gene products (including the location of 191P4D12(b)

O expressing cells) as well as the level, and biological activity of expressed gene products (such as 191P4012(b) mRNA,

CI polynucleotides and polypeptides). Typically, an alteration in the status of 191P4D12(b) comprises a change in the location

of 191P4D12(b) and/or 191P4D12(b) expressing cells and/or an increase in 191P4D12(b) mRNA and/or protein expression.

191P4D12(b) status in a sample can be analyzed by a number of means well known in the art, including without

aC limitation, immunohistochemical analysis, in situ hybridization, RT-PCR analysis on laser capture micro-dissected samples,

Western blot analysis, and tissue array analysis. Typical protocols for evaluating the status of a 191P4D12(b) gene and gene

rC products are found, for example in Ausubel et al. eds., 1995, Current Protocols In Molecular Biology, Units 2 (Northern000 Blotting), 4 (Southern Blotting), 15 (Immunoblotting) and 18 (PCR Analysis). Thus, the status of 191P4D12(b) in a biological

sample is evaluated by various methods utilized by skilled artisans including, but not limited to genomic Southern analysis (to

examine, for example perturbations in a 191P4D12(b) gene), Northern analysis and/or PCR analysis of 191P4D12(b) mRNA

(to examine, for example alterations in the polynucleotide sequences or expression levels of 191P4D12(b) mRNAs), and,

Western and/or immunohistochemical analysis (to examine, for example alterations in polypeptide sequences, alterations in

polypeptide localization within a sample, alterations in expression levels of 191P4D12(b) proteins and/or associations of

191P4D12(b) proteins with polypeptide binding partners). Detectable 191P4D12(b) polynucleotides include, for example, a

191P4D12(b) gene or fragment thereof, 191P4D12(b) mRNA, alternative splice variants, 191P4D12(b) mRNAs, and recombinant

DNA or RNA molecules containing a 191P4D12(b) polynucleotide.

The expression profile of 191P4D12(b) makes it a diagnostic marker for local and/or metastasized disease, and

provides information on the growth or oncogenic potential of a biological sample. In particular, the status of 191P4D12(b) provides

information useful for predicting susceptibility to particular disease stages, progression, and/or tumor aggressiveness. The

invention provides methods and assays for determining 191P4D12(b) status and diagnosing cancers that express 191P4D12(b),

such as cancers of the tissues listed in Table I. For example, because 191P4D12(b) mRNA is so highly expressed in prostate and

other cancers relative to normal prostate tissue, assays that evaluate the levels of 191P4D12(b) mRNA transcripts or proteins in a

biological sample can be used to diagnose a disease associated with 191P4D12(b) dysregulation, and can provide prognostic

information useful in defining appropriate therapeutic options.

The expression status of 191P4D12(b) provides information including the presence, stage and location of dysplastic,

precancerous and cancerous cells, predicting susceptibility to various stages of disease, and/or for gauging tumor

aggressiveness. Moreover, the expression profile makes it useful as an imaging reagent for metastasized disease.

Consequently, an aspect of the invention is directed to the various molecular prognostic and diagnostic methods for examining the

status of 191P4D12(b) in biological samples such as those from individuals suffering from, or suspected of suffering from a

pathology characterized by dysregulated cellular growth, such as cancer.

As described above, the status of 191P4D12(b) in a biological sample can be examined by a number of well-known

procedures in the art. For example, the status of 191P4012(b) in a biological sample taken from a specific location in the

body can be examined by evaluating the sample for the presence or absence of 191P4D12(b) expressing cells those

that express 191P4D12(b) mRNAs or proteins). This examination can provide evidence of dysregulated cellular growth, for

example, when 191P4D12(b)-expressing cells are found in a biological sample that does not normally contain such cells

(such as a lymph node), because such alterations in the status of 191P4D12(b) in a biological sample are often associated

with dysregulated cellular growth. Specifically, one indicator of dysregulated cellular growth is the metastases of cancer cells

from an organ of origin (such as the prostate) to a different area of the body (such as a lymph node). In this context,

00 evidence of dysregulated cellular growth is important for example because occult lymph node metastases can be detected in

a substantial proportion of patients with prostate cancer, and such metastases are associated with known predictors of

S disease progression (see, Murphy et al., Prostate 42(4): 315-317 (2000);Su et al., Semin. Surg. Oncol. 18(1): 17-28

(2000) and Freeman et al., J Urol 1995 Aug 154(2 Pt 1):474-8).

In one aspect, the invention provides methods for monitoring 191P4D12(b) gene products by determining the

0 status of 191P4D12(b) gene products expressed by cells from an individual suspected of having a disease associated with

dysregulated cell growth (such as hyperplasia or cancer) and then comparing the status so determined to the status of

191P4D12(b) gene products in a corresponding normal sample. The presence of aberrant 191P4012(b) gene products in

S the test sample relative to the normal sample provides an indication of the presence of dysregulated cell growth within the

cells of the individual.

In another aspect, the invention provides assays useful in determining the presence of cancer in an individual,

00 comprising detecting a significant increase in 191P4D12(b) mRNA or protein expression in a test cell or tissue sample

relative to expression levels in the corresponding normal cell or tissue. The presence of 191P4D12(b) mRNA can, for

Cl example, be evaluated in tissues including but not limited to those listed in Table I. The presence of significant 191P4D12(b).

expression in any of these tissues is useful to indicate the emergence, presence and/or severity of a cancer, since the

corresponding normal tissues do not express 191P4D12(b) mRNA or express it at lower levels.

In a related embodiment, 191P4D12(b) status is determined at the protein level rather than at the nucleic acid level. For

example, such a method comprises determining the level of 191P4D12(b) protein expressed by cells in a test tissue sample and

comparing the level so determined to the level of 191P4D12(b) expressed in a corresponding normal sample. In one

embodiment, the presence of 191P4D12(b) protein is evaluated, for example, using immunohistochemical methods.

191P4D12(b) antibodies or binding partners capable of detecting 191P4D12(b) protein expression are used in a variety of assay

formats well known in the art for this purpose.

In a further embodiment, one can evaluate the status of 191P4D12(b) nudeotide and amino acid sequences in a

biological sample in order to identify perturbations in the structure of these molecules. These perturbations can include insertions,

deletions, substitutions and the like. Such evaluations are useful because perturbations in the nudeotide and amino acid

sequences are observed in a large number of proteins associated with a growth dysregulated phenotype (see, Marrogi et

at., 1999, J. Cutan. Pathol. 26(8):369-378). For example, a mutation in the sequence of 191P4D12(b) may be indicative of the

presence or promotion of a tumor. Such assays therefore have diagnostic and predictive value where a mutation in 191P4D12(b)

indicates a potential loss of function or increase in tumor growth.

A wide variety of assays for observing perturbations in nudeotide and amino acid sequences are well known in the art

For example, the size and structure of nuceic acid or amino acd sequences of 191P4D12(b) gene products are observed by the

Northern, Southern, Western, PCR and DNA sequencing protocols discussed herein. In addition, other methods for observing

perturbations in nucleotide and amino acid sequences such as single strand conformation polymorphism analysis are well known

in the art (see, U.S. Patent Nos. 5,382,510 issued 7 September 1999, and 5,952,170 issued 17 January 1995).

Additionally, one can examine the methylation status of a 191P4D12(b) gene in a biological sample. Aberrant

demethylation andlor hypermethylation of CpG islands in gene 5' regulatory regions frequently occurs in immortalized and

transformed cells, and can result in altered expression of various genes. For example, promoter hypermethylation of the pi-class

glutathione S-transferase (a protein expressed in normal prostate but not expressed in >90% of prostate carcinomas)

appears to permanently silence transcription of this gene and is the most frequently detected genomic alteration in prostate

carcinomas (De Marzo et al., Am. J. Pathol. 155(6): 1985-1992 (1999)). In addition, this alteration is present in at least

of cases of high-grade prostatic intraepithelial neoplasia (PIN) (Brooks et al., Cancer Epidemiol. Biomarkers Prev., 1998,

7:531-536). In another example, expression of the LAGE-I tumor specific gene (which is not expressed in normal prostate

;0 but is expressed in 25-50% of prostate cancers) is Induced by deoxy-azacytidine in lymphoblastoid cells, suggesting that

tumoral expression is due to demethylation (Lethe et al., Int. J. Cancer 76(6): 903-908 (1998)). A variety of assays for

examining methylation status of a gene are well known in the art For example, one can utilize, in Southern hybridization

S approaches, methylation-sensitive restriction enzymes that cannot cleave sequences that contain methylated CpG sites to assess

the methylation status of CpG islands. In addition, MSP (methylation specific PCR) can rapidly profile the methylation status of all

the CpG sites present in a CpG island of a given gene. This procedure involves initial modification of DNA by sodium blsulfite

(which will convert all unmethylated cytosines to uracil) followed by amplification using primers specific for methylated versus

unmethylated DNA. Protocols involving methylation interference can also be found for example in Current Protocols In Molecular

Biology, Unit 12, Frederick M. Ausubel et al. eds., 1995.C Gene amplification is an additional method for assessing the status of 191P4D12(b). Gene amplification is

measured in a sample directly, for example, by conventional Southern blotting or Northern blotting to quantitate the

00 transcription of mRNA (Thomas, 1980, Proc. Natl. Acad. Sci. USA, 77:5201-5205), dot blotting (DNA analysis), or in situ

hybridization, using an appropriately labeled probe, based on the sequences provided herein. Alternatively, antibodies are

CK" employed that recognize specific duplexes, including DNA duplexes, RNA duplexes, and DNA-RNA hybrid duplexes or

DNA-protein duplexes. The antibodies in turn are labeled and the assay carried out where the duplex is bound to a surface,

so that upon the formation of duplex on the surface, the presence of antibody bound to the duplex can be detected.

Biopsied tissue or peripheral blood can be conveniently assayed for the presence of cancer cells using for example,

Northern, dot blot or RT-PCR analysis to detect 191P4D12(b) expression. The presence of RT-PCR amplifiable 191P4D12(b)

mRNA provides an indication of the presence of cancer. RT-PCR assays are well known in the art. RT-PCR detection assays for

tumor cells in peripheral blood are currently being evaluated for use in the diagnosis and management of a number of human solid

tumors. In the prostate cancer field, these include RT-PCR assays for the detection of cells expressing PSA and PSM (Verkaik et

al., 1997, Urol. Res. 25:373-384; Ghossein et al., 1995, J. Clin. Oncol. 13:1195-2000; Heston etal., 1995, Clin. Chem. 41:1687-

1688).

A further aspect of the invention is an assessment of the susceptibility that an individual has for developing cancer. In

one embodiment, a method for predicting susceptibility to cancer comprises detecting 191P4D12(b) mRNA or 191P4D12(b)

protein in a tissue sample, its presence indicating susceptibility to cancer, wherein the degree of 191P4D12(b) mRNA expression

correlates to the degree of susceptibility. In a specific embodiment, the presence of 191P4D12(b) in prostate or other tissue is

examined, with the presence of 191P4D12(b) in the sample providing an indication of prostate cancer susceptibility (or the

emergence or existence of a prostate tumor). Similarly, one can evaluate the integrity 191P4D12(b) nuceotide and amino acid

sequences in a biological sample, in order to identify perturbations in the structure of these molecules such as insertions,

deletions, substitutions and the like. The presence of one or more perturbations in 191P4D12(b) gene products in the sample is

an indication of cancer susceptibility (or the emergence or existence of a tumor).

The invention also comprises methods for gauging tumor aggressiveness. In one embodiment, a method for gauging

aggressiveness of a tumor comprises determining the level of 191P4D12(b) mRNA or 191P4D12(b) protein expressed by tumor

cells, comparing the level so determined to the level of 191P4D12(b) mRNA or 191P4D12(b) protein expressed in a

corresponding normal tissue taken from the same individual or a normal tissue reference sample, wherein the degree of191P4D12(b) mRNA or 191 P4D12(b) protein expression in the tumor sample relative to the normal sample indicates the degree

of aggressiveness. In a specific embodiment, aggressiveness of a tumor is evaluated by determining the extent to which

191P4D12(b) is expressed in the tumor cells, with higher expression levels indicating more aggressive tumors. Anotherembodiment is the evaluation of the integrity of 191P4D12(b) nudeotide and amino acid sequences in a biological sample, in

order to identify perturbations in the structure of these molecules such as insertions, deletions, substitutions and the like. The

presence of one or more perturbations indicates more aggressive tumors.

C0 Another embodiment of the invention is directed to methods for observing the progression of a malignancy in an

S individual over time. In one embodiment, methods for observing the progression of a malignancy in an individual over time

comprise determining the level of 191P4D12(b) mRNA or 191P4D12(b) protein expressed by cells in a sample of the tumor,

comparing the level so determined to the level of 191P4D12(b) mRNA or 191P4D12(b) protein expressed in an equivalent tissue

S sample taken from the same individual at a different time, wherein the degree of 191P4D12(b) mRNA or 191P4D12(b) protein

expression in the tumor sample over time provides information on the progression of the cancer. In a specific embodiment, the

S progression of a cancer is evaluated by determining 191P4D12(b) expression in the tumor cells over time, where Increased

expression over time indicates a progression of the cancer. Also, one can evaluate the integrity 191P4D12(b) nudeotide and

amino acid sequences in a biological sample in order to identify perturbations in the structure of these molecules such as

insertions, deletions, substitutions and the like, where the presence of one or more perturbations indicates a progression of the

cancer.

CK1 The above diagnostic approaches can be combined with any one of a wide variety of prognostic and diagnostic00

protocols known in the art. For example, another embodiment of the invention is directed to methods for observing a coincidence

between the expression of 191P4D12(b) gene and 191P4D12(b) gene products (or perturbations in 191P4D12(b) gene and

191P4D12(b) gene products) and a factor that is associated with malignancy, as a means for diagnosing and prognosticating the

status of a tissue sample. A wide variety of factors associated with malignancy can be utilized, such as the expression of genes

associated with malignancy PSA, PSCA and PSM expression for prostate cancer etc.) as well as gross cytological

observations (see, Bocking et al., 1984, Anal. Quant Cytol. 6(2):74-88; Epstein, 1995, Hum. Pathol. 26(2):223-9; Thorson

et al., 1998, Mod. Pathol. 11(6):543-51; Baisden et al., 1999, Am. J. Surg. Pathol. 23(8):918-24). Methods for observing a

coincidence between the expression of 191P4D12(b) gene and 191P4D12(b) gene products (or perturbations in 191P4012(b)

gene and 191P4D12(b) gene products) and another factor that is associated with malignancy are useful, for example, because the

presence of a set of specific factors that coincide with disease provides information crucial for diagnosing and prognosticating the

status of a tissue sample.

In one embodiment, methods for observing a coincidence between the expression of 191P4D12(b) gene and

191P4D12(b) gene products (or perturbations in 191P4D12(b) gene and 191P4D12(b) gene products) and another factor

associated with malignancy entails detecting the overexpression of 191P4D12(b) mRNA or protein in a tissue sample, detecting

the overexpression of PSA mRNA or protein in a tissue sample (or PSCA or PSM expression), and observing a coincidence of

191P4D12(b) mRNA or protein and PSA mRNA or protein overexpression (or PSCA or PSM expression). In a specific

embodiment the expression of 191P4D12(b) and PSA mRNA in prostate tissue is examined, where the coincidence of

191P4D12(b) and PSA mRNA overexpression in the sample indicates the existence of prostate cancer, prostate cancer

susceptibility or the emergence or status of a prostate tumor.

Methods for detecting and quantifying the expression of 191P4D12(b) mRNA or protein are described herein, and

standard nudeic acid and protein detection and quantification technologies are well known in the art. Standard methods for the

detection and quantification of 191P4D12(b) mRNA include in situ hybridization using labeled 191P4D12(b) riboprobes, Northern

blot and related techniques using 191P4D12(b) polynucleotide probes, RT-PCR analysis using primers specific for 191P4D12(b),

and other amplification type detection methods, such as, for example, branched DNA, SISBA, TMA and the like. In a specific

embodiment, semi-quantitative RT-PCR is used to detect and quantify 191P4D12(b) mRNA expression. Any number of primers

capable of amplifying 191P4D12(b) can be used for this purpose, including but not limited to the various primer sets specifically

described herein. In a specific embodiment, polyclonal or monoclonal antibodies specifically reactive with the wild-type

191P4D12(b) protein can be used in an immunohistochemical assay of biopsied tissue.

IX.) Identification of Molecules That Interact With 191P4D12(b)000 The 191P4012(b) protein and nucleic acid sequences disclosed herein allow a skilled artisan to identify proteins,

01 small molecules and other agents that interact with 191P4D12(b), as well as pathways activated by 191P4D12(b) via any

one of a variety of art accepted protocols. For example, one can utilize one of the so-called interaction trap systems (also

referred to as the "two-hybrid assay"). In such systems, molecules interact and reconstitute a transcription factor which

directs expression of a reporter gene, whereupon the expression of the reporter gene is assayed. Other systems identify

L-i protein-protein interactions In vivo through reconstitution of a eukaryotic transcriptional activator, see, U.S. Patent Nos.

5,955,280 issued 21 September 1999, 5,925,523 issued 20 July 1999, 5,846,722 issued 8 December 1998 and 6,004,746

issued 21 December 1999. Algorithms are also available in the art for genome-based predictions of protein function (see,

Marcotte, et al., Nature 402: 4 November 1999, 83-86).

Cl Alternatively one can screen peptide libraries to identify molecules that interact with 191P4012(b) protein

L) sequences. In such methods, peptides that bind to 191P4D12(b) are identified by screening libraries that encode a random

S or controlled collection of amino acids. Peptides encoded by the libraries are expressed as fusion proteins of bacteriophage

0 coat proteins, the bacteriophage particles are then screened against the 191P4D12(b) protein(s).

Accordingly, peptides having a wide variety of uses, such as therapeutic, prognostic or diagnostic reagents, are

thus identified without any prior information on the structure of the expected ligand or receptor molecule. Typical peptide

libraries and screening methods that can be used to identify molecules that interact with 191P4D12(b) protein sequences are

disclosed for example in U.S. Patent Nos. 5,723,286 issued 3 March 1998 and 5,733,731 issued 31 March 1998.

Alternatively, cell lines that express 191 P4D12(b) are used to identify protein-protein interactions mediated by

191P4D12(b). Such interactions can be examined using immunoprecipitation techniques (see, Hamilton et al.

Biochem. Biophys. Res. Commun. 1999, 261:646-51). 191P4D12(b) protein can be immunoprecipitated from 191P4D12(b)-

expressing cell lines using anti-191P4D12(b) antibodies. Alternatively, antibodies against His-tag can be used in a cell line

engineered to express fusions of 191P4D12(b) and a His-tag (vectors mentioned above). The immunoprecipitated complex

can be examined for protein association by procedures such as Western blotting, 5S-methlonine labeling of proteins, protein

microsequencing, silver staining and two-dimensional gel electrophoresis.

Small molecules and ligands that interact with 191P4D12(b) can be identified through related embodiments of such

screening assays. For example, small molecules can be identified that interfere with protein function, including molecules

that interfere with 191P4D12(b)'s ability to mediate phosphorylation and de-phosphorylation, interaction with DNA or RNA

molecules as an indication of regulation of cell cycles, second messenger signaling or tumorigenesis. Similarly, small

molecules that modulate 191P4D12(b)-related ion channel, protein pump, or cell communication functions are identified and

used to treat patients that have a cancer that expresses 191P4D12(b) (see, Hille, Ionic Channels of Excitable

Membranes 2nd Ed., Sinauer Assoc., Sunderland, MA, 1992). Moreover, ligands that regulate 191P4D12(b) function can be

identified based on their ability to bind 191P4D12(b) and activate a reporter construct. Typical methods are discussed for

example in U.S. Patent No. 5,928,868 issued 27 July 1999, and include methods for forming hybrid ligands in which at least

one ligand is a small molecule. In an illustrative embodiment, cells engineered to express a fusion protein of 191P4D12(b)

and a DNA-binding protein are used to co-express a fusion protein of a hybrid ligand/small molecule and a cDNA library

transcriptional activator protein. The cells further contain a reporter gene, the expression of which is conditioned on the

proximity of the first and second fusion proteins to each other, an event that occurs only if the hybrid ligand binds to target

sites on both hybrid proteins. Those cells that express the reporter gene are selected and the unknown small molecule or

the unknown ligand is identified. This method provides a means of identifying modulators, which activate or inhibit

191P4D12(b).

An embodiment of this invention comprises a method of screening for a molecule that interacts with a 191P4D12(b)

amino acid sequence shown In Figure 2 or Figure 3, comprising the steps of contacting a population of molecules with a

0 0 191P4D12(b) amino acid sequence, allowing the population of molecules and the 191P4D12(b) amino acid sequence to

0 interact under conditions that facilitate an interaction, determining the presence of a molecule that interacts with the

191P4D12(b) amino acid sequence, and then separating molecules that do not interact with the 191P4D12(b) amino acid

sequence from molecules that do. In a specific embodiment, the method further comprises purifying, characterizing and

identifying a molecule that interacts with the 191P4D12(b) amino acid sequence. The identified molecule can be used to

modulate a function performed by 191P4D12(b). In a preferred embodiment, the 191P4D12(b) amino acid sequence is

contacted with a library of peptides.

X) Therapeutic Methods and Compositions

The identification of 191P4D12(b) as a protein that is normally expressed in a restricted set of tissues, but which is

also expressed in cancers such as those listed in Table I, opens a number of therapeutic approaches to the treatment of

00 such cancers.

SOf note, targeted antitumor therapies have been useful even when the targeted protein is expressed on normal

tissues, even vital normal organ tissues. A vital organ is one that is necessary to sustain life, such as the heart or colon. A

non-vital organ is one that can be removed whereupon the individual is still able to survive. Examples of non-vital organs are

ovary, breast, and prostate.

For example, Herceptin® is an FDA approved pharmaceutical that has as its active ingredient an antibody which is

immunoreactive with the protein variously known as HER2, HER2/neu, and erb-b-2. It is marketed by Genentech and has

been a commercially successful antitumor agent. Herceptin sales reached almost $400 million in 2002. Herceptin is a

treatment for HER2 positive metastatic breast cancer. However, the expression of HER2 is not limited to such tumors. The

same protein is expressed in a number of normal tissues. In particular, it is known that HER2/neu is present in normal

kidney and heart, thus these tissues are present in all human recipients of Herceptin. The presence of HER2/neu in normal

kidney is also confirmed by Latif, et al., B.J.U. International (2002) 89:5-9. As shown in this article (which evaluated

whether renal cell carcinoma should be a preferred indication for anti-HER2 antibodies such as Herceptin) both protein and

mRNA are produced in benign renal tissues. Notably, HER2/neu protein was strongly overexpressed in benign renal tissue.

Despite the fact that HER2/neu is expressed in such vital tissues as heart and kidney, Herceptin is a very useful, FDA

approved, and commercially successful drug. The effect of Herceptin on cardiac tissue, "cardiotoxicity," has merely been

a side effect to treatment. When patients were treated with Herceptin alone, significant cardiotoxicity occurred in a very low

percentage of patients.

Of particular note, although kidney tissue is indicated to exhibit normal expression, possibly even higher expression

than cardiac tissue, kidney has no appreciable Herceptin side effect whatsoever. Moreover, of the diverse array of normal

tissues in which HER2 is expressed, there is very little occurrence of any side effect. Only cardiac tissue has manifested any

appreciable side effect at all. A tissue such as kidney, where HER2/neu expression is especially notable, has not been the

basis for any side effect.

Furthermore, favorable therapeutic effects have been found for antitumor therapies that target epidermal growth

factor receptor (EGFR). EGFR is also expressed in numerous normal tissues. There have been very limited side effects in

normal tissues following use of anti-EGFR therapeutics.

Thus, expression of a target protein in normal tissue, even vital normal tissue, does not defeat the utility of a

targeting agent for the protein as a therapeutic for certain tumors in which the protein is also overexpressed.

Accordingly, therapeutic approaches that inhibit the activity of a 191P4D12(b) protein are useful for patients

suffering from a cancer that expresses 191P4D12(b). These therapeutic approaches generally fall into two classes. OneOO class comprises various methods for inhibiting the binding or association of a 191P4D12(b) protein with its binding partner or

with other proteins. Another class comprises a variety of methods for inhibiting the transcription of a 191P4D12(b) gene or

translation of 191P4D12(b) mRNA.

Anti-Cancer Vaccines

SThe invention provides cancer vaccines comprising a 191P4D12(b)-related protein or 191P4D12(b)-related nucleic acid.

In view of the expression of 191P4D12(b), cancer vaccines prevent and/or treat 191P4D12(b)-expressing cancers with minimal or

no effects on non-target tissues. The use of a tumor antigen in a vaccine that generates humoral and/or cell-mediated immune

responses as anti-cancer therapy is well known in the art and has been employed in prostate cancer using human PSMA and

C rodent PAP immunogens (Hodge et al., 1995, Int J. Cancer 63:231-237; Fong et al, 1997, J. Immunol. 159:3113-3117).

Such methods can be readily practiced by employing a 191 P4D12(b)-related protein, or a 191P4D12(b)-encoding0 0 nucleic acid molecule and recombinant vectors capable of expressing and presenting the 191P4D12(b) immunogen (which

0 typically comprises a number of antibody or T cell epitopes). Skilled artisans understand that a wide variety of vaccine

systems for delivery of immunoreactive epitopes are known in the art (see, Heryln et al., Ann Med 1999 Feb 31(1):66-

78; Maruyama et al., Cancer Immunol Immunother 2000 Jun 49(3):123-32) Briefly, such methods of generating an immune

response humoral and/or cell-mediated) in a mammal, comprise the steps of: exposing the mammal's immune system

to an immunoreactive epitope an epitope present in a 191P4D12(b) protein shown in Figure 3 or analog or homolog

thereof) so that the mammal generates an immune response that is specific for that epitope generates antibodies that

specifically recognize that epitope). In a preferred method, a 191P4D12(b) immunogen contains a biological motif, see e.g.,

Tables VIII-XXI and XXII-XLIX, or a peptide of a size range from 191P4D12(b) indicated in Figure 5, Figure 6, Figure 7,

Figure 8, and Figure 9.

The entire 191P4D12(b) protein, immunogenic regions or epitopes thereof can be combined and delivered by

various means. Such vaccine compositions can include, for example, lipopeptides (e.g.,Vitiello, A. et al., J. Clin. Invest.

95:341, 1995), peptide compositions encapsulated in poly(DL-lactide-co-glycolide) microspheres (see, Eldridge,

et al., Molec. Immunol. 28:287-294,1991: Alonso et al., Vaccine 12:299-306,1994; Jones et al., Vaccine 13:675-681, 1995),

peptide compositions contained in immune stimulating complexes (ISCOMS) (see, Takahashi et al., Nature 344:873-

875,1990; Hu et al., Clin Exp Immunol. 113:235-243, 1998), multiple antigen peptide systems (MAPs) (see Tam, J. P.,

Proc. Natl. Acad. Sci. U.S.A. 85:5409-5413,1988; Tam, J. Immunol. Methods 196:17-32, 1996), peptides formulated as

multivalent peptides; peptides for use in ballistic delivery systems, typically crystallized peptides, viral delivery vectors

(Perkus, M. E. et al., In: Concepts in vaccine development, Kaufmann, S. H. ed., p. 379, 1996; Chakrabarti, S. et al.,

Nature 320:535, 1986; Hu, S. L. et al., Nature 320:537,1986; Kieny, et al., AIDS Bio/Technology4:790, 1986; Top, F.

H. etal., J. Infect. Dis. 124:148, 1971; Chanda, P. K. et al., Virology 175:535, 1990), particles of viral or synthetic origin

Kofler, N. et al., J. Immunol. Methods. 192:25, 1996; Eldridge, J. et al., Sem. Hematol. 30:16, 1993; Falo, L. Jr. et al.,

Nature Med. 7:649,1995), adjuvants (Warren, H. Vogel, F. and Chedid, L. A. Annu. Rev. Immunol. 4:369,1986;

Gupta, R. K. et al., Vaccine 11:293,1993), liposomes (Reddy, R. et al., J. Immunol. 148:1585,1992; Rock, K. Immunol.

Today 17:131, 1996), or, naked or particle absorbed cDNA (Ulmer, J. B. et al., Science 259:1745, 1993; Robinson, H. L.,

Hunt, L. and Webster, R. Vaccine 11:957, 1993; Shiver, J. W. et al., In: Concepts in vaccine development, Kaufmann,

S. H. ed., p. 423,1996; Cease, K. and Berzofsky, J. Annu. Rev. Immunol. 12:923,1994 and Eldridge, J. H. etal.,

Sem. Hematol. 30:16, 1993). Toxin-targeted delivery technologies, also known as receptor mediated targeting, such as

those of Avant Immunotherapeutics, Inc. (Needham, Massachusetts) may also be used.

In patients with 191P4D12(b)-associated cancer, the vaccine compositions of the invention can also be used in

conjunction with other treatments used for cancer, surgery, chemotherapy, drug therapies, radiation therapies, etc.

00 including use in combination with immune adjuvants such as IL-2, IL-12, GM-CSF, and the like.

Cellular Vaccines:

K CTL epitopes can be determined using specific algorithms to identify peptides within 191P4D12(b) protein that bind

S corresponding HLA alleles (see Table IV; EpimerM and EpimatrixTM Brown University (URL brown.edulResearch/TB-

HIV.Lab/epimalrix/epimatrix.html); and, BIMAS, (URL bimas.dcrtnih.gov/; SYFPEITHI at URL syfpeithi.bmi-heidelberg.com/).

0 In a preferred embodiment, a 191P4D12(b) Immunogen contains one or more amino acid sequences identified using

techniques well known in the art, such as the sequences shown in Tables VIII-XXI and XXII-XLIX or a peptide of 8, 9, 10 or 11

amino acids specified by an HLA Class I motif/supermotif Table IV Table IV or Table IV and/or a peptide

S of at least 9 amino acids that comprises an HLA Class II motif/supermotif Table IV or Table IV As is

appreciated in the art, the HLA Class I binding groove is essentially closed ended so that peptides of only a particular size

S range can fit into the groove and be bound, generally HLA Class I epitopes are 8, 9, 10, or 11 amino acids long. In contrast,

00 the HLA Class II binding groove is essentially open ended; therefore a peptide of about 9 or more amino acids can be bound

0 by an HLA Class II molecule. Due to the binding groove differences between HLA Class I and II, HLA Class I motifs are

C1 length specific, position two of a Class I motif is the second amino acid in an amino to carboxyl direction of the peptide;

The amino acid positions in a Class II motif are relative only to each other, not the overall peptide, additional amino acids

can be attached to the amino and/or carboxyl termini of a motif-bearing sequence. HLA Class II epitopes are often 9, 10, 11,

12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, or 25 amino acids long, or longer than 25 amino acids.

Antibody-based Vaccines

A wide variety of methods for generating an immune response in a mammal are known in the art (for example as

the first step in the generation of hybridomas). Methods of generating an immune response in a mammal comprise exposing

the mammal's immune system to an immunogenic epitope on a protein a 191P4D12(b) protein) so that an immune

response is generated. A typical embodiment consists of a method for generating an immune response to 191P4D12(b) in a

host, by contacting the host with a sufficient amount of at least one 191P4D12(b) B cell or cytotoxic T-cell epitope or analog

thereof; and at least one periodic interval thereafter re-contacting the host with the 191P4D12(b) B cell or cytotoxic T-cell

epitope or analog thereof. A specific embodiment consists of a method of generating an immune response against a

191P4D12(b)-related protein or a man-made multiepitopic peptide comprising: administering 191P4D12(b) immunogen (e.g.

a 191P4D12(b) protein or a peptide fragment thereof, a 191P4D12(b) fusion protein or analog etc.) in a vaccine preparation

to a human or another mammal. Typically, such vaccine preparations further contain a suitable adjuvant (see, U.S.

Patent No. 6,146,635) or a universal helper epitope such as a PADRE M peptide (Epimmune Inc., San Diego, CA; see, e.g.,

Alexander et al., J. Immunol. 2000 164(3); 164(3): 1625-1633; Alexander et al., Immunity 1994 751-761 and Alexander

et al., Immunol. Res. 1998 18(2): 79-92). An alternative method comprises generating an immune response in an individual

against a 191P4D12(b) immunogen by: administering in vivo to muscle or skin of the individual's body a DNA molecule that

comprises a DNA sequence that encodes a 191P4D12(b) immunogen, the DNA sequence operatively linked to regulatory

sequences which control the expression of the DNA sequence; wherein the DNA molecule is taken up by cells, the DNA

sequence is expressed in the cells and an immune response is generated against the immunogen (see, U.S. Patent No.

5,962,428). Optionally a genetic vaccine facilitator such as anionic lipids; saponins; lectins; estrogenic compounds;

hydroxylated lower alkyls; dimethyl sulfoxide; and urea is also administered. In addition, an antiidiotypic antibody can be

administered that mimics 191P4D12(b), in order to generate a response to the target antigen.

Nucleic Acid Vaccines:

Vaccine compositions of the invention include nucleic acid-mediated modalities. DNA or RNA that encode

protein(s) of the invention can be administered to a patient. Genetic immunization methods can be employed to generateOO0 prophylactic or therapeutic humoral and cellular immune responses directed against cancer cells expressing 191P4D12(b).

S Constructs comprising DNA encoding a 191P4D12(b)-related proteinlimmunogen and appropriate regulatory sequences can

be injected directly into muscle or skin of an individual, such that the cells of the muscle or skin take-up the construct and

express the encoded 191P4D12(b) protein/immunogen. Alternatively, a vaccine comprises a 191P4D12(b)-related protein.

Expression of the 191P4D12(b)-related protein immunogen results in the generation of prophylactic or therapeutic humoral

LC and cellular immunity against cells that bear a 191P4D12(b) protein. Various prophylactic and therapeutic genetic

immunization techniques known in the art can be used (for review, see information and references published at Internet

address genweb.com). Nucleic acid-based delivery is described, for instance, in Wolff et. al., Science 247:1465 (1990) as

well as U.S. Patent Nos. 5,580,859; 5,589,466; 5,804,566; 5,739,118; 5,736,524; 5,679,647; WO 98/04720. Examples of

C-l DNA-based delivery technologies include "naked DNA", facilitated (bupivicaine, polymers, peptide-mediated) delivery,

cationic lipid complexes, and particle-mediated ("gene gun") or pressure-mediated delivery (see, U.S. Patent No.

S 5,922,687).

SFor therapeutic or prophylactic immunization purposes, proteins of the invention can be expressed via viral or

bacterial vectors. Various viral gene delivery systems that can be used in the practice of the invention include, but are not limited

to, vaccinia, fowlpox, canarypox, adenovirus, Influenza, poliovirus, adeno-associated virus, lentivirus, and sindbis virus (see, e.g.,

Restifo, 1996, Curr. Opin. Immunol. 8:658-663; Tsang etal. J. Natl. Cancer Inst. 87:982-990 (1995)). Non-viral delivery systems

can also be employed by introducing naked DNA encoding a 191P4D12(b)-related protein into the patient intramuscularly or

intradermally) to induce an anti-tumor response.

Vaccinia virus is used, for example, as a vector to express nucleotide sequences that encode the peptides of the

invention. Upon introduction into a host, the recombinant vaccinia virus expresses the protein immunogenic peptide, and

thereby elicits a host immune response. Vaccinia vectors and methods useful in immunization protocols are described in,

U.S. Patent No. 4,722,848. Another vector is BCG (Bacille Calmette Guerin). BCG vectors are described in Stover et

al., Nature 351:456-460 (1991). A wide variety of other vectors useful for therapeutic administration or immunization of the

peptides of the invention, e.g. adeno and adeno-associated virus vectors, retroviral vectors, Salmonella typhi vectors,

detoxified anthrax toxin vectors, and the like, will be apparent to those skilled in the art from the description herein.

Thus, gene delivery systems are used to deliver a 191P4D12(b)-related nucleic acid molecule. In one embodiment, the

full-length human 191P4D12(b) cDNA is employed. In another embodiment 191P4D12(b) nucleic acid molecules encoding

specific cytotoxic T lymphocyte (CTL) andlor antibody epitopes are employed.

Ex Vivo Vaccines

Various ex vivo strategies can also be employed to generate an immune response. One approach involves the use of

antigen presenting cells (APCs) such as dendritic cells (DC) to present 191P4D12(b) antigen to a patient's immune system.

Dendritic cells express MHC class I and II molecules, B7 co-stimulator, and IL-12, and are thus highly specialized antigen

presenting cells. In prostate cancer, autologous dendritic cells pulsed with peptides of the prostate-specific membrane

antigen (PSMA) are being used in a Phase I clinical trial to stimulate prostate cancer patients' immune systems (Tjoa et al.,

1996, Prostate 28:65-69; Murphy et al., 1996, Prostate 29:371-380). Thus, dendritic cells can be used to present

191P4D12(b) peptides to T cells in the context of MHC class I or II molecules. In one embodiment, autologous dendritic cells

are pulsed with 191P4D12(b) peptides capable of binding to MHC class I and/or class II molecules. In another embodiment,

dendritic cells are pulsed with the complete 191P4D12(b) protein. Yet another embodiment involves engineering the

overexpression of a 191P4D12(b) gene in dendritic cells using various implementing vectors known in the art, such as

adenovirus (Arthur et al., 1997, Cancer Gene Ther. 4:17-25), retrovirus (Henderson et al., 1996, Cancer Res. 56:3763-3770),

lentivlrus, adeno-associated virus, DNA transfection (Ribas et 1997, Cancer Res. 57:2865-2869), or tumor-derived RNA

transfection (Ashley et al., 1997, J. Exp. Med. 186:1177-1182). Cells that express 191P4D12(b) can also be engineered to

0 express immune modulators, such as GM-CSF, and used as immunizing agents.O

C 191P4D12(b) as a Target for Antibody-based Therapy

191P4D12(b) is an attractive target for antibody-based therapeutic strategies. A number of antibody strategies are

known in the art for targeting both extracellular and intracellular molecules (see, complement and ADCC mediated

killing as well as the use of intrabodies). Because 191 P4D12(b) is expressed by cancer cells of various lineages relative to

C1 corresponding normal cells, systemic administration of 191P4D12(b)-immunoreactive compositions are prepared that exhibit

excellent sensitivity without toxic, non-specific and/or non-target effects caused by binding of the immunoreactive

composition to non-target organs and tissues. Antibodies specifically reactive with domains of 191P4D12(b) are useful to

C=K treat 191P4D12(b)-expressing cancers systemically, either as conjugates with a toxin or therapeutic agent, or as naked

antibodies capable of inhibiting cell proliferation or function.

ri 191P4D12(b) antibodies can be introduced into a patient such that the antibody binds to 191P4D12(b) and00

modulates a function, such as an interaction with a binding partner, and consequently mediates destruction of the tumor cells

S and/or inhibits the growth of the tumor cells. Mechanisms by which such antibodies exert a therapeutic effect can include

complement-mediated cytolysis, antibody-dependent cellular cytotoxicity, modulation of the physiological function of

191P4D12(b), inhibition of ligand binding or signal transduction pathways, modulation of tumor cell differentiation, alteration

of tumor angiogenesis factor profiles, and/or apoptosis.

Those skilled in the art understand that antibodies can be used to specifically target and bind immunogenic

molecules such as an immunogenic region of a 191P4D12(b) sequence shown in Figure 2 or Figure 3. In addition, skilled

artisans understand that it is routine to conjugate antibodies to cytotoxic agents (see, Slevers et al. Blood 93:11 3678-

3684 (June 1, 1999)). When cytotoxic and/or therapeutic agents are delivered directly to cells, such as by conjugating them

to antibodies specific for a molecule expressed by that cell 191P4D12(b)), the cytotoxic agent will exert its known

biological effect cytotoxicity) on those cells.

A wide variety of compositions and methods for using antibody-cytotoxic agent conjugates to kill cells are known in

the art In the context of cancers, typical methods entail administering to an animal having a tumor a biologically effective

amount of a conjugate comprising a selected cytotoxic and/or therapeutic agent linked to a targeting agent an anti-

191P4D12(b) antibody) that binds to a marker 191P4D12(b)) expressed, accessible to binding or localized on the cell

surfaces. A typical embodiment is a method of delivering a cytotoxic and/or therapeutic agent to a cell expressing

191P4D12(b), comprising conjugating the cytotoxic agent to an antibody that immunospecifically binds to a 191P4D12(b)

epitope, and, exposing the cell to the antibody-agent conjugate. Another illustrative embodiment is a method of treating an

individual suspected of suffering from metastasized cancer, comprising a step of administering parenterally to said individual

a pharmaceutical composition comprising a therapeutically effective amount of an antibody conjugated to a cytotoxic and/or

therapeutic agent

Cancer immunotherapy using anti-191P4D12(b) antibodies can be done in accordance with various approaches

that have been successfully employed in the treatment of other types of cancer, including but not limited to colon cancer

(Arlen et al., 1998, Crit. Rev. Immunol. 18:133-138), multiple myeloma (Ozaki et al., 1997, Blood 90:3179-3186, Tsunenari et

al., 1997, Blood 90:2437-2444), gastric cancer (Kasprzyk et 1992, Cancer Res. 52:2771-2776), B-cell lymphoma

(Funakoshi et al., 1996, J. Immunother. Emphasis Tumor Immunol. 19:93-101), leukemia (Zhong et 1996, Leuk. Res.

20:581-589), colorectal cancer (Moun etal., 1994, Cancer Res. 54:6160-6166; Velders et 1995, Cancer Res. 55:4398-

4403), and breast cancer (Shepard et 1991, J. Clin. Immunol. 11:117-127). Some therapeutic approaches involve

conjugation of naked antibody to a toxin or radioisotope, such as the conjugation of Y91 or I131 to anti-CD20 antibodies

00 ZevalinTM, IDEC Pharmaceuticals Corp. or BexxarM, Coulter Pharmaceuticals), while others involve co-administration of

0 antibodies and other therapeutic agents, such as HerceptinTM (trastuzumab) with paclitaxel (Genentech, Inc.). The

C<1 antibodies can be conjugated to a therapeutic agent. To treat prostate cancer, for example, 191P4D12(b) antibodies can be

S administered in conjunction with radiation, chemotherapy or hormone ablation. Also, antibodies can be conjugated to a toxin

S such as calicheamicin Mylotarg T Wyeth-Ayerst, Madison, NJ, a recombinant humanized IgG4 kappa antibody

conjugated to antitumor antibiotic calicheamicin) or a maytansinoid taxane-based Tumor-Activated Prodrug, TAP,

Cl platform, ImmunoGen, Cambridge, MA, also see US Patent 5,416,064).

Although 191P4D12(b) antibody therapy is useful for all stages of cancer, antibody therapy can be particularly

S appropriate in advanced or metastatic cancers. Treatment with the antibody therapy of the invention is indicated for patients

S who have received one or more rounds of chemotherapy. Alternatively, antibody therapy of the invention is combined with a

ri chemotherapeutic or radiation regimen for patients who have not received chemotherapeutic treatment. Additionally,

Cl antibody therapy can enable the use of reduced dosages of concomitant chemotherapy, particularly for patients who do not00

tolerate the toxicity of the chemotherapeutic agent very well. Fan et al. (Cancer Res. 53:4637-4642, 1993), Prewett et al.

(International J. of Onco. 9:217-224, 1996), and Hancock et al. (Cancer Res. 51:4575-4580, 1991) describe the use of

various antibodies together with chemotherapeutic agents.

Although 191P4D12(b) antibody therapy is useful for all stages of cancer, antibody therapy can be particularly

appropriate in advanced or metastatic cancers. Treatment with the antibody therapy of the invention is Indicated for patients

who have received one or more rounds of chemotherapy. Alternatively, antibody therapy of the invention is combined with a

chemotherapeutic or radiation regimen for patients who have not received chemotherapeutic treatment. Additionally,

antibody therapy can enable the use of reduced dosages of concomitant chemotherapy, particularly for patients who do not

tolerate the toxicity of the chemotherapeutic agent very well.

Cancer patients can be evaluated for the presence and level of 191P4D12(b) expression, preferably using

immunohistochemical assessments of tumor tissue, quantitative 191P4D12(b) imaging, or other techniques that reliably

indicate the presence and degree of 191P4D12(b) expression. Immunohistochemical analysis of tumor biopsies or surgical

specimens is preferred for this purpose. Methods for immunohistochemical analysis of tumor tissues are well known in the

art.

Anti-191P4D12(b) monoclonal antibodies that treat prostate and other cancers include those that initiate a potent

immune response against the tumor or those that are directly cytotoxic. In this regard, anti-191P4D12(b) monoclonal

antibodies (mAbs) can elicit tumor cell lysis by either complement-mediated or antibody-dependent cell cytotoxicity (ADCC)

mechanisms, both of which require an intact Fc portion of the Immunoglobulin molecule for interaction with effector cell Fc

receptor sites on complement proteins. In addition, anti-191P4D12(b) mAbs that exert a direct biological effect on tumor

growth are useful to treat cancers that express 191P4D12(b). Mechanisms by which directly cytotoxic mAbs act Include:

inhibition of cell growth, modulation of cellular differentiation, modulation of tumor angiogenesis factor profiles, and the

induction of apoptosis. The mechanism(s) by which a particular anti-191P4D12(b) mAb exerts an anti-tumor effect is

evaluated using any number of in vitro assays that evaluate cell death such as ADCC, ADMMC, complement-mediated cell

lysis, and so forth, as is generally known in the art.

In some patients, the use of murine or other non-human monoclonal antibodies, or human/mouse chimeric mAbs

can induce moderate to strong immune responses against the non-human antibody. This can result in clearance of the

antibody from circulation and reduced efficacy. In the most severe cases, such an immune response can lead to the

extensive formation of immune complexes which, potentially, can cause renal failure. Accordingly, preferred monoclonal

antibodies used in the therapeutic methods of the invention are those that are either fully human or humanized and that bind

specifically to the target 191P4D12(b) antigen with high affinity but exhibit low or no antigenicity in the patient.

00 Therapeutic methods of the invention contemplate the administration of single anti-191P4D12(b) mAbs as well as

0 combinations, or cocktails, of different mAbs. Such mAb cocktails can have certain advantages inasmuch as they contain

SmAbs that target different epitopes, exploit different effector mechanisms or combine directly cytotoxic mAbs with mAbs that

c rely on immune effector functionality. Such mAbs in combination can exhibit synergistic therapeutic effects. In addition, anti-

191P4D12(b) mAbs can be administered concomitantly with other therapeutic modalities, including but not limited to various

O chemotherapeutic agents, androgen-blockers, immune modulators IL-2, GM-CSF), surgery or radiation. The anti-

191P4D12(b) mAbs are administered in their "naked" or unconjugated form, or can have a therapeutic agent(s) conjugated to

them.

Anti-191P4D12(b) antibody formulations are administered via any route capable of delivering the antibodies to a

tumor cell. Routes of administration include, but are not limited to, intravenous, intraperitoneal, intramuscular, intratumor,

0 intradermal, and the like. Treatment generally involves repeated administration of the anti-191P4D12(b) antibody

OO preparation, via an acceptable route of administration such as intravenous injection typically at a dose in the range of

O about 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or 25 mg/kg body weight. In general, doses in the

C1 range of 10-1000 mg mAb per week are effective and well tolerated.

Based on clinical experience with the HerceptinTM mAb in the treatment of metastatic breast cancer, an initial

loading dose of approximately 4 mg/kg patient body weight IV, followed by weekly doses of about 2 mg/kg IV of the anti-

191P4012(b) mAb preparation represents an acceptable dosing regimen. Preferably, the initial loading dose is administered

as a 90-minute or longer infusion. The periodic maintenance dose is administered as a 30 minute or longer infusion,

provided the initial dose was well tolerated. As appreciated by those of skill in the art, various factors can influence the ideal

dose regimen in a particular case. Such factors include, for example, the binding affinity and half life of the Ab or mAbs

used, the degree of 191P4D12(b) expression in the patient, the extent of circulating shed 191P4D12(b) antigen, the desired

steady-state antibody concentration level, frequency of treatment, and the influence of chemotherapeutic or other agents

used in combination with the treatment method of the invention, as well as the health status of a particular patient.

Optionally, patients should be evaluated for the levels of 191P4012(b) in a given sample the levels of

circulating 191P4D12(b) antigen and/or 191P4D12(b) expressing cells) in order to assist in the determination of the most

effective dosing regimen, etc. Such evaluations are also used for monitoring purposes throughout therapy, and are useful to

gauge therapeutic success in combination with the evaluation of other parameters (for example, urine cytology and/or

ImmunoCyt levels in bladder cancer therapy, or by analogy, serum PSA levels in prostate cancer therapy).

Anti-idiotypic anti-191P4D12(b) antibodies can also be used in anti-cancer therapy as a vaccine for inducing an

immune response to cells expressing a 191P4D12(b)-related protein. In particular, the generation of anti-idiotypic antibodies

is well known in the art; this methodology can readily be adapted to generate anti-idiotypic anti-191P4D12(b) antibodies that

mimic an epitope on a 191P4D12(b)-related protein (see, for example, Wagner et al., 1997, Hybridoma 16: 33-40; Foon et

al., 1995, J. Clin. Invest. 96:334-342; Herlyn et al., 1996, Cancer Immunol. Immunother. 43:65-76). Such an anti-idiotypic

antibody can be used in cancer vaccine strategies.

191P4D12(b) as a Target for Cellular Immune Responses

Vaccines and methods of preparing vaccines that contain an immunogenically effective amount of one or more

HLA-binding peptides as described herein are further embodiments of the invention. Furthermore, vaccines in accordance

with the invention encompass compositions of one or more of the claimed peptides. A peptide can be present in a vaccine

individually. Alternatively, the peptide can exist as a homopolymer comprising multiple copies of the same peptide, or as a

heteropolymer of various peptides. Polymers have the advantage of increased immunological reaction and, where different

peptide epitopes are used to make up the polymer, the additional ability to induce antibodies and/or CTLs that react withOO0 different antigenic determinants of the pathogenic organism or tumor-related peptide targeted for an immune response. The

composition can be a naturally occurring region of an antigen or can be prepared, recombinantly or by chemical

S synthesis.

Carriers that can be used with vaccines of the invention are well known in the art, and include, thyroglobulin,

albumins such as human serum albumin, tetanus toxoid, polyamino acids such as poly L-lyslne, poly L-glutamic acid,

(C influenza, hepatitis B virus core protein, and the like. The vaccines can contain a physiologically tolerable acceptable)

diluent such as water, or saline, preferably phosphate buffered saline. The vaccines also typically include an adjuvant.

Adjuvants such as incomplete Freund's adjuvant, aluminum phosphate, aluminum hydroxide, or alum are examples of

materials well known In the art. Additionally, as disclosed herein, CTL responses can be primed by conjugating peptides of

CK the invention to lipids, such as tripalmitoyl-S-glycerylcysteinlyseryl- serine (P3CSS). Moreover, an adjuvant such as a

Ni synthetic cytosine-phosphorothiolated-guanine-containing (CpG) oligonucleotides has been found to increase CTL00 responses 10- to 100-fold. (see, e.g. Davila and Cells, J. Immunol. 165:539-547 (2000))

SUpon immunization with a peptide composition in accordance with the invention, via injection, aerosol, oral,

transdermal, transmucosal, intrapleural, intrathecal, or other suitable routes, the immune system of the host responds to the

vaccine by producing large amounts of CTLs and/or HTLs specific for the desired antigen. Consequently, the host becomes

at least partially immune to later development of cells that express or overexpress 191 P4D12(b) antigen, or derives at least

some therapeutic benefit when the antigen was tumor-associated.

In some embodiments, it may be desirable to combine the class I peptide components with components that

induce or facilitate neutralizing antibody and or helper T cell responses directed to the target antigen. A preferred

embodiment of such a composition comprises class I and class II epitopes in accordance with the invention. An alternative

embodiment of such a composition comprises a class I and/or class II epitope in accordance with the invention, along with a

cross reactive HTL epitope such as PADRET (Epimmune, San Diego, CA) molecule (described in U.S. Patent Number

5,736,142).

A vaccine of the invention can also include antigen-presenting cells (APC), such as dendritic cells as a

vehicle to present peptides of the invention. Vaccine compositions can be created in vitro, following dendritic cell

mobilization and harvesting, whereby loading of dendritic cells occurs in vitro. For example, dendritic cells are transfected,

with a minigene in accordance with the invention, or are pulsed with peptides. The dendritic cell can then be

administered to a patient to elicit immune responses in vivo. Vaccine compositions, either DNA- or peptide-based, can also

be administered in vivo in combination with dendritic cell mobilization whereby loading of dendritic cells occurs in vivo.

Preferably, the following principles are utilized when selecting an array of epitopes for inclusion in a polyepitopic

composition for use in a vaccine, or for selecting discrete epitopes to be included in a vaccine and/or to be encoded by

nucleic acids such as a minigene. It is preferred that each of the following principles be balanced in order to make the

selection. The multiple epitopes to be incorporated in a given vaccine composition may be, but need not be, contiguous in

sequence in the native antigen from which the epitopes are derived.

Epitopes are selected which, upon administration, mimic immune responses that have been observed to

be correlated with tumor clearance. For HLA Class I this includes 3-4 epitopes that come from at least one tumor associated

antigen (TAA). For HLA Class II a similar rationale is employed; again 3-4 epitopes are selected from at least one TAA (see,

Rosenberg et aL, Science 278:1447-1450). Epitopes from one TAA may be used in combination with epitopes from one

or more additional TAAs to produce a vaccine that targets tumors with varying expression patterns of frequently-expressed

TAAs.

Epitopes are selected that have the requisite binding affinity established to be correlated with

immunogenicity: for HLA Class I an ICso of 500 nM or less, often 200 nM or less; and for Class II an ICso of 1000 nM or less.

00 Sufficient supermotif bearing-peptides, or a sufficient array of allele-specific motif-bearing peptides, are

S selected to give broad population coverage. For example, it is preferable to have at least 80% population coverage. A

CN Monte Carlo analysis, a statistical evaluation known in the art, can be employed to assess the breadth, or redundancy of,

population coverage.

When selecting epitopes from cancer-related antigens it is often useful to select analogs because the

patient may have developed tolerance to the native epitope.

C Of particular relevance are epitopes referred to as "nested epitopes." Nested epitopes occur where at

least two epitopes overlap in a given peptide sequence. A nested peptide sequence can comprise B cell, HLA class I and/or

S HLA class II epitopes. When providing nested epitopes, a general objective is to provide the greatest number of epitopes per

C sequence. Thus, an aspect is to avoid providing a peptide that is any longer than the amino terminus of the amino terminal

Q epitope and the carboxyl terminus of the carboxyl terminal epitope in the peptide. When providing a multi-epitopic sequence,

C such as a sequence comprising nested epitopes, it is generally important to screen the sequence in order to insure that it000 does not have pathological or other deleterious biological properties.

S6.) If a polyepitopic protein is created, or when creating a minigene, an objective is to generate the smallest

peptide that encompasses the epitopes of interest. This principle is similar, if not the same as that employed when selecting

a peptide comprising nested epitopes. However, with an artificial polyepitopic peptide, the size minimization objective is

balanced against the need to integrate any spacer sequences between epitopes in the polyepitopic protein. Spacer amino

acid residues can, for example, be introduced to avoid junctional epitopes (an epitope recognized by the immune system, not

present in the target antigen, and only created by the man-made juxtaposition of epitopes), or to facilitate cleavage between

epitopes and thereby enhance epitope presentation. Junctional epitopes are generally to be avoided because the recipient

may generate an immune response to that non-native epitope. Of particular concern is a junctional epitope that is a

"dominant epitope." A dominant epitope may lead to such a zealous response that immune responses to other epitopes are

diminished or suppressed.

Where the sequences of multiple variants of the same target protein are present, potential peptide

epitopes can also be selected on the basis of their conservancy. For example, a criterion for conservancy may define that

the entire sequence of an HLA class I binding peptide or the entire 9-mer core of a class II binding peptide be conserved in a

designated percentage of the sequences evaluated for a specific protein antigen.

Minigene Vaccines

A number of different approaches are available which allow simultaneous delivery of multiple epitopes. Nucleic

acids encoding the peptides of the invention are a particularly useful embodiment of the invention. Epitopes for inclusion in a

minigene are preferably selected according to the guidelines set forth in the previous section. A preferred means of

administering nucleic acids encoding the peptides of the invention uses minigene constructs encoding a peptide comprising

one or multiple epitopes of the invention.

The use of multi-epitope minigenes is described below and in, Ishioka et al., J. Immunol. 162:3915-3925, 1999; An,

L. and Whitton, J. J. Virol. 71:2292, 1997; Thomson, S. A. et al., J. Immunol. 157:822, 1996; Whitton, J. L. et al., J. Virol.

67:348, 1993; Hanke, R. et al., Vaccine 16:426, 1998. For example, a multi-epitope DNA plasmid encoding supermotif-

and/or motif-bearing epitopes derived 191P4D12(b), the PADRE® universal helper T cell epitope or multiple HTL epitopes

from 191P4D12(b) (see Tables VIII-XXI and XXII to XLIX), and an endoplasmic reticulum-translocating signal sequence

can be engineered. A vaccine may also comprise epitopes that are derived from other TAAs.

The immunogenicity of a multi-epitopic minigene can be confirmed in transgenic mice to evaluate the magnitude of

0 CTL induction responses against the epitopes tested. Further, the immunogenicity of DNA-encoded epitopes in vivo can be

0 correlated with the in vitro responses of specific CTL lines against target cells transfected with the DNA plasmid. Thus, these

C-l experiments can show that the minigene serves to both: generate a CTL response and that the induced CTLs

S recognized cells expressing the encoded epitopes.

For example, to create a DNA sequence encoding the selected epitopes (minigene) for expression In human cells,

the amino acid sequences of the epitopes may be reverse translated. A human codon usage table can be used to guide the

CKl codon choice for each amino acid. These epitope-encoding DNA sequences may be directly adjoined, so that when

translated, a continuous polypeptide sequence is created. To optimize expression andlor immunogenicity, additional

S elements can be incorporated into the minigene design. Examples of amino acid sequences that can be reverse translated

S and included in the minigene sequence include: HLA class I epitopes, HLA class II epitopes, antibody epitopes, a

S ubiquitination signal sequence, and/or an endoplasmic reticulum targeting signal. In addition, HLA presentation of CTL and

CKl HTL epitopes may be improved by including synthetic poly-alanine) or naturally-occurring flanking sequences adjacent000 to the CTL or HTL epitopes; these larger peptides comprising the epitope(s) are within the scope of the invention.

The minigene sequence may be converted to DNA by assembling oligonucleotides that encode the plus and minus

strands of the minigene. Overlapping oligonucleotides (30-100 bases long) may be synthesized, phosphorylated, purified

and annealed under appropriate conditions using well known techniques. The ends of the oligonucleotides can be joined, for

example, using T4 DNA ligase. This synthetic minigene, encoding the epitope polypeptide, can then be cloned into a desired

expression vector.

Standard regulatory sequences well known to those of skill in the art are preferably included in the vector to ensure

expression in the target cells. Several vector elements are desirable: a promoter with a down-stream cloning site for

minigene insertion; a polyadenylation signal for efficient transcription termination; an E. coil origin of replication; and an E.

coil selectable marker ampicillin or kanamycin resistance). Numerous promoters can be used for this purpose, the

human cytomegalovirus (hCMV) promoter. See, U.S. Patent Nos. 5,580,859 and 5,589,466 for other suitable promoter

sequences.

Additional vector modifications may be desired to optimize minigene expression and immunogenicity. In some

cases, introns are required for efficient gene expression, and one or more synthetic or naturally-occurring Introns could be

incorporated into the transcribed region of the minigene. The inclusion of mRNA stabilization sequences and sequences for

replication in mammalian cells may also be considered for increasing minigene expression.

Once an expression vector is selected, the minigene is cloned into the polylinker region downstream of the

promoter. This plasmid is transformed into an appropriate E. coli strain, and DNA is prepared using standard techniques.

The orientation and DNA sequence of the minigene, as well as all other elements included in the vector, are confirmed using

restriction mapping and DNA sequence analysis. Bacterial cells harboring the correct plasmid can be stored as a master cell

bank and a working cell bank.

In addition, immunostimulatory sequences (ISSs or CpGs) appear to play a role in the immunogenicity of DNA

vaccines. These sequences may be included in the vector, outside the minigene coding sequence, if desired to enhance

immunogenicity.

In some embodiments, a bi-cistronic expression vector which allows production of both the minigene-encoded

epitopes and a second protein (included to enhance or decrease immunogenicity) can be used. Examples of proteins or

polypeptides that could beneficially enhance the immune response if co-expressed include cytokines IL-2, IL-12, GM-

CSF), cytokine-inducing molecules LelF), costimulatory molecules, or for HTL responses, pan-DR binding proteins

(PADRETM, Epimmune, San Diego, CA). Helper (HTL) epitopes can be joined to intracellular targeting signals and

expressed separately from expressed CTL epitopes; this allows direction of the HTL epitopes to a cell compartment different

than that of the CTL epitopes. If required, this could facilitate more efficient entry of HTL epitopes into the HLA class II

00 pathway, thereby improving HTL induction. In contrast to HTL or CTL induction, specifically decreasing the immuneO

S response by co-expression of immunosuppressive molecules TGF-P) may be beneficial in certain diseases.

Therapeutic quantities of plasmid DNA can be produced for example, by fermentation in E, coli, followed by

ct purification. Aliquots from the working cell bank are used to inoculate growth medium, and grown to saturation in shaker

flasks or a bioreactor according to well-known techniques. Plasmid DNA can be purified using standard bioseparation

0 technologies such as solid phase anion-exchange resins supplied by QIAGEN, Inc. (Valencia, California). If required,

supercoiled DNA can be isolated from the open circular and linear forms using gel electrophoresis or other methods.

Purified plasmid DNA can be prepared for injection using a variety of formulations. The simplest of these is

reconstitution of lyophilized DNA in sterile phosphate-buffer saline (PBS). This approach, known as "naked DNA," is

currently being used for intramuscular (IM) administration in clinical trials. To maximize the immunotherapeutic effects of

S minigene DNA vaccines, an alternative method for formulating purified plasmid DNA may be desirable. A variety of methods

00 have been described, and new techniques may become available. Cationic lipids, glycolipids, and fusogenic liposomes can

O also be used in the formulation (see, as described by WO 93/24640; Mannino Gould-Fogerite, BioTechniques 6(7):

C1 682 (1988); U.S. Pat No. 5,279,833; WO 91/06309; and Feigner, et al., Proc. Nat'l Acad. Scl. USA 84:7413 (1987). In

addition, peptides and compounds referred to collectively as protective, interactive, non-condensing compounds (PINC)

could also be complexed to purified plasmid DNA to influence variables such as stability, intramuscular dispersion, or

trafficking to specific organs or cell types.

Target cell sensitization can be used as a functional assay for expression and HLA class I presentation of

minigene-encoded CTL epitopes. For example, the plasmid DNA is introduced into a mammalian cell line that is suitable as

a target for standard CTL chromium release assays. The transfection method used will be dependent on the final

formulation. Electroporation can be used for "naked" DNA, whereas cationic lipids allow direct in vitro transfection. A

plasmid expressing green fluorescent protein (GFP) can be co-transfected to allow enrichment of transfected cells using

fluorescence activated cell sorting (FACS). These cells are then chromium-51 5sCr) labeled and used as target cells for

epitope-specific CTL lines; cytolysis, detected by 5sCr release, indicates both production of, and HLA presentation of,

mlnigene-encoded CTL epitopes. Expression of HTL epitopes may be evaluated in an analogous manner using assays to

assess HTL activity.

In vivo immunogenicity is a second approach for functional testing of minigene DNA formulations. Transgenic mice

expressing appropriate human HLA proteins are immunized with the DNA product. The dose and route of administration are

formulation dependent IM for DNA in PBS, intraperitoneal for lipid-complexed DNA). Twenty-one days after

immunization, splenocytes are harvested and restimulated for one week in the presence of peptides encoding each epitope

being tested. Thereafter, for CTL effector cells, assays are conducted for cytolysis of peptide-loaded, 5'Cr-labeled target

cells using standard techniques. Lysis of target cells that were sensitized by HLA loaded with peptide epitopes,

corresponding to minigene-encoded epitopes, demonstrates DNA vaccine function for in vivo induction of CTLs.

Immunogenicity of HTL epitopes is confirmed in transgenic mice in an analogous manner.

Alternatively, the nucleic acids can be administered using ballistic delivery as described, for instance, in U.S.

Patent No. 5,204,253. Using this technique, particles comprised solely of DNA are administered. In a further alternative

embodiment, DNA can be adhered to particles, such as gold particles.

Minigenes can also be delivered using other bacterial or viral delivery systems well known in the art, an

expression construct encoding epitopes of the invention can be incorporated into a viral vector such as vaccinia.

X.C.2. Combinations of CTL Peptides with Helper Peptides

I

Vaccine compositions comprising CTL peptides of the invention can be modified, analoged, to provide desired

attributes, such as improved serum half life, broadened population coverage or enhanced immunogenicity.00

O For instance, the ability of a peptide to induce CTL activity can be enhanced by linking the peptide to a sequence

which contains at least one epitope that is capable of inducing a T helper cell response. Although a CTL peptide can be

directly linked to a T helper peptide, often CTL epitope/HTL epitope conjugates are linked by a spacer molecule. The spacer

is typically comprised of relatively small, neutral molecules, such as amino acids or amino acid mimetics, which are

substantially uncharged under physiological conditions. The spacers are typically selected from, Ala, Gly, or other

S neutral spacers of nonpolar amino acids or neutral polar amino acids. It will be understood that the optionally present spacer

need not be comprised of the same residues and thus may be a hetero- or homo-oligomer. When present, the spacer will

S usually be at least one or two residues, more usually three to six residues and sometimes 10 or more residues. The CTL

peptide epitope can be linked to the T helper peptide epitope either directly or via a spacer either at the amino or carboxy

CK terminus of the CTL peptide. The amino terminus of either the immunogenic peptide or the T helper peptide may be

C acylated.00 In certain embodiments, the T helper peptide is one that is recognized by T helper cells present in a majority of a

0 genetically diverse population. This can be accomplished by selecting peptides that bind to many, most, or all of the HLA

class II molecules. Examples of such amino acid bind many HLA Class II molecules include sequences from antigens such

as tetanus toxoid at positions 830-843 (QYIKANSKFIGITE; SEQ ID NO: 44), Plasmodium falciparum circumsporozoite (CS)

protein at positions 378-398 (DIEKKIAKMEKASSVFNWNS; SEQ ID NO: 45), and Streptococcus 18kD protein at positions

116-131 (GAVDSILGGVATYGAA; SEQ ID NO: 46). Other examples include peptides bearing a DR 1-4-7 supermotif, or

either of the DR3 motifs.

Alternatively, it is possible to prepare synthetic peptides capable of stimulating T helper lymphocytes, in a loosely

HLA-restricted fashion, using amino acid sequences not found in nature (see, PCT publication WO 95/07707). These

synthetic compounds called Pan-DR-binding epitopes PADRETM Epimmune, Inc., San Diego, CA) are designed, most

preferably, to bind most HLA-DR (human HLA class II) molecules. For instance, a pan-DR-binding epitope peptide having.

the formula: XKXVAAWTLKAAX (SEQ ID NO: 47), where is either cyclohexylalanine, phenylalanine, or tyrosine, and a is

either o-alanine or L-alanine, has been found to bind to most HLA-DR alleles, and to stimulate the response of T helper

lymphocytes from most individuals, regardless of their HLA type. An altemative of a pan-DR binding epitope comprises all

natural amino acids and can be provided in the form of nucleic acids that encode the epitope.

HTL peptide epitopes can also be modified to alter their biological properties., For example, they can be modified

to include 0-amino acids to increase their resistance to proteases and thus extend their serum half life, or they can be

conjugated to other molecules such as lipids, proteins, carbohydrates, and the like to increase their biological activity. For

example, a T helper peptide can be conjugated to one or more palmitic acid chains at either the amino or carboxyl termini.

X.C.3. Combinations of CTL Peptides with T Cell Priming Agents

In some embodiments it may be desirable to include in the pharmaceutical compositions of the invention at least

one component which primes B lymphocytes or T lymphocytes. Lipids have been identified as agents capable of priming

CTL in vivo. For example, palmitic acid residues can be attached to the e-and a- amino groups of a lysine residue and then

linked, via one or more linking residues such as Gly, Gly-Gly-, Ser, Ser-Ser, or the like, to an immunogenic peptide.

The lipidated peptide can then be administered either directly in a micelle or particle, incorporated into a liposome, or

emulsified in an adjuvant, incomplete Freund's adjuvant. In a preferred embodiment, a particularly effective

immunogenic composition comprises palmitic acid attached to e- and a- amino groups of Lys, which is attached via linkage,

Ser-Ser, to the amino terminus of the immunogenic peptide.

As another example of lipid priming of CTL responses, E. coli lipoproteins, such as tripalmitoyl-S-

glycerylcysteinlyseryl- serine (P3CSS) can be used to prime virus specific CTL when covalently attached to an appropriate0 0 peptide (see, Deres, et at., Nature 342:561, 1989), Peptides of the invention can be coupled to P3CSS, for example,

0 and the lipopeptide administered to an Individual to prime specifically an immune response to the target antigen. Moreover,

because the induction of neutralizing antibodies can also be primed with P3CSS-conjugated epitopes, two such compositions

can be combined to more effectively elicit both humoral and cell-mediated responses.

X.C.4. Vaccine Compositions Comprising DC Pulsed with CTL andlor HTL Peptides

O An embodiment of a vaccine composition in accordance with the invention comprises ex vivo administration of a

cocktail of epitope-bearing peptides to PBMC, or isolated DC therefrom, from the patient's blood. A pharmaceutical to

facilitate harvesting of DC can be used, such as ProgenipoietinTM (Pharmacia-Monsanto, St Louis, MO) or GM-CSFIIL-4.

After pulsing the DC with peptides and prior to reinfusion into patients, the DC are washed to remove unbound peptides. In

C= this embodiment, a vaccine comprises peptide-pulsed DCs which present the pulsed peptide epitopes complexed with HLA

molecules on their surfaces.

00 The DC can be pulsed ex vivo with a cocktail of peptides, some of which stimulate CTL responses to 191P4D12(b).

0 Optionally, a helper T cell (HTL) peptide, such as a natural or artificial loosely restricted HLA Class 11 peptide, can be

included to facilitate the CTL response. Thus, a vaccine in accordance with the invention is used to treat a cancer which

expresses or overexpresses 191P4D12(b).

X.D. Adoptive Immunotherapy

Antigenic 191P4D12(b)-related peptides are used to elicit a CTL and/or HTL response ex vivo, as well. The

resulting CTL or HTL cells, can be used to treat tumors in patients that do not respond to other conventional forms of

therapy, or will not respond to a therapeutic vaccine peptide or nucleic acid in accordance withithe invention. Ex vivo CTL or

HTL responses to a particular antigen are induced by incubating in tissue culture the patient's, or genetically compatible, CTL

or HTL precursor cells together with a source of antigen-presenting cells (APC), such as dendritic cells, and the appropriate

immunogenic peptide. After an appropriate incubation time (typically about 7-28 days), in which the precursor cells are

activated and expanded into effector cells, the cells are infused back into the patient, where they will destroy (CTL) or

facilitate destruction (HTL) of their specific target cell a tumor cell). Transfected dendritic cells may also be used as

antigen presenting cells.

X.E. Administration of Vaccines for Therapeutic or Prophylactic Purposes

Pharmaceutical and vaccine compositions of the invention are typically used to treat and/or prevent a cancer that

expresses or overexpresses 191P4D12(b). In therapeutic applications, peptide and/or nucleic acid compositions are

administered to a patient in an amount sufficient to elicit an effective B cell, CTL and/or HTL response to the antigen and to

cure or at least partially arrest or slow symptoms and/or complications. An amount adequate to accomplish this is defined as

'therapeutically effective dose." Amounts effective for this use will depend on, the particular composition administered,

the manner of administration, the stage and severity of the disease being treated, the weight and general state of health of

the patient, and the judgment of the prescribing physician.

For pharmaceutical compositions, the immunogenic peptides of the invention, or DNA encoding them, are

generally administered to an individual already bearing a tumor that expresses 191P4D12(b). The peptides or DNA

encoding them can be administered individually or as fusions of one or more peptide sequences. Patients can be treated

with the immunogenic peptides separately or in conjunction with other treatments, such as surgery, as appropriate.

For therapeutic use, administration should generally begin at the first diagnosis of 191 P4D1 2(b)-associated cancer.

00 This is followed by boosting doses until at least symptoms are substantially abated and for a period thereafter. The

0 embodiment of the vaccine composition including, but not limited to embodiments such as peptide cocktails,

C=K polyepitopic polypeptides, minigenes, or TAA-specific CTLs or pulsed dendritic cells) delivered to the patient may vary

according to the stage of the disease or the patient's health status. For example, in a patient with a tumor that expressest 191P4D12(b), a vaccine comprising 191P4D12(b)-specific CTL may be more efficacious in killing tumor cells in patient with

advanced disease than alternative embodiments.

CKl It is generally important to provide an amount of the peptide epitope delivered by a mode of administration

sufficient to stimulate effectively a cytotoxic T cell response; compositions which stimulate helper T cell responses can also

be given in accordance with this embodiment of the invention.

L\i The dosage for an initial therapeutic immunization generally occurs in a unit dosage range where the lower value is

LC about 1, 5, 50, 500, or 1,000 pg and the higher value is about 10,000; 20,000; 30,000; or 50,000 pg. Dosage values for a

CKl human typically range from about 500 pg to about 50,000 pg per 70 kilogram patient. Boosting dosages of between about000 1.0 pg to about 50,000 pg of peptide pursuant to a boosting regimen over weeks to months may be administered depending

Ci upon the patient's response and condition as determined by measuring the specific activity of CTL and HTL obtained from

the patient's blood. Administration should continue until at least clinical symptoms or laboratory tests indicate that the

neoplasia, has been eliminated or reduced and for a period thereafter. The dosages, routes of administration, and dose

schedules are adjusted in accordance with methodologies known in the art.

In certain embodiments, the peptides and compositions of the present Invention are employed In serious disease

states, that is, life-threatening or potentially life threatening situations. In such cases, as a result of the minimal amounts of

extraneous substances and the relative nontoxic nature of the peptides in preferred compositions of the invention, it is

possible and may be felt desirable by the treating physician to administer substantial excesses of these peptide compositions

relative to these stated dosage amounts.

The vaccine compositions of the invention can also be used purely as prophylactic agents. Generally the dosage

for an initial prophylactic immunization generally occurs in a unit dosage range where the lower value is about 1, 5, 50, 500,

or 1000 pg and the higher value is about 10,000; 20,000; 30,000; or 50,000 pg. Dosage values for a human typically range

from about 500 pg to about 50,000 pg per 70 kilogram patient. This is followed by boosting dosages of between about

pg to about 50,000 jig of peptide administered at defined Intervals from about four weeks to six months after the initial

administration of vaccine. The immunogenicity of the vaccine can be assessed by measuring the specific activity of CTL and

HTL obtained from a sample of the patient's blood.

The pharmaceutical compositions for therapeutic treatment are intended for parenteral, topical, oral, nasal,

intrathecal, or local as a cream or topical ointment) administration. Preferably, the pharmaceutical compositions are

administered parentally, intravenously, subcutaneously, intradermally, or Intramuscularly. Thus, the invention provides

compositions for parenteral administration which comprise a solution of the immunogenic peptides dissolved or suspended in

an acceptable carrier, preferably an aqueous carrier.

A variety of aqueous carriers may be used, water, buffered water, 0.8% saline, 0.3% glyclne, hyaluronic acid

and the like. These compositions may be sterilized by conventional, well-known sterilization techniques, or may be sterile

filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being

combined with a sterile solution prior to administration.

The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate

physiological conditions, such as pH-adjusting and buffering agents, tonicity adjusting agents, wetting agents, preservatives,

and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan

monolaurate, triethanolamine oleate, etc.

00 The concentration of peptides of the invention in the pharmaceutical formulations can vary widely, from less

than about usually at or at least about 2% to as much as 20% to 50% or more by weight, and will be selected primarily

by fluid volumes, viscosities, etc., in accordance with the particular mode of administration selected.

c A human unit dose form of a composition is typically included in a pharmaceutical composition that comprises a

human unit dose of an acceptable carrier, in one embodiment an aqueous carrier, and is administered in a volume/quantity

0 that is known by those of skill in the art to be used for administration of such compositions to humans (see, Remington's

Pharmaceutical Sciences, 17 Edition, A. Gennaro, Editor, Mack Publishing Co., Easton, Pennsylvania, 1985). For example

a peptide dose for initial immunization can be from about 1 to about 50,000 pig, generally 100-5,000 Rpg, for a 70 kg patient.

For example, for nucleic acids an initial immunization may be performed using an expression vector in the form of naked

nucleic acid administered IM (or SC or ID) in the amounts of 0.5-5 mg at multiple sites. The nucleic acid (0.1 to 1000 Ig)

can also be administered using a gene gun. Following an incubation period of 3-4 weeks, a booster dose is then

00 administered. The booster can be recombinant fowlpox virus administered at a dose of 5-107 to 5x10 9 pfu.

For antibodies, a treatment generally involves repeated administration of the anti-191P4D12(b) antibody

preparation, via an acceptable route of administration such as intravenous Injection typically at a dose in the range of

about 0.1 to about 10 mg/kg body weight. In general, doses in the range of 10-500 mg mAb per week are effective and well

tolerated. Moreover, an initial loading dose of approximately 4 mg/kg patient body weight IV, followed by weekly doses of

about 2 mg/kg IV of the anti- 191P4D12(b) mAb preparation represents an acceptable dosing regimen. As appreciated by

those of skill in the art, various factors can influence the ideal dose in a particular case. Such factors include, for example,

half life of a composition, the binding affinity of an Ab, the immunogenicity of a substance, the degree of 191P4D12(b)

expression in the patient, the extent of circulating shed 191P4D12(b) antigen, the desired steady-state concentration level,

frequency of treatment, and the influence of chemotherapeutic or other agents used in combination with the treatment

method of the invention, as well as the health status of a particular patient. Non-limiting preferred human unit doses are, for

example, 500g 1mg, 1mg 50mg, 50mg 100mg, 100mg 200mg, 200mg 300mg, 400mg 500mg, 500mg 600mg,

600mg 700mg, 700mg 800mg, 800mg 900mg, 900mg ig, or 1mg 700mg. In certain embodiments, the dose is in a

range of 2-5 mglkg body weight, with follow on weekly doses of 1-3 mglkg; 0.5mg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10mg/kg body

weight followed, in two, three or four weeks by weekly doses; 0.5 10mg/kg body weight, followed in two, three or

four weeks by weekly doses; 225, 250, 275, 300, 325, 350, 375, 400mg m2 of body area weekly; 1-600mg m2 of body area

weekly; 225-400mg m2 of body area weekly; these does can be followed by weekly doses for 2, 3, 4, 5, 6, 7, 8, 9, 19, 11, 12

or more weeks.

In one embodiment, human unit dose forms of polynuceotides comprise a suitable dosage range or effective

amount that provides any therapeutic effect As appreciated by one of ordinary skill in the art a therapeutic effect depends

on a number of factors, including the sequence of the polynucleotide, molecular weight of the polynucleotide and route of

administration. Dosages are generally selected by the physician or other health care professional in accordance with a

variety of parameters known in the art, such as severity of symptoms, history of the patient and the like. Generally, for a

polynucleotide of about 20 bases, a dosage range may be selected from, for example, an independently selected lower limit

such as about 0.1,0.25, 0.5, 1, 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400 or 500 mg/kg up to an

independently selected upper limit, greater than the lower limit, of about 60, 80, 100, 200, 300, 400, 500, 750, 1000, 1500,

2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000 or 10,000 mg/kg. For example, a dose may be about any of the following:

0.1 to 100 mg/kg, 0.1 to 50 mg/kg, 0.1 to 25 mg/kg, 0.1 to 10 mg/kg, 1 to 500 mg/kg, 100 to 400 mg/kg, 200 to 300 mg/kg, 1

to 100 mg/kg, 100 to 200 mg/kg, 300 to 400 mg/kg, 400 to 500 mg/kg, 500 to 1000 mg/kg, 500 to 5000 mg/kg, or 500 to

10,000 mg/kg. Generally, parenteral routes of administration may require higher doses of polynucleotide compared to more

00 direct application to the nucleotide to diseased tissue, as do polynucleotides of increasing length.

O In one embodiment, human unit dose forms of T-cells comprise a suitable dosage range or effective amount that

provides any therapeutic effect. As appreciated by one of ordinary skill in the art, a therapeutic effect depends on a number

of factors. Dosages are generally selected by the physician or other health care professional in accordance with a variety of

parameters known in the art, such as severity of symptoms, history of the patient and the like. A dose may be about 104

cells to about 106 cells, about 108 cells to about 108 cells, about 108 to about 1011 cells, or about 108 to about 5 x 1010 cells.

CN A dose may also about 106 cells/m 2 to about 1010 cells/m2 or about 106 cells/m 2 to about 108 cells/m 2

Proteins(s) of the invention, and/or nucleic acids encoding the protein(s), can also be administered via liposomes,

S which may also serve to: 1) target the proteins(s) to a particular tissue, such as lymphoid tissue; 2) to target selectively to

diseases cells; or, 3) to increase the half-life of the peptide composition. Liposomes include emulsions, foams, micelles,

S insoluble monolayers, liquid crystals, phospholipid dispersions, lamellar layers and the like. In these preparations, the

CK1 peptide to be delivered is incorporated as part of a liposome, alone or In conjunction with a molecule which binds to a00

receptor prevalent among lymphoid cells, such as monoclonal antibodies which bind to the CD45 antigen, or with other

therapeutic or immunogenic compositions. Thus, liposomes either filled or decorated with a desired peptide of the invention

can be directed to the site of lymphoid cells, where the liposomes then deliver the peptide compositions. Liposomes for use

in accordance with the invention are formed from standard vesicle-forming lipids, which generally include neutral and

negatively charged phospholipids and a sterol, such as cholesterol. The selection of lipids is generally guided by

consideration of, liposome size, acid lability and stability of the liposomes in the blood stream. A variety of methods are

available for preparing liposomes, as described in, Szoka, et al., Ann. Rev. Biophys. Bioeng. 9:467 (1980), and U.S.

Patent Nos. 4,235,871, 4,501,728, 4,837,028, and 5,019,369.

For targeting cells of the immune system, a ligand to be incorporated into the liposome can include, e.g.,

antibodies or fragments thereof specific for cell surface determinants of the desired immune system cells. A liposome

suspension containing a peptide may be administered intravenously, locally, topically, etc. In a dose which varies according

to, inter alia, the manner of administration, the peptide being delivered, and the stage of the disease being treated.

For solid compositions, conventional nontoxic solid carriers may be used which include, for example,

pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose,

sucrose, magnesium carbonate, and the like. For oral administration, a pharmaceutically acceptable nontoxic composition is

formed by incorporating any of the normally employed excipients, such as those carriers previously listed, and generally

of active ingredient, that is, one or more peptides of the invention, and more preferably at a concentration of 25%-75%.

For aerosol administration, immunogenic peptides are preferably supplied in finely divided form along with a

surfactant and propellant. Typical percentages of peptides are about 0.01%-20% by weight, preferably about The

surfactant must, of course, be nontoxic, and preferably soluble in the propellant. Representative of such agents are the

esters or partial esters of fatty acids containing from about 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic,

stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride. Mixed esters,

such as mixed or natural glycerides may be employed. The surfactant may constitute about 0.1%-20% by weight of the

composition, preferably about 0.25-5%. The balance of the composition Is ordinarily propellant. A carrier can also be

included, as desired, as with, lecithin for intranasal delivery.

XI.) Diagnostic and Prognostic Embodiments of 191P4D12(b).

As disclosed herein, 191P4D12(b) polynucleotides, polypeptides, reactive cytotoxic T cells (CTL), reactive helper T

cells (HTL) and anti-polypeptide antibodies are used in well known diagnostic, prognostic and therapeutic assays that

examine conditions associated with dysregulated cell growth such as cancer, in particular the cancers listed in Table I (see,

both its specific pattern of tissue expression as well as its overexpression in certain cancers as described for example in

00 the Example entitled "Expression analysis of 191P4D12(b) in normal tissues, and patient specimens").O

191P4D12(b) can be analogized to a prostate associated antigen PSA, the archetypal marker that has been used

by medical practitioners for years to Identify and monitor the presence of prostate cancer (see, Merrill et al., J. Urol.

t 163(2): 503-5120 (2000); Polascik et al., J. Urol. Aug; 162(2):293-306 (1999) and Fortier et al., J. Nat. Cancer Inst. 91(19):

1635-1640(1999)). A variety of other diagnostic markers are also used in similar contexts including p53 and K-ras (see, e.g.,

S Tulchinsky et al., Int J Mol Med 1999 Jul 4(1):99-102 and Minimoto et al., Cancer Detect Prev 2000;24(1):1-12). Therefore,

this disclosure of 191 P4D12(b) polynucleotides and polypeptides (as well as 191 P4D12(b) polynucleotide probes and anti-

191P4D12(b) antibodies used to identify the presence of these molecules) and their properties allows skilled artisans to

utilize these molecules in methods that are analogous to those used, for example, in a variety of diagnostic assays directed

to examining conditions associated with cancer.

STypical embodiments of diagnostic methods which utilize the 191 P4D12(b) polynucleotides, polypeptides, reactive

00 T cells and antibodies are analogous to those methods from well-established diagnostic assays, which employ, PSA

polynucleotides, polypeptides, reactive T cells and antibodies. For example, just as PSA polynucleotides are used as probes

CK (for example in Northern analysis, see, Sharief et al., Biochem. Mol. Biol. Int. 33(3):567-74(1994)) and primers (for

example in PCR analysis, see, Okegawa et al., J. Urol. 163(4): 1189-1190 (2000)) to observe the presence and/or the

level of PSA mRNAs in methods of monitoring PSA overexpression or the metastasis of prostate cancers, the 191P4D12(b)

polynucleotides described herein can be utilized in the same way to detect 191P4D12(b) overexpression or the metastasis of

prostate and other cancers expressing this gene. Alternatively, just as PSA polypeptides are used to generate antibodies

specific for PSA which can then be used to observe the presence and/or the level of PSA proteins in methods to monitor

PSA protein overexpression (see, Stephan et al., Urology 55(4):560-3 (2000)) or the metastasis of prostate cells (see,

Alanen et Pathol. Res. Pract. 192(3):233-7 (1996)), the 191P4D12(b) polypeptides described herein can be utilized

to generate antibodies for use in detecting 191P4D12(b) overexpression or the metastasis of prostate cells and cells of other

cancers expressing this gene.

Specifically, because metastases involves the movement of cancer cells from an organ of origin (such as the lung

or prostate gland etc.) to a different area of the body (such as a lymph node), assays which examine a biological sample for

the presence of cells expressing 191P4D12(b) polynucleotides and/or polypeptides can be used to provide evidence of

metastasis. For example, when a biological sample from tissue that does not normally contain 191P4D12(b)-expressing cells

(lymph node) is found to contain 191P4D12(b)-expressing cells such as the 191P4D12(b) expression seen in LAPC4 and

LAPC9, xenografts isolated from lymph node and bone metastasis, respectively, this finding is indicative of metastasis.

Alternatively 191 P4D12(b) polynucleotides and/or polypeptides can be used to provide evidence of cancer, for

example, when cells in a biological sample that do not normally express 191P4D12(b) or express 191P4D12(b) at a different

level are found to express 191P4D12(b) or have an increased expression of 191P4D12(b) (see, the 191P4D12(b)

expression in the cancers listed in Table I and in patient samples etc. shown in the accompanying Figures). In such assays,

artisans may further wish to generate supplementary evidence of metastasis by testing the biological sample for the

presence of a second tissue restricted marker (in addition to 191P4D12(b)) such as PSA, PSCA etc. (see, Alanen et al.,

Pathol. Res. Pract. 192(3): 233-237 (1996)).

The use of immunohistochemistry to identify the presence of a 191P4D12(b) polypeptide within a tissue section

can indicate an altered state of certain cells within that tissue. It is well understood in the art that the ability of an antibody to

localize to a polypeptide that is expressed in cancer cells is a way of diagnosing presence of disease, disease stage,

progression and/or tumor aggressiveness. Such an antibody can also detect an altered distribution of the polypeptide within

00 the cancer cells, as compared to corresponding non-malignant tissue.

O The 191P4D12(b) polypeptide and immunogenic compositions are also useful in view of the phenomena of altered

C subcellular protein localization in disease states. Alteration of cells from normal to diseased state causes changes in cellular

morphology and Is often associated with changes in subcellular protein localizationldistribution. For example, cell membrane

S proteins that are expressed in a polarized manner in normal cells can be altered in disease, resulting in distribution of the

protein in a non-polar manner over the whole cell surface.

CK1 The phenomenon of altered subcellular protein localization in a disease state has been demonstrated with MUC1

and Her2 protein expression by use of immunohistochemical means. Normal epithelial cells have a typical apical distribution

S of MUC1, in addition to some supranuclear localization of the glycoprotein, whereas malignant lesions often demonstrate an

S apolar staining pattern (Diaz et al, The Breast Journal, 7; 40-45 (2001); Zhang et al, Clinical Cancer Research, 4; 2669-2676

rC (1998): Cao, et al, The Journal of Histochemistry and Cytochemistry, 45:1547-1557 (1997)). In addition, normal breast

rC epithelium is either negative for Her2 protein or exhibits only a basolateral distribution whereas malignant cells can express00

the protein over the whole cell surface (De Potter, et al, International Journal of Cancer, 44; 969-974 (1989): McCormick, et

al, 117; 935-943 (2002)). Alternatively, distribution of the protein may be altered from a surface only localization to include

diffuse cytoplasmic expression in the diseased state. Such an example can be seen with MUC1 (Diaz, et al, The Breast

Journal, 7: 40-45 (2001)).

Alteration in the localization/distribution of a protein in the cell, as detected by immunohistochemical methods, can

also provide valuable information concerning the favorability of certain treatment modalities. This last point is illustrated by a

situation where a protein may be intracellular in normal tissue, but cell surface in malignant cells; the cell surface location

makes the cells favorably amenable to antibody-based diagnostic and treatment regimens. When such an alteration of

protein localization occurs for 191P4D12(b), the 191P4D12(b) protein and immune responses related thereto are very useful.

Accordingly, the ability to determine whether alteration of subcellular protein localization occurred for 24P4C12 make the

191P4D12(b) protein and immune responses related thereto very useful. Use of the 191P4D12(b) compositions allows thoseskilled in the art to make important diagnostic and therapeutic decisions.

Immunohistochemical reagents specific to 191P4D12(b) are also useful to detect metastases of tumors expressing

191P4D12(b) when the polypeptide appears in tissues where 191P4D12(b) is not normally produced.

Thus, 191P4D12(b) polypeptides and antibodies resulting from immune responses thereto are useful in a variety of

important contexts such as diagnostic, prognostic, preventative and/or therapeutic purposes known to those skilled in the art.

Just as PSA polynucleotide fragments and polynucleotide variants are employed by skilled artisans for use in

methods of monitoring PSA, 191P4D12(b) polynucleotide fragments and polynucleotide variants are used in an analogous

manner. In particular, typical PSA polynucleotides used in methods of monitoring PSA are probes or primers which consist

of fragments of the PSA cDNA sequence. Illustrating this, primers used to PCR amplify a PSA polynucleotide must include

less than the whole PSA sequence to function in the polymerase chain reaction. In the context of such PCR reactions,

skilled artisans generally create a variety of different polynucleotide fragments that can be used as primers in order to amplify

different portions of a polynucleotide of interest or to optimize amplification reactions (see, Caetano-Anolles, G.

Biotechniques 25(3): 472-476, 478-480 (1998); Robertson et al., Methods Mol. Biol. 98:121-154 (1998)). An additional

illustration of the use of such fragments is provided in the Example entitled "Expression analysis of 191P4D12(b) in normal

tissues, and patient specimens," where a 191P4D12(b) polynucleotide fragment is used as a probe to show the expression

of 191P4D12(b) RNAs in cancer cells. In addition, variant polynucleotide sequences are typically used as primers andprobes for the corresponding mRNAs in PCR and Northern analyses (see, Sawai et al., Fetal Diagn. Ther. 1996 Nov-

Dec 11(6):407-13 and Current Protocols In Molecular Biology, Volume 2, Unit 2, Frederick M. Ausubel et al. eds., 1995)).

Polynucleotide fragments and variants are useful in this context where they are capable of binding to a target polynucleotide

sequence a 191P4D12(b) polynucleotide shown in Figure 2 or variant thereof) under conditions of high stringency.

00 Furthermore, PSA polypeptides which contain an epitope that can be recognized by an antibody or T cell that

O specifically binds to that epitope are used in methods of monitoring PSA. 191P4D12(b) polypeptide fragments and

polypeptide analogs or variants can also be used in an analogous manner. This practice of using polypeptide fragments or

polypeptide variants to generate antibodies (such as anti-PSA antibodies or T cells) is typical in the art with a wide variety of

systems'such as fusion proteins being used by practitioners (see, Current Protocols In Molecular Biology, Volume 2,

Unit 16, Frederick M. Ausubel et al. eds., 1995). In this context, each epitope(s) functions to provide the architecture with

which an antibody or T cell is reactive. Typically, skilled artisans create a variety of different polypeptide fragments that can

be used in order to generate immune responses specific for different portions of a polypeptide of interest (see, U.S.

S Patent No. 5,840,501 and U.S. Patent No. 5,939,533). For example it may be preferable to utilize a polypeptide comprising

CN one of the 191P4D12(b) biological motifs discussed herein or a motif-bearing subsequence which is readily identified by one

of skill in the art based on motifs available in the art. Polypeptide fragments, variants or analogs are typically useful in this

0c context as long as they comprise an epitope capable of generating an antibody or T cell specific for a target polypeptide

sequence a 191P4D12(b) polypeptide shown in Figure 3).

C As shown herein, the 191P4D12(b) polynudeotides and polypeptides (as well as the 191P4D12(b) polynucleotide

probes and anti-191P4D12(b) antibodies or T cells used to identify the presence of these molecules) exhibit specific

properties that make them useful in diagnosing cancers such as those listed in Table I. Diagnostic assays that measure the

presence of 191P4D12(b) gene products, in order to evaluate the presence or onset of a disease condition described herein,

such as prostate cancer, are used to identify patients for preventive measures or further monitoring, as has been done so

successfully with PSA. Moreover, these materials satisfy a need in the art for molecules having similar or complementary

characteristics to PSA in situations where, for example, a definite diagnosis of metastasis of prostatic origin cannot be made

on the basis of a test for PSA alone (see, Alanen et al., Pathol. Res. Pract. 192(3): 233-237 (1996)), and consequently,

materials such as 191P4D12(b) polynucleotides and polypeptides (as well as the 191P4D12(b) polynucleotide probes and

anti-191P4D12(b) antibodies used to identify the presence of these molecules) need to be employed to confirm a metastases

of prostatic origin.

Finally, in addition to their use in diagnostic assays, the 191P4D12(b) polynucleotides disclosed herein have a

number of other utilities such as their use in the identification of oncogenetic associated chromosomal abnormalities in the

chromosomal region to which the 191P4D12(b) gene maps (see the Example entitled "Chromosomal Mapping of

191P4D12(b)" below). Moreover, in addition to their use in diagnostic assays, the 191P4D12(b)-related proteins and

polynucleotides disclosed herein have other utilities such as their use in the forensic analysis of tissues of unknown origin

(see, Takahama K Forensic Sc Int 1996 Jun 28;80(1-2): 63-9).

Additionally, 191P4D12(b)-related proteins or polynucleotides of the invention can be used to treat a pathologic

condition characterized by the over-expression of 191P4D12(b). For example, the amino acid or nucleic acid sequence of

Figure 2 or Figure 3, or fragments of either, can be used to generate an immune response to a 191P4D12(b) antigen.

Antibodies or other molecules that react with 191P4D12(b) can be used to modulate the function of this molecule, and

thereby provide a therapeutic benefit.

XII.) Inhibition of 191P4D12(b) Protein Function

The invention includes various methods and compositions for inhibiting the binding of 191P4D12(b) to its binding

partner or its association with other protein(s) as well as methods for inhibiting 191P4D12(b) function.

XII.A.) Inhibition of 191P4D12(b) With Intracellular Antibodies

OO In one approach, a recombinant vector that encodes single chain antibodies that specifically bind to 191P4D12(b)

0 are introduced into 191P4D12(b) expressing cells via gene transfer technologies. Accordingly, the encoded single chain

CN anti-191P4D12(b) antibody Is expressed intracellularly, binds to 191P4D12(b) protein, and thereby inhibits its function.

Methods for engineering such intracellular single chain antibodies are well known. Such intracellular antibodies, also known

as "intrabodies", are specifically targeted to a particular compartment within the cell, providing control over where the

s inhibitory activity of the treatment is focused. This technology has been successfully applied in the art (for review, see

C Richardson and Marasco, 1995, TIBTECH vol. 13). Intrabodies have been shown to virtually eliminate the expression of

otherwise abundant cell surface receptors (see, Richardson et al., 1995, Proc. Natl. Acad. Scd. USA 92: 3137-3141;

Beerli et al., 1994, J. Biol. Chem. 289: 23931-23936; Deshane et al., 1994, Gene Ther. 1: 332-337).

iSingle chain antibodies comprise the variable domains of the heavy and light chain joined by a flexible linker

polypeptide, and are expressed as a single polypeptide. Optionally, single chain antibodies are expressed as a single chain

C- variable region fragment joined to the light chain constant region. Well-known intracellular trafficking signals are engineered000 into recombinant polynucleotide vectors encoding such single chain antibodies in order to target precisely the intrabody to

O the desired intracellular compartment. For example, intrabodies targeted to the endoplasmic reticulum (ER) are engineered

to incorporate a leader peptide and, optionally, a C-terminal ER retention signal, such as the KDEL amino acid motif.

Intrabodies intended to exert activity in the nucleus are engineered to include a nuclear localization signal. Lipid moieties are

joined to intrabodies in order to tether the intrabody to the cytosolic side of the plasma membrane. Intrabodies can also be

targeted to exert function in the cytosol. For example, cytosolic intrabodies are used to sequester factors within the cytosol,

thereby preventing them from being transported to their natural cellular destination.

In one embodiment, intrabodies are used to capture 191P4D12(b) in the nucleus, thereby preventing its activity

within the nucleus. Nuclear targeting signals are engineered into such 191P4D12(b) intrabodies in order to achieve the

desired targeting. Such 191P4D12(b) intrabodies are designed to bind specifically to a particular 191P4D12(b) domain. In

another embodiment, cytosolic intrabodies that specifically bind to a 191P4D12(b) protein are used to prevent 191P4D12(b)

from gaining access to the nucleus, thereby preventing it from exerting any biological activity within the nucleus

preventing 191P4D12(b) from forming transcription complexes with other factors).

In order to specifically direct the expression of such intrabodies to particular cells, the transcription of the intrabody

Is placed under the regulatory control of an appropriate tumor-specific promoter andlor enhancer. In order to target intrabody

expression specifically to prostate, for example, the PSA promoter and/or promoter/enhancer can be utilized (See, for

example, U.S. Patent No. 5,919,652 issued 6 July 1999).

XII.B.) Inhibition of 191P4D12(b) with Recombinant Proteins

In another approach, recombinant molecules bind to 191P4D12(b) and thereby inhibit 191P4D12(b) function. For

example, these recombinant molecules prevent or inhibit 191P4D12(b) from accessing/binding to its binding partner(s) or

associating with other protein(s). Such recombinant molecules can, for example, contain the reactive part(s) of a 191P4D12(b)

specific antibody molecule. In a particular embodiment, the 191P4D12(b) binding domain of a 191P4D12(b) binding partner Is

engineered into a dimeric fusion protein, whereby the fusion protein comprises two 191P4D12(b) ligand binding domains linked to

the Fc portion of a human IgG, such as human IgG1. Such IgG portion can contain, for example, the CH2 and CH3 domains and

the hinge region, but not the CH1 domain. Such dimeric fusion proteins are administered in soluble form to patients suffering from

a cancer associated with the expression of 191P4D12(b), whereby the dimeric fusion protein specifically binds to 191P4D12(b)

and blocks 191P4D12(b) interaction with a binding partner. Such dimeric fusion proteins are further combined into multimeric

proteins using known antibody linking technologies.

XII.C.) Inhibition of 191P4D12(b) Transcription or Translation

00 The present invention also comprises various methods and compositions for inhibiting the transcription of the

S 191P4D12(b) gene. Similarly, the invention also provides methods and compositions for inhibiting the translation of

191P4D12(b) mRNA into protein.

SIn one approach, a method of inhibiting the transcription of the 191P4D12(b) gene comprises contacting the

191P4D12(b) gene with a 191P4D12(b) antisense polynucleotide. In another approach, a method of inhibiting 191P4D12(b)

mRNA translation comprises contacting a 191P4D12(b) mRNA with an antisense polynucleotide. In another approach, a

191P4D12(b) specific ribozyme is used to cleave a 191P4D12(b) message, thereby inhibiting translation. Such antisense

and ribozyme based methods can also be directed to the regulatory regions of the 191P4D12(b) gene, such as 191P4D12(b)

promoter and/or enhancer elements. Similarly, proteins capable of inhibiting a 191P4D12(b) gene transcription factor are

C used to inhibit 191P4D12(b) mRNA transcription. The various polynucleotides and compositions useful in the

aforementioned methods have been described above. The use of antisense and ribozyme molecules to inhibit transcription

00 and translation is well known in the art.

SOther factors that inhibit the transcription of 191P4D12(b) by interfering with 191P4D12(b) transcriptional activation

C are also useful to treat cancers expressing 191P4D12(b). Similarly, factors that interfere with 191P4D12(b) processing are

useful to treat cancers that express 191P4D12(b). Cancer treatment methods utilizing such factors are also within the scope

of the invention.

XII.D.) General Considerations for Therapeutic Strategies

Gene transfer and gene therapy technologies can be used to deliver therapeutic polynucleotide molecules to tumor cells

synthesizing 191P4D12(b) antisense, ribozyme, polynucleotides encoding intrabodies and other 191P4D12(b) inhibitory

molecules). A number of gene therapy approaches are known in the art Recombinant vectors encoding 191P4D12(b) antisense

polynucleotides, ribozymes, factors capable of interfering with 191P4D12(b) transcription, and so forth, can be delivered to target

tumor cells using such gene therapy approaches.

The above therapeutic approaches can be combined with any one of a wide variety of surgical, chemotherapy or

radiation therapy regimens. The therapeutic approaches of the invention can enable the use of reduced dosages of

chemotherapy (or other therapies) and/or less frequent administration, an advantage for all patients and particularly for those that

do not tolerate the toxicity of the chemotherapeutic agent well.

The anti-tumor activity of a particular composition antisense, ribozyme, intrabody), or a combination of such

compositions, can be evaluated using various in vitro and in vivo assay systems. In vitro assays that evaluate therapeutic activity

include cell growth assays, soft agar assays and other assays indicative of tumor promoting activity, binding assays capable of

determining the extent to which a therapeutic composition will inhibit the binding of 191P4D12(b) to a binding partner, etc.

In vivo, the effect of a 191P4D12(b) therapeutic composition can be evaluated in a suitable animal model. For example,

xenogenic prostate cancer models can be used, wherein human prostate cancer explants or passaged xenograft tissues are

Introduced into immune compromised animals, such as nude or SCID mice (Klein et al., 1997, Nature Medicine 3: 402-408). For

example, PCT Patent Application W098/16628 and U.S. Patent 6,107,540 describe various xenograft models of human

prostate cancer capable of recapitulating the development of primary tumors, micrometastasis, and the formation of

osteoblastic metastases characteristic of late stage disease. Efficacy can be predicted using assays that measure inhibition

of tumor formation, tumor regression or metastasis, and the like.

In vivo assays that evaluate the promotion of apoptosis are useful in evaluating therapeutic compositions. In one

embodiment, xenografts from tumor bearing mice treated with the therapeutic composition can be examined for the presence

of apoptotic foci and compared to untreated control xenograft-bearing mice. The extent to which apoptotic fod are found in

the tumors of the treated mice provides an indication of the therapeutic efficacy of the composition.

The therapeutic compositions used In the practice of the foregoing methods can be formulated into pharmaceutical

LC- compositions comprising a carrier suitable for the desired delivery method. Suitable carriers include any material that when

combined with the therapeutic composition retains the anti-tumor function of the therapeutic composition and is generally

i non-reactive with the patient's Immune system. Examples Include, but are not limited to, any of a number of standard

pharmaceutical carriers such as sterile phosphate buffered saline solutions, bacteriostatic water, and the like (see, generally,

C-K Remington's Pharmaceutical Sciences 16(h Edition, A. Osal., Ed., 1980).

Therapeutic formulations can be solubilized and administered via any route capable of delivering the therapeutic

composition to the tumor site. Potentially effective routes of administration include, but are not limited to, intravenous,

Lq parenteral, intraperitoneal, intramuscular, intratumor, intradermal, intraorgan, orthotopic, and the like. A preferred formulation

Cl for intravenous injection comprises the therapeutic composition in a solution of preserved bacteriostatic water, sterile

LC- unpreserved water, and/or diluted in polyvinylchloride or polyethylene bags containing 0.9% sterile Sodium Chloride for00SInjection, USP. Therapeutic protein preparations can be lyophilized and stored as sterile powders, preferably under vacuum,

Sand then reconstituted in bacteriostatic water (containing for example, benzyl alcohol preservative) or in sterile water prior to

injection.

Dosages and administration protocols for the treatment of cancers using the foregoing methods will vary with the

method and the target cancer, and will generally depend on a number of other factors appreciated in the art.

XIII.) Identification, Characterization and Use of Modulators of 191 P4D12(b)

Methods to Identify and Use Modulators

In one embodiment, screening is performed to identify modulators that induce or suppress a particular expression

profile, suppress or induce specific pathways, preferably generating the associated phenotype thereby. In another

embodiment, having identified differentially expressed genes important in a particular state; screens are performed to identify

modulators that alter expression of individual genes, either increase or decrease. In another embodiment, screening is

performed to identify modulators that alter a biological function of the expression product of a differentially expressed gene.

Again, having identified the importance of a gene in a particular state, screens are performed to identify agents that bind

and/or modulate the biological activity of the gene product.

In addition, screens are done for genes that are induced In response to a candidate agent After identifying a

modulator (one that suppresses a cancer expression pattern leading to a normal expression pattern, or a modulator of a

cancer gene that leads to expression of the gene as in normal tissue) a screen is performed to identify genes that are

specifically modulated in response to the agent. Comparing expression profiles between normal tissue and agent-treated

cancer tissue reveals genes that are not expressed in normal tissue or cancer tissue, but are expressed in agent treated

tissue, and vice versa. These agent-specific sequences are identified and used by methods described herein for cancer

genes or proteins. In particular these sequences and the proteins they encode are used in marking or identifying agent-

treated cells. In addition, antibodies are raised against the agent-induced proteins and used to target novel therapeutics to

the treated cancer tissue sample.

Modulator-related Identification and Screening Assays:

Gene Expression-related Assays

Proteins, nucleic acids, and antibodies of the invention are used in screening assays. The cancer-associated

proteins, antibodies, nucleic acids, modified proteins and cells containing these sequences are used in screening assays,

such as evaluating the effect of drug candidates on a "gene expression profile," expression profile of polypeptides or

alteration of biological function. In one embodiment, the expression profiles are used, preferably in conjunction with high

00 throughput screening techniques to allow monitoring for expression profile genes after treatment with a candidate agent

Davis, GF, et al, J Biol Screen 7:69 (2002); Zlokarnik, et al., Science 279:84-8 (1998); Heid, Genome Res 6:986-

Lc 94,1996).

The cancer proteins, antibodies, nucleic acids, modified proteins and cells containing the native or modified cancer

S proteins or genes are used In screening assays. That Is, the present invention comprises methods for screening for

S compositions which modulate the cancer phenotype or a physiological function of a cancer protein of the invention. This is

done on a gene itself or by evaluating the effect of drug candidates on a "gene expression profile" or biological function. In

one embodiment, expression profiles are used, preferably in conjunction with high throughput screening techniques to allow

monitoring after treatment with a candidate agent, see Zlokamik, supra.

rli A variety of assays are executed directed to the genes and proteins of the invention. Assays are run on an

individual nucleic acid or protein level. That is, having identified a particular gene as up regulated in cancer, test compounds

00 are screened for the ability to modulate gene expression or for binding to the cancer protein of the invention. "Modulation" in

this context includes an increase or a decrease in gene expression. The preferred amount of modulation will depend on the

Cl original change of the gene expression in normal versus tissue undergoing cancer, with changes of at least 10%, preferably

more preferably 100-300%, and in some embodiments 300-1000% or greater. Thus, if a gene exhibits a 4-fold

increase in cancer tissue compared to normal tissue, a decrease of about four-fold is often desired; similarly, a

decrease in cancer tissue compared to normal tissue a target value of a 10-fold increase in expression by the test compound

is often desired. Modulators that exacerbate the type of gene expression seen in cancer are also useful, as an

upregulated target in further analyses.

The amount of gene expression is monitored using nucleic acid probes and the quantification of gene expression

levels, or, alternatively, a gene product itself is monitored, through the use of antibodies to the cancer protein and

standard immunoassays. Proteomics and separation techniques also allow for quantification of expression.

Expression Monitoring to Identify Compounds that Modify Gene Expression

In one embodiment, gene expression monitoring, an expression profile, is monitored simultaneously for a

number of entities. Such profiles will typically Involve one or more of the genes of Figure 2. In this embodiment, cancer

nucleic acid probes are attached to biochips to detect and quantify cancer sequences in a particular cell. Alternatively, PCR

can be used. Thus, a series, wells of a microtiter plate, can be used with dispensed primers in desired wells. A PCR

reaction can then be performed and analyzed for each well.

Expression monitoring is performed to identify compounds that modify the expression of one or more cancer-

associated sequences, a polynucleotide sequence set out in Figure 2. Generally, a test modulator is added to the cells

prior to analysis. Moreover, screens are also provided to identify agents that modulate cancer, modulate cancer proteins of

the invention, bind to a cancer protein of the invention, or interfere with the binding of a cancer protein of the invention and

an antibody or other binding partner.

In one embodiment, high throughput screening methods involve providing a library containing a large number of

potential therapeutic compounds (candidate compounds). Such "combinatorial chemical libraries" are then screened in one

or more assays to identify those library members (particular chemical species or subclasses) that display a desired

characteristic activity. The compounds thus identified can serve as conventional "lead compounds," as compounds for

screening, or as therapeutics.

In certain embodiments, combinatorial libraries of potential modulators are screened for an ability to bind to a

cancer polypeptide or to modulate activity. Conventionally, new chemical entities with useful properties are generated by

identifying a chemical compound (called a "lead compound") with some desirable property or activity, inhibiting activity,

creating variants of the lead compound, and evaluating the property and activity of those variant compounds. Often, high000 throughput screening (HTS) methods are employed for such an analysis.

SAs noted above, gene expression monitoring is conveniently used to test candidate modulators protein,

S nucleic acid or small molecule). After the candidate agent has been added and the cells allowed to Incubate for a period, the

sample containing a target sequence to be analyzed is, added to a blochip.

If required, the target sequence is prepared using known techniques. For example, a sample Is treated to lyse the

C' cells, using known lysis buffers, electroporation, etc., with purification and/or amplification such as PCR performed as

appropriate. For example, an in vitro transcription with labels covalently attached to the nucleotides is performed. Generally,

the nucleic acids are labeled with biotin-FITC or PE, or with cy3 or

The target sequence can be labeled with, a fluorescent, a chemiluminescent, a chemical, or a radioactive

C1 signal, to provide a means of detecting the target sequence's specific binding to a probe. The label also can be an enzyme,

Ssuch as alkaline phosphatase or horseradish peroxidase, which when provided with an appropriate substrate produces a

00 product that is detected. Alternatively, the label is a labeled compound or small molecule, such as an enzyme inhibitor, that

S binds but is not catalyzed or altered by the enzyme. The label also can be a moiety or compound, such as, an epitope tag or

biotin which specifically binds to streptavidin. For the example of biotin, the streptavldin is labeled as described above,

thereby, providing a detectable signal for the bound target sequence. Unbound labeled streptavidin Is typically removed prior

to analysis.

As will be appreciated by those in the art, these assays can be direct hybridization assays or can comprise

"sandwich assays", which include the use of multiple probes, as is generally outlined in U.S. Patent Nos. 5, 681,702;

5,597,909; 5,545,730; 5,594,117; 5,591,584; 5,571,670; 5,580,731; 5,571,670; 5,591,584; 5,624,802; 5,635,352; 5,594,118;

5,359,100; 5,124, 246; and 5,681,697. In this embodiment, in general, the target nucleic acid Is prepared as outlined above,

and then added to the biochip comprising a plurality of nucleic acid probes, under conditions that allow the formation of a

hybridization complex.

A variety of hybridization conditions are used in the present invention, including high, moderate and low stringency

conditions as outlined above. The assays are generally run under stringency conditions which allow formation of the label

probe hybridization complex only in the presence of target. Stringency can be controlled by altering a step parameter that is

a thermodynamic variable, including, but not limited to, temperature, formamide concentration, salt concentration, chaotropic

.salt concentration pH, organic solvent concentration, etc. These parameters may also be used to control non-specific

binding, as is generally outlined in U.S. Patent No. 5,681,697. Thus, it can be desirable to perform certain steps at higher

stringency conditions to reduce non-specific binding.

The reactions outlined herein can be accomplished in a variety of ways. Components of the reaction can be added

simultaneously, or sequentially, in different orders, with preferred embodiments outlined below. In addition, the reaction may

include a variety of other reagents. These include salts, buffers, neutral proteins, e.g. albumin, detergents, etc. which can be

used to facilitate optimal hybridization and detection, and/or reduce nonspecific or background Interactions. Reagents that

otherwise improve the efficiency of the assay, such as protease inhibitors, nuclease Inhibitors, anti-microbial agents, etc.,

may also be used as appropriate, depending on the sample preparation methods and purity of the target. The assay data

are analyzed to determine the expression levels of individual genes, and changes in expression levels as between states,

forming a gene expression profile.

Biological Activity-related Assays

The invention provides methods identify or screen for a compound that modulates the activity of a cancer-related

gene or protein of the invention. The methods comprise adding a test compound, as defined above, to a cell comprising a

00 cancer protein of the invention. The cells contain a recombinant nucleic acid that encodes a cancer protein of the invention.

O In another embodiment, a library of candidate agents is tested on a plurality of cells.

CK1 In one aspect, the assays are evaluated in the presence or absence or previous or subsequent exposure of

S physiological signals, e.g. hormones, antibodies, peptides, antigens, cytokines, growth factors, action potentials,

pharmacological agents including chemotherapeutics, radiation, carcinogenics, or other cells cell-cell contacts). In

another example, the determinations are made at different stages of the cell cycle process. In this way, compounds that

C1 modulate genes or proteins of the invention are identified. Compounds with pharmacological activity are able to enhance or

interfere with the activity of the cancer protein of the invention. Once Identified, similar structures are evaluated to identify

critical structural features of the compound.

CNS In one embodiment, a method of modulating inhibiting) cancer cell division is provided; the method

c comprises administration of a cancer modulator. In another embodiment, a method of modulating inhibiting) cancer is

Cr provided; the method comprises administration of a cancer modulator. In a further embodiment, methods of treating cells or00

individuals with cancer are provided; the method comprises administration of a cancer modulator.

SIn one embodiment, a method for modulating the status of a cell that expresses a gene of the invention is provided.

As used herein status comprises such art-accepted parameters such as growth, proliferation, survival, function, apoptosis,

senescence, location, enzymatic activity, signal transduction, etc. of a cell. In one embodiment, a cancer inhibitor is an

antibody as discussed above. In another embodiment, the cancer inhibitor is an antisense molecule. A variety of cell

growth, proliferation, and metastasis assays are known to those of skill in the art, as described herein.

High Throughput Screening to Identify Modulators

The assays to identify suitable modulators are amenable to high throughput screening. Preferred assays thus

detect enhancement or inhibition of cancer gene transcription, inhibition or enhancement of polypeptide expression, and

inhibition or enhancement of polypeptide activity.

In one embodiment, modulators evaluated in high throughput screening methods are proteins, often naturally

occurring proteins or fragments of naturally occurring proteins. Thus, cellular extracts containing proteins, or random or

directed digests of proteinaceous cellular extracts, are used. In this way, libraries of proteins are made for screening in the

methods of the invention. Particularly preferred in this embodiment are libraries of bacterial, fungal, viral, and mammalian

proteins, with the latter being preferred, and human proteins being especially preferred. Particularly useful test compound

will be directed to the class of proteins to which the target belongs, substrates for enzymes, or ligands and receptors.

Use of Soft Aaar Growth and Colony Formation to Identify and Characterize Modulators

Normal cells require a solid substrate to attach and grow. When cells are transformed, they lose this phenotype

and grow detached from the substrate. For example, transformed cells can grow in stirred suspension culture or suspended

in semi-solid media, such as semi-solid or soft agar. The transformed cells, when transfected with tumor suppressor genes,

can regenerate normal phenotype and once again require a solid substrate to attach to and grow. Soft agar growth or colony

formation in assays are used to identify modulators of cancer sequences, which when expressed in host cells, inhibit

abnormal cellular proliferation and transformation. A modulator reduces or eliminates the host cells' ability to grow

suspended in solid or semisolid media, such as agar.

Techniques for soft agar growth or colony formation in suspension assays are described in Freshney, Culture of

Animal Cells a Manual of Basic Technique (3rd ed., 1994). See also, the methods section of Garkavtsev et al. (1996), supra.

Evaluation of Contact Inhibition and Growth Density Limitation to Identify and Characterize Modulators

Normal cells typically grow in a flat and organized pattern in cell culture until they touch other cells. When the cells

touch one another, they are contact inhibited and stop growing. Transformed cells, however, are not contact inhibited and

0 continue to grow to high densities in disorganized foci. Thus, transformed cells grow to a higher saturation density than

corresponding normal cells. This is detected morphologically by the formation of a disoriented monolayer of cells or cells in

foci. Alternatively, labeling index with 3H)-thymidine at saturation density is used to measure density limitation of growth,

similarly an MTT or Alamar blue assay will reveal proliferation capacity of cells and the the ability of modulators to affect

same. See Freshney (1994), supra. Transformed cells, when transfected with tumor suppressor genes, can regenerate a

normal phenotype and become contact inhibited and would grow to a lower density.

In this assay, labeling index with 3H)-thymidine at saturation density is a preferred method of measuring density

limitation of growth. Transformed host cells are transfected with a cancer-associated sequence and are grown for 24 hours

at saturation density in non-limiting medium conditions. The percentage of cells labeling with 3H)-thymidine is determined by

C= incorporated cpm.

SContact independent growth is used to identify modulators of cancer sequences, which had led to abnormal cellular00 proliferation and transformation. A modulator reduces or eliminates contact independent growth, and returns the cells to a

normal phenotype.

Evaluation of Growth Factor or Serum Dependence to Identify and Characterize Modulators

Transformed cells have lower serum dependence than their normal counterparts (see, Temin, J. Natl. Cancer

Inst. 37:167-175 (1966); Eagle et al., J. Exp. Med 131:836-879 (1970)); Freshney, supra. This is in part due to release of

various growth factors by the transformed cells. The degree of growth factor or serum dependence of transformed host cells

can be compared with that of control. For example, growth factor or serum dependence of a cell is monitored in methods toidentify and characterize compounds that modulate cancer-associated sequences of the invention.

Use of Tumor-specific Marker Levels to Identify and Characterize Modulators

Tumor cells release an increased amount of certain factors (hereinafter "tumor specific markers") than their normal

counterparts. For example, plasminogen activator (PA) is released from human glioma at a higher level than from normal

brain cells (see, Gullino, Angiogenesis, Tumor Vascularization, and Potential Interference with Tumor Growth, in

Biological Responses in Cancer, pp. 178-184 (Mihich 1985)). Similarly, Tumor Angiogenesis Factor (TAF) is released

at a higher level in tumor cells than their normal counterparts. See, Folkman, Angiogenesis and Cancer, Sem Cancer

Biol. (1992)), while bFGF is released from endothelial tumors (Ensoli, B et al).

Various techniques which measure the release of these factors are described in Freshney (1994), supra. Also,see, Unkless et al., J. Biol. Chem. 249:4295-4305 (1974); Strickland Beers, J. Biol. Chem. 251:5694-5702 (1976); Whur et

al., Br. J. Cancer 42:305 312 (1980); Gullino, Angiogenesis, Tumor Vascularization, and Potential Interference with Tumor

Growth, in Biological Responses in Cancer, pp. 178-184 (Mihich 1985); Freshney, Anticancer Res. 5:111-130 (1985).

For example, tumor specific marker levels are monitored in methods to identify and characterize compounds that modulate

cancer-associated sequences of the invention.

Invasiveness into Matrinel to Idenlify and Characterize Modulators

The degree of invasiveness into Matrigel or an extracellular matrix constituent can be used as an assay to identifyand characterize compounds that modulate cancer associated sequences. Tumor cells exhibit a positive correlation betweenmalignancy and invasiveness of cells into Matrigel or some other extracellular matrix constituent. In this assay, tumorigeniccells are typically used as host cells. Expression of a tumor suppressor gene in these host cells would decrease

invasiveness of the host cells. Techniques described in Cancer Res. 1999; 59:6010; Freshney (1994), supra, can be used.Briefly, the level of invasion of host cells is measured by using filters coated with Matrigel or some other extracellular matrixconstituent. Penetration into the gel, or through to the distal side of the filler, is rated as invasiveness, and rated

histologically by number of cells and distance moved, or by prelabeling the cells with 125s and counting the radioactivity on

the distal side of the filter or bottom of the dish. See, Freshney (1984), supra.

00 Evaluation of Tumor Growth In Vivo to Identify and Characterize Modulators

SEffects of cancer-associated sequences on cell growth are tested in transgenic or immune-suppressed organisms.

Transgenic organisms are prepared in a variety of art-accepted ways. For example, knock-out transgenic organisms, e.g.,

mammals such as mice, are made, in which a cancer gene is disrupted or in which a cancer gene is inserted. Knock-out

transgenic mice are made by insertion of a marker gene or other heterologous gene into the endogenous cancer gene site in

the mouse genome via homologous recombination. Such mice can also be made by substituting the endogenous cancer

gene with a mutated version of the cancer gene, or by mutating the endogenous cancer gene, by exposure to

carcinogens.

To prepare transgenlc chimeric animals, mice, a DNA construct is introduced into the nuclei of embryonic

CK1 stem cells. Cells containing the newly engineered genetic lesion are injected into a host mouse embryo, which is re-

implanted into a recipient female. Some of these embryos develop into chimeric mice that possess germ cells some of which

00 are derived from the mutant cell line. Therefore, by breeding the chimeric mice it is possible to obtain a new line of mice

containing the introduced genetic lesion (see, Capecchi et al., Science 244:1288 (1989)). Chimeric mice can be derived

NC according to US Patent 6,365,797, issued 2 April 2002; US Patent 6,107,540 issued 22 August 2000; Hogan et al.,

Manipulating the Mouse Embryo: A laboratory Manual, Cold Spring Harbor Laboratory (1988) and Teratocarcinomas and

Embryonic Stem Cells: A Practical Approach, Robertson, ed., IRL Press, Washington, (1987).

Alternatively, various immune-suppressed or immune-deficient host animals can be used. For example, a

genetically athymic "nude" mouse (see, Giovanella et al., J. Natl. Cancer Inst. 52:921 (1974)), a SCID mouse, a

thymectornized mouse, or an irradiated mouse (see, Bradley et al., Br. J. Cancer 38:263 (1978); Selby et al., Br. J.

Cancer 41:52 (1980)) can be used as a host. Transplantable tumor cells (typically about 106 cells) injected into isogenic

hosts produce invasive tumors in a high proportion of cases, while normal cells of similar origin will not. In hosts which

developed invasive tumors, cells expressing cancer-associated sequences are injected subcutaneously or orthotopically.

Mice are then separated into groups, including control groups and treated experimental groups) e.g. treated with a

modulator). After a suitable length of time, preferably 4-8 weeks, tumor growth is measured by volume or by its two

largest dimensions, or weight) and compared to the control. Tumors that have statistically significant reduction (using, e.g.,

Student's T test) are said to have inhibited growth.

In Vitro Assays to Identify and Characterize Modulators

Assays to identify compounds with modulating activity can be performed in vitro. For example, a cancer

polypeptide is first contacted with a potential modulator and incubated for a suitable amount of time, from 0.5 to 48

hours. In one embodiment, the cancer polypeptide levels are determined in vitro by measuring the level of protein or mRNA.

The level of protein is measured using immunoassays such as Western blotting, ELISA and the like with an antibody that

selectively binds to the cancer polypeptide or a fragment thereof. For measurement of mRNA, amplification, using

PCR, LCR, or hybridization assays, e. Northern hybridization, RNAse protection, dot blotting, are preferred. The level of

protein or mRNA is detected using directly or indirectly labeled detection agents, fluorescently or radioactively labeled

nucleic acids, radioactively or enzymatically labeled antibodies, and the like, as described herein.

Alternatively, a reporter gene system can be devised using a cancer protein promoter operably linked to a reporter

gene such as luciferase, green fluorescent protein, CAT, or P-gal. The reporter construct is typically transfected into a cell.

After treatment with a potential modulator, the amount of reporter gene transcription, translation, or activity is measured

according to standard techniques known to those of skill In the art (Davis GF, supra; Gonzalez, J. Negulescu, P. Curr.

Opin. Biotechnol. 1998: 9:624).00 As outlined above, in vitro screens are done on individual genes and gene products. That Is, having identified a

Sparticular differentially expressed gene as important in a particular state, screening of modulators of the expression of the

gene or the gene product itself is performed.

In one embodiment, screening for modulators of expression of specific gene(s) is performed. Typically, the

expression of only one or a few genes is evaluated. In another embodiment, screens are designed to first find compoundsthat bind to differentially expressed proteins. These compounds are then evaluated for the ability to modulate differentially

expressed activity. Moreover, once initial candidate compounds are identified, variants can be further screened to better

evaluate structure activity relationships.

Binding Assays to Identify and Characterize Modulators

In binding assays in accordance with the invention, a purified or isolated gene product of the invention is generally

00 used. For example, antibodies are generated to a protein of the invention, and immunoassays are run to determine the

Samount andfor location of protein. Alternatively, cells comprising the cancer proteins are used in the assays.Thus, the methods comprise combining a cancer protein of the invention and a candidate compound such as a

ligand, and determining the binding of the compound to the cancer protein of the invention. Preferred embodiments utilize

the human cancer protein; animal models of human disease of can also be developed and used. Also, other analogous

mammalian proteins also can be used as appreciated by those of skill in the art. Moreover, in some embodiments variant or

derivative cancer proteins are used.

Generally, the cancer protein of the invention, or the ligand, is non-diffusibly bound to an insoluble support. The

support can, be one having isolated sample receiving areas (a microtiter plate, an array, etc.). The insoluble supports

can be made of any composition to which the compositions can be bound, is readily separated from soluble material, and isotherwise compatible with the overall method of screening. The surface of such supports can be solid or porous and of any

convenient shape.

Examples of suitable insoluble supports include microtiter plates, arrays, membranes and beads. These are

typically made of glass, plastic polystyrene), polysaccharide, nylon, nitrocellulose, or Teflon T etc. Microtiter plates

and arrays are especially convenient because a large number of assays can be carried out simultaneously, using small

amounts of reagents and samples. The particular manner of binding of the composition to the support is not crucial so longas it is compatible with the reagents and overall methods of the invention, maintains the activity of the composition and is

nondiffusable. Preferred methods of binding include the use of antibodies which do not sterically block either the ligandbinding site or activation sequence when attaching the protein to the support, direct binding to "sticky" or ionic supports,chemical crosslinking, the synthesis of the protein or agent on the surface, etc. Following binding of the protein or

ligand/binding agent to the support, excess unbound material is removed by washing. The sample receiving areas may thenbe blocked through incubation with bovine serum albumin (BSA), casein or other innocuous protein or other moiety.

Once a cancer protein of the invention is bound to the support, and a test compound Is added to the assay.Alternatively, the candidate binding agent is bound to the support and the cancer protein of the invention is then added.

Binding agents include specific antibodies, non-natural binding agents identified in screens of chemical libraries, peptideanalogs, etc.

Of particular interest are assays to identify agents that have a low toxicity for human cells. A wide variety of assayscan be used for this purpose, including proliferation assays, cAMP assays, labeled In vitro protein-protein binding assays,

electrophoretic mobility shift assays, immunoassays for protein binding, functional assays (phosphorylation assays, etc.) and

the like.

00 A determination of binding of the test compound (ligand, binding agent, modulator, etc.) to a cancer protein of the

S invention can be done in a number of ways. The test compound can be labeled, and binding determined directly, by

C attaching all or a portion of the cancer protein of the invention to a solid support, adding a labeled candidate compound

Ct a fluorescent label), washing off excess reagent, and determining whether the label is present on the solid support. Various

blocking and washing steps can be utilized as appropriate.

In certain embodiments, only one of the components is labeled, a protein of the invention or ligands labeled.

Alternatively, more than one component is labeled with different labels, 1125, for the proteins and a fluorophor for the

compound. Proximity reagents, quenching or energy transfer reagents are also useful.

Competitive Binding to Identify and Characterize Modulators

In one embodiment, the binding of the "test compound" is determined by competitive binding assay with a

C00 "competitor." The competitor is a binding moiety that binds to the target molecule a cancer protein of the invention).

Competitors include compounds such as antibodies, peptides, binding partners, ligands, etc. Under certain circumstances,

C<1 the competitive binding between the test compound and the competitor displaces the test compound. In one embodiment,

the test compound is labeled. Either the test compound, the competitor, or both, is added to the protein for a time sufficient

to allow binding. Incubations are performed at a temperature that facilitates optimal activity, typically between four and 400C.

Incubation periods are typically optimized, to facilitate rapid high throughput screening; typically between zero and one

hour will be sufficient. Excess reagent Is generally removed or washed away. The second component is then added, and

the presence or absence of the labeled component is followed, to indicate binding.

In one embodiment, the competitor is added first, followed by the test compound. Displacement of the competitor

is an indication that the test compound is binding to the cancer protein and thus is capable of binding to, and potentially

modulating, the activity of the cancer protein. In this embodiment, either component can be labeled. Thus, if the

competitor is labeled, the presence of label in the post-test compound wash solution indicates displacement by the test

compound. Alternatively, if the test compound is labeled, the presence of the label on the support indicates displacement.

In an alternative embodiment, the test compound is added first, with incubation and washing, followed by the

competitor. The absence of binding by the competitor indicates that the test compound binds to the cancer protein with

higher affinity than the competitor. Thus, if the test compound is labeled, the presence of the label on the support, coupled

with a lack of competitor binding, indicates that the test compound binds to and thus potentially modulates the cancer protein

of the invention.

Accordingly, the competitive binding methods comprise differential screening to identity agents that are capable of

modulating the activity of the cancer proteins of the invention. In this embodiment, the methods comprise combining a

cancer protein and a competitor in a first sample. A second sample comprises a test compound, the cancer protein, and a

competitor. The binding of the competitor is determined for both samples, and a change, or difference in binding between

the two samples indicates the presence of an agent capable of binding to the cancer protein and potentially modulating its

activity. That is, if the binding of the competitor is different in the second sample relative to the first sample, the agent is

capable of binding to the cancer protein.

Alternatively, differential screening is used to identify drug candidates that bind to the native cancer protein, but

cannot bind to modified cancer proteins. For example the structure of the cancer protein is modeled and used in rational

drug design to synthesize agents that interact with that site, agents which generally do not bind to site-modified proteins.

Moreover, such drug candidates that affect the activity of a native cancer protein are also identified by screening drugs for

the ability to either enhance or reduce the activity of such proteins.

0 Positive controls and negative controls can be used In the assays. Preferably control and test samples are

CN performed in at least triplicate to obtain statistically significant results. Incubation of all samples occurs for a time sufficient to

S allow for the binding of the agent to the protein. Following incubation, samples are washed free of non-specifically bound

material and the amount of bound, generally labeled agent determined. For example, where a radiolabel is employed, the

samples can be counted in a scintillation counter to determine the amount of bound compound.

LC= A variety of other reagents can be included in the screening assays. These include reagents like salts, neutral

proteins, e.g. albumin, detergents, etc. which are used to facilitate optimal protein-protein binding and/or reduce non-specific

or background interactions. Also reagents that otherwise improve the efficiency of the assay, such as protease Inhibitors,

nuclease inhibitors, anti-microbial agents, etc., can be used. The mixture of components is added in an order that provides

Cl for the requisite binding.

00 SUse of Polynucleotldes to Down-regulate or Inhibit a Protein of the Invention.

O Polynucleotide modulators of cancer can be introduced into a cell containing the target nuceotide sequence by

formation of a conjugate with a ligand-binding molecule, as described in WO 91/04753. Suitable ligand-binding molecules

include, but are not limited to, cell surface receptors, growth factors, other cytokines, or other ligands that bind to cell surface

receptors. Preferably, conjugation of the ligand binding molecule does not substantially interfere with the ability of the ligand

binding molecule to bind to its corresponding molecule or receptor, or block entry of the sense or antisense oligonucleotide

or its conjugated version into the cell. Alternatively, a polynucleotide modulator of cancer can be introduced into a cell

containing the target nucleic acid sequence, by formation of a polynucleotide-lipid complex, as described in WO

90/10448. It is understood that the use of antisense molecules or knock out and knock in models may also be used in

screening assays as discussed above, in addition to methods of treatment.

Inhibitory and Antisense Nucleotides

In certain embodiments, the activity of a cancer-associated protein is down-regulated, or entirely inhibited, by the

use of antisense polynucleotide or Inhibitory small nuclear RNA (snRNA), a nucleic acid complementary to, and which

can preferably hybridize specifically to, a coding mRNA nucleic acid sequence, a cancer protein of the invention, mRNA,

or a subsequence thereof. Binding of the antisense polynucleotide to the mRNA reduces the translation and/or stability of

the mRNA.

In the context of this invention, antisense polynucleotides can comprise naturally occurring nucleotides, or

synthetic species formed from naturally occurring subunits or their close homologs. Antisense polynucleotides may also

have altered sugar moieties or inter-sugar linkages. Exemplary among these are the phosphorothioate and other sulfur

containing species which are known for use in the art. Analogs are comprised by this invention so long as they function

effectively to hybridize with nucleotides of the invention. See, Isis Pharmaceuticals, Carlsbad, CA; Sequitor, Inc.,Natick, MA.

Such antisense polynucleotides can readily be synthesized using recombinant means, or can be synthesized invitro. Equipment for such synthesis is sold by several vendors, including Applied Biosystems. The preparation of otheroligonucleotides such as phosphorothioates and alkylated derivatives is also well known to those of skill in the art.

Antisense molecules as used herein include antisense or sense oligonudeotides. Sense oligonucleotides can,be employed to block transcription by binding to the anti-sense strand. The antisense and sense oligonucleotide

comprise a single stranded nucleic acid sequence (either RNA or DNA) capable of binding to target mRNA (sense) or DNA(antisense) sequences for cancer molecules. Antisense or sense oligonucleotides, according to the present invention,

comprise a fragment generally at least about 12 nucleotides, preferably from about 12 to 30 nucleotides. The ability to derive

an antisense or a sense oligonucleotide, based upon a cDNA sequence encoding a given protein is described in, Stein

00 &Cohen (Cancer Res. 48:2659 (1988 and van der Krol et al. (BioTechniques 6:958 (1988)).

Ribozvmesc In addition to antisense polynucleotides, ribozymes can be used to target and inhibit transcription of cancer-

associated nucleotide sequences. A ribozyme is an RNA molecule that catalytically cleaves other RNA molecules. Different

kinds of ribozymes have been described, including group I ribozymes, hammerhead ribozymes, hairpin ribozymes, RNase P,

and axhead ribozymes (see, Castanotto et al., Adv. In Pharmacology 25: 289-317 (1994) for a general review of the

properties of different ribozymes).

The general features of hairpin ribozymes are described, in Hampel et al., Nucl. Acids Res. 18:299-304

S (1990); European Patent Publication No. 0360257; U.S. Patent No. 5,254,678. Methods of preparing are well known to

CN those of skill in the art (see, WO 94/26877; Ojwang et al., Proc. Natl. Acad. Sci. USA 90:6340-6344 (1993); Yamada et

al., Human Gene Therapy 1:39-45 (1994); Leavitt et al., Proc. Natl. Acad Sci. USA 92:699- 703 (1995); Leavitt et al., Human

00 Gene Therapy 5: 1151-120 (1994); and Yamada et al., Virology 205: 121-126 (1994)).

0

CN Use of Modulators in Phenotypic Screening

In one embodiment, a test compound is administered to a population of cancer cells, which have an associated

cancer expression profile. By "administration" or "contacting" herein is meant that the modulator is added to the cells in such

a manner as to allow the modulator to act upon the cell, whether by uptake and intracellular action, or by action at the cell

surface. In some embodiments, a nucleic acid encoding a proteinaceous agent a peptide) is put into a viral construct

such as an adenoviral or retroviral construct, and added to the cell, such that expression of the peptide agent is

accomplished, PCT US97/01019. Regulatable gene therapy systems can also be used. Once the modulator has been

administered to the cells, the cells are washed if desired and are allowed to incubate under preferably physiological

conditions for some period. The cells are then harvested and a new gene expression profile is generated. Thus, e.g.,

cancer tissue is screened for agents that modulate, induce or suppress, the cancer phenotype. A change in at least

one gene, preferably many, of the expression profile indicates that the agent has an effect on cancer activity. Similarly,

altering a biological function or a signaling pathway is indicative of modulator activity. By defining such a signature for the

cancer phenotype, screens for new drugs that alter the phenotype are devised. With this approach, the drug target need not

be known and need not be represented in the original gene/protein expression screening platform, nor does the level of

transcript for the target protein need to change. The modulator inhibiting function will serve as a surrogate marker

As outlined above, screens are done to assess genes or gene products. That is, having identified a particular

differentially expressed gene as important in a particular state, screening of modulators of either the expression of the gene

or the gene product itself is performed.

Use of Modulators to Affect Peotides of the Invention

Measurements of cancer polypeptide activity, or of the cancer phenotype are performed using a variety of assays.

For example, the effects of modulators upon the function of a cancer polypeptide(s) are measured by examining parameters

described above. A physiological change that affects activity is used to assess the influence of a test compound on the

polypeptides of this invention. When the functional outcomes are determined using intact cells or animals, a variety of

effects can be assesses such as, in the case of a cancer associated with solid tumors, tumor growth, tumor metastasis,

neovascularization, hormone release, transcriptional changes to both known and uncharacterized genetic markers by

Northern blots), changes in cell metabolism such as cell growth or pH changes, and changes in intracellular second

messengers such as cGNIP.000O Methods of Identifying Characterizing Cancer-associated Sequences

Expression of various gene sequences is correlated with cancer. Accordingly, disorders based on mutant or

variant cancer genes are determined. In one embodiment, the invention provides methods for identifying cells containing

S variant cancer genes, determining the presence of, all or part, the sequence of at least one endogenous cancer gene in

Sa cell. This is accomplished using any number of sequencing techniques. The invention comprises methods of identifying

the cancer genotype of an individual, determining all or part of the sequence of at least one gene of the invention in the

individual. This is generally done in at least one tissue of the individual, a tissue set forth in Table I, and may include

the evaluation of a number of tissues or different samples of the same tissue. The method may include comparing the

CK1 sequence of the sequenced gene to a known cancer gene, a wild-type gene to determine the presence of family

Smembers, homologies, mutations or variants. The sequence of all or part of the gene can then be compared to the

00 sequence of a known cancer gene to determine if any differences exist. This is done using any number of known homology

programs, such as BLAST, Bestfit, etc. The presence of a difference in the sequence between the cancer gene of the

patient and the known cancer gene correlates with a disease state or a propensity for a disease state, as outlined herein.

In a preferred embodiment, the cancer genes are used as probes to determine the number of copies of the cancer

gene in the genome. The cancer genes are used as probes to determine the chromosomal localization of the cancer genes.

Information such as chromosomal localization finds use in providing a diagnosis or prognosis in particular when

chromosomal abnormalities such as translocations, and the like are identified in the cancer gene locus.

XIV.) KitslArticles of Manufacture

For use in the diagnostic and therapeutic applications described herein, kits are also within the scope of the

invention. Such kits can comprise a carrier, package, or container that is compartmentalized to receive one or more

containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in

the method. For example, the container(s) can comprise a probe that is or can be detectably labeled. Such probe can be an

antibody or polynucleotide specific for a Figure 2-related protein or a Figure 2 gene or message, respectively. Where the

method utilizes nucleic acid hybridization to detect the target nucleic acid, the kit can also have containers containing

nucleotide(s) for amplification of the target nucleic acid sequence and/or a container comprising a reporter-means, such as a

biotin-binding protein, such as avidin or streptavidin, bound to a reporter molecule, such as an enzymatic, florescent, or

radioisotope label. The kit can include all or part of the amino acid sequences in Figure 2 or Figure 3 or analogs thereof, or a

nucleic acid molecules that encodes such amino acid sequences.

The kit of the invention will typically comprise the container described above and one or more other containers

comprising materials desirable from a commercial and user standpoint, including buffers, diluents, filters, needles, syringes;

carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions

for use.

A label can be present on the container to indicate that the composition is used for a specific therapy or non-therapeutic

application, such as a diagnostic or laboratory application, and can also indicate directions for either in vivo or in vitro use, such as

those described herein. Directions and or other information can also be included on an insert(s) or label(s) which is included with

or on the kit.

The terms "kit" and "article of manufacture" can be used as synonyms.

In another embodiment of the invention, an article(s) of manufacture containing compositions, such as amino acid

sequence(s), small molecule(s), nucleic acid sequence(s), and/or antibody(s), materials useful for the diagnosis,

00 prognosis, prophylaxis and/or treatment of neoplasias of tissues such as those set forth in Table I is provided. The article of

manufacture typically comprises at least one container and at least one label. Suitable containers include, for example,

C bottles, vials, syringes, and test tubes. The containers can be formed from a variety of materials such as glass or plastic.

The container can hold amino acid sequence(s), small molecule(s), nucleic acid sequence(s), and/or antibody(s), in one

embodiment the container holds a polynucleotide for use in examining the mRNA expression profile of a cell,, together with

reagents used for this purpose.cl The container can alternatively hold a composition which is effective for treating, diagnosis, prognosing or

prophylaxing a condition and can have a sterile access port (for example the container can be an intravenous solution bag or

S a vial having a stopper pierceable by a hypodermic injection needle). The active agents in the composition can be an

r antibody capable of specifically binding 191P4D12(b) and modulating the function of 191P4D12(b).

The label can be on or associated with the container. A label a can be on a container when letters, numbers or

c0 other characters forming the label are molded or etched into the container itself; a label can be associated with a container

when it is present within a receptacle or carrier that also holds the container, as a package insert. The label can

CN indicate that the composition is used for diagnosing, treating, prophylaxing or prognosing a condition, such as a neoplasia of

a tissue set forth in Table I. The article of manufacture can further comprise a second container comprising a

pharmaceutically-acceptable buffer, such as phosphate-buffered saline, Ringer's solution and/ordextrose solution. It can

further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters,

stirrers, needles, syringes, and/or package inserts with indications and/or instructions for use.

EXAMPLES:

Various aspects of the invention are further described and illustrated by way of the several examples that follow,

none of which are intended to limit the scope of the invention.

Example 1: SSH-Generated Isolation of cDNA Fragment of the 191P4D12(b) Gene

To isolate genes that are over-expressed in prostate cancer we used the Suppression Subtractive Hybridization (SSH)

procedure using cDNA derived from prostate cancer tissues. The 191P4D12(b) SSH cDNA sequence was derived from bladder

tumor minus cDNAs derived from a pool of 9 normal tissues. The 191P4D12(b) cDNA was identified as highly expressed in the

bladder cancer.

Materials and Methods

Human Tissues:

The patient cancer and normal tissues were purchased from different sources such as the NDRI (Philadelphia, PA).

mRNA for some normal tissues were purchased from Clontech, Palo Alto, CA.

RNA Isolation:

Tissues were homogenized in Trizol reagent (Life Technologies, Gibco BRL) using 10 ml/ g tissue isolate total RNA. Poly

A RNA was purified from total RNA using Qiagen's Oligotex mRNA Mini and Midi kits. Total and mRNA were quantified by

spectrophotometric analysis 260/280 nm) and analyzed by gel electrophoresis.

Oliqonucleotides:

The following HPLC purified oligonucleotides were used.

DPNCDN (cDNA synthesis primer):

5'TTTTGATCAAGCTT3o3' (SEQ ID NO: 48)

Adaptor 1:

S5'CTAATACGACTCACTATAGGGCTCGAGCGGCCGCCCGGGCAG3' (SEQ ID NO: 49)

(SEQ ID NO:

Adaptor 2:

5'GTAATACGACTCACTATAGGGCAGCGTGGTCGCGGCCGAG3' (SEQ ID NO: 51)

(SEQ ID NO: 52)

PCR primer 1:

5'CTAATACGACTCACTATAGGGC3' (SEQ ID NO: 53)

Nested primer (NP)1:

N 5'TCGAGCGGCCGCCCGGGCAGGA3' (SEQ ID NO: 54)

SNested primer (NP)2:00 5'AGCGTGGTCGCGGCCGAGGA3' (SEQ ID NO:

Suppression Subtractive Hybridization:

Suppression Subtractive Hybridization (SSH) was used to identify cDNAs corresponding to genes that may be

differentially expressed in bladder cancer. The SSH reaction utilized cDNA from bladder cancer and normal tissues.

The gene 191P4D12(b) sequence was derived from bladder cancer minus normal tissue cDNA subtraction. The SSH

DNA sequence (Figure 1) was identified.

The cDNA derived from of pool of normal tissues was used as the source of the "driver" cDNA, while the cDNA from

bladder cancer was used as the source of the "tester" cDNA. Double stranded cDNAs corresponding to tester and driver cDNAs

were synthesized from 2 pig of poly(A)* RNA isolated from the relevant xenograft tissue, as described above, using CLONTECH's

PCR-Select cDNA Subtraction Kit and 1 ng of oligonucleotide DPNCDN as primer. First- and second-strand synthesis were carried

out as described in the Kit's user manual protocol (CLONTECH Protocol No. PT1117-1, Catalog No. K1804-1). The resulting

cDNA was digested with Dpn II for 3 hrs at 370C. Digested cDNA was extracted with phenol/chloroform and ethanol

precipitated.

Driver cDNA was generated by combining in a 1:1 ratio Dpn II digested cDNA from the relevant tissue source (see

above) with a mix of digested cDNAs derived from the nine normal tissues: stomach, skeletal muscle, lung, brain, liver, kidney,

pancreas, small intestine, and heart.

Tester cDNA was generated by diluting 1 pd of Dpn II digested cDNA from the relevant tissue source (see above) (400

ng) in 5 pi of water. The diluted cDNA (2 pi, 160 ng) was then ligated to 2 pI of Adaptor 1 and Adaptor 2 (10 pM), in separate

ligation reactions, in a total volume of 10 pl at 160C overnight, using 400 u ofT4 DNA ligase (CLONTECH). Ugation was

terminated with 1 pl of 0.2 M EDTA and heating at 72oC for 5 min.

The first hybridization was performed by adding 1.5 pi (600 ng) of driver cDNA to each of two tubes containing 1.5 l

ng) Adaptor 1- and Adaptor 2- ligated tester cDNA. In a final volume of 4 pl, the samples were overlaid with mineral oil, denatured

in an MJ Research thermal cycler at 980C for 1.5 minutes, and then were allowed to hybridize for 8 hrs at 680C. The two

hybridizations were then mixed together with an additional 1 pi of fresh denatured driver cDNA and were allowed to hybridize

overnight at 68C0. The second hybridization was then diluted in 200 pl of 20 mM Hepes, pH 8.3, 50 mM NaCI, 0.2 mM EDTA,heated at 70C0 for 7 min. and stored at -200C.

PCR Amplification, Cloning and Sequencing of Gene Fragments Generated from SSH:

To amplify gene fragments resulting from SSH reactions, two PCR amplifications were performed. In the primary PCR

reaction 1 pl of the diluted final hybridization mix was added to 1 Ip of PCR primer 1 (10 pM), 0.5 pl dNTP mix (10 pM), 2.5 pi 10 x

00 reaction buffer (CLONTECH) and 0.5 pi 50 x Advantage cDNA polymerase Mix (CLONTECH) in a final volume of 25 pi. PCR 1O

was conducted using the following conditions: 75oC for 5 min., 940C for 25 sec., then 27 cycles of 94°C for 10 sec, 660C for 30 sec,

72oC for 1.5 min. Five separate primary PCR reactions were performed for each experiment. The products were pooled and

diluted 1:10 with water. For the secondary PCR reaction, 1 pl from the pooled and diluted primary PCR reaction was added to the

same reaction mix as used for PCR 1, except that primers NP1 and NP2 (10 pM) were used instead of PCR primer 1. PCR 2 was

performed using 10-12 cycles of 94oC for 10 sec, 680C for 30 sec, and 72oC for 1.5 minutes. The PCR products were analyzed

using 2% agarose gel electrophoresis.

The PCR products were inserted into pCR2.1 using the T/A vector cloning kit (Invitrogen). Transformed E. coli were

subjected to blue/white and ampicillin selection. White colonies were picked and arrayed into 96 well plates and were grown in

liquid culture overnight. To identify inserts, PCR amplification was performed on 1 pl of bacterial culture using the conditions of

PCR1 and NP1 and NP2 as primers. PCR products were analyzed using 2% agarose gel electrophoresis.

00 Bacterial clones were stored in 20% glycerol in a 96 well format. Plasmid DNA was prepared, sequenced, and subjected

to nucleic acid homology searches of the GenBank, dBest, and NCI-CGAP databases.

SRT-PCR Expression Analysis:

First strand cDNAs can be generated from 1 pg of mRNA with oligo (dT)12-18 priming using the Gibco-BRL Superscript

Preamplification system. The manufacturers protocol was used which included an incubation for 50 min at 420C with reverse

transcriptase followed by RNAse H treatment at 370C for 20 min. After completing the reaction, the volume can be increased to

200 pl with water prior to normalization. First strand cDNAs from 16 different normal human tissues can be obtained from

Clontech.

Normalization of the first strand cDNAs from multiple tissues was performed by using the primers

5'atatcgccgcgctcgtcgtcgacaa3' (SEQ ID NO: 56) and 5'agccacacgcagctcattgtagaagg 3' (SEQ ID NO: 57) to amplify p-actin. First

strand cDNA (5 pi) were amplified In a total volume of 50 pC containing 0.4 pM primers, 0.2 pM each dNTPs, 1XPCR buffer

(Clontech, 10 mM Tris-HCL, 1.5 mM MgCI2, 50 mM KCI, pH8.3) and 1X Klentaq DNA polymerase (Clontech). Five pl of the PCR

reaction can be removed at 18, 20, and 22 cycles and used for agarose gel electrophoresis. PCR was performed using an MJ

Research thermal cycler under the following conditions: Initial denaturation can be at 94oC for 15 sec, followed by a 18, 20, and 22

cycles of 94oC for 15, 650C for 2 min, 720C for 5 sec. A final extension at 72oC was carried out for 2 min. After agarose gel

electrophoresis, the band intensities of the 283 b.p. p-actin bands from multiple tissues were compared by visual inspection.

Dilution factors for the first strand cDNAs were calculated to result in equal p-actin band intensities in all tissues after 22 cycles of

PCR. Three rounds of normalization can be required to achieve equal band intensities in all tissues after 22 cycles of PCR.

To determine expression levels of the 191P4D12(b) gene, 5 pl of normalized first strand cDNA were analyzed by PCR

using 26, and 30 cycles of amplification. Semi-quantitative expression analysis can be achieved by comparing the PCR products

at cycle numbers that give light band intensities. The primers used for RT-PCR were designed using the 191P4D12(b) SSH

sequence and are listed below:

191P4D12(b).1GGCTGGAGTTCAATGAGGTTTATTT 3' (SEQ ID NO: 58)

191P4D12(b).2TCCAGCAGATTTCAGACTAAAAGAAGA- 3' (SEQ ID NO: 59)

A typical RT-PCR expression analysis is shown in Figure 14. First strand cDNA was prepared from vital pool 1 (liver, lung

00 and kidney), vital pool 2 (pancreas, colon and stomach), normal kidney, prostate cancer pool, bladder cancer pool, colon cancer pool,

lung cancer pool, breast cancer pool and cancer metastasis pool. Normalization was performed by PCR using primers to actin and

ri GAPDH. Semi-quantitative PCR, using primers to 191P4D12(b), was performed at 26 and 30 cycles of amplification. Results show

strong expression of 191P4D12(b) in bladder cancer pool. Expression of 191P4D12(b) was also detected in prostate cancer pool,

colon cancer pool, lung cancer pool, breast cancer pool and cancer metastasis pool but very weakly in vital pool 1 and vital pool 2.

Example 2: Isolation of Full Length 191P4D12(b) Encoding cDNA

The 191P4D12(b) SSH cDNA sequence was derived from a subtraction consisting of bladder cancer minus a mixture of

9 normal tissues: stomach, skeletal muscle, lung, brain, liver, kidney, pancreas, small intestine and heart. The SSH cDNA

C sequence of 223 bp (Figure 1) was designated 191P4D12(b).

O 191P4D12(b) v.1 (clone 1Al) of 3464 bp was cloned from bladder cancer cDNA library, revealing an ORF of 510 amino

00 acids (Figure 2 and Figure Other variants of 191P4D12(b) were also identified and these are listed in Figures 2 and 3,

191P4D12(b) v.1, v.2, v.10, v.11, and v.12 proteins are 510 amino acids in length and differ from each other by one

amino acid as shown in Figure 11. 191P4D12(b) v.3, v.4, v.5, and v.8 code for the same protein as 191P4D12(b) v.1.

191P4D12(b) v.6 and v.7 are splice variants and code for proteins of 295 and 485 amino acids, respectively. 191P4D12(b) v.13

clone 9C was cloned from bladder cancer cDNA and has one amino acid insertion at position 334 compared to 191P4D12(b) v.1.

191P4D12(b) v.9 clone BCP1 is a splice variant of 191P4D12(b) v.1 and was cloned from a bladder cancer cDNA library.

191P4D12(b) v.14 is a SNP variant and differs from 191P4D12(b) v.9 by one amino acid as shown in Figure 2.

191P4D12(b) v.1 shows 99% identity over 2744 to the Ig superfamily receptor LNIR (nectin-4), accession number

NM_030916. 191P4D12(b) v.9 protein is 100% identical to clone AF218028 with function of inhibiting cancer cell growth.

Example 3: Chromosomal Mapping of 191P4D12(b)

Chromosomal localization can implicate genes in disease pathogenesis. Several chromosome mapping approaches are

available including fluorescent in situ hybridization (FISH), human/hamster radiation hybrid (RH) panels (Walter et al., 1994;

Nature Genetics 7:22; Research Genetics, Huntsville Al), human-rodent somatic cell hybrid panels such as is available from the

Comell Institute (Camden, New Jersey), and genomic viewers utilizing BLAST homologies to sequenced and mapped genomic

clones (NCBI, Bethesda, Maryland).

191P4D12(b) maps to chromosome 1q22-q23.2 using 191P4D12(b) sequence and the NCBI BLAST tool located on the World

Wide Web at (.ncbi.nlm.nih.gov/genomelseq/page.cgi?F=HsBlast.html&&ORG=Hs).

Example 4: Expression Analysis of 191P4D12(b) In Normal Tissues and Patient Specimens

Expression analysis by RT-PCR demonstrated that 191P4D12(b) is strongly expressed in bladder cancer patient

specimens (Figure 14). First strand cDNA was prepared from vital pool 1 (liver, lung and kidney), vital pool 2 (pancreas,

colon and stomach), normal kidney, prostate cancer pool, bladder cancer pool, colon cancer pool, lung cancer pool, breast

cancer pool and cancer metastasis pool; prostate cancer metastasis to lymph node, prostate cancer pool, bladder cancer

pool, kidney cancer pool, colon cancer pool, lung cancer pool, ovary cancer pool, breast cancer pool, cancer metastasis

pool, pancreas cancer pool, and LAPC prostate xenograft pool. Normalization was performed by PCR using primers to actin

and GAPDH. Semi-quantitative PCR, using primers to 191P4D12(b), was performed at 26 and 30 cycles of amplification. In

results show strong expression of 191P4D12(b) in bladder cancer pool. Expression of 191P4D12(b) was also detected

in prostate cancer pool, colon cancer pool, lung cancer pool, breast cancer pool and cancer metastasis pool but very weakly

In vital pool 1 and vital pool 2. In results show strong expression of 191P4D12(b) in prostate, bladder, kidney, colon,

lung, ovary, breast, cancer metastasis, and pancreas cancer specimens.

00 Northern blot analysis of 251 P5G2 is a technique known to those skilled in the art to detect 251 P5G2 protein

C production. Northern blotting detects relative levels of mRNA expressed from a 251 P5G2 gene. Specific mRNA is

Smeasured using a nucleic acid hybridization technique and the signal is detected on an autoradiogram. The stronger the

C signal, the more abundant is the mRNA. For 251 P5G2 genes that produce mRNA that contains an open reading frame

S flanked by a good Kozak translation initiation site and a stop codon, in the vast majority of cases the synthesized mRNA is

expressed as a protein.

The level of expression of the 251P5G2 gene is determined in various normal tissues and in various tumor tissues

and tumor cell lines using the technique of Northern blotting, which detects production of messenger RNA. It is well known in1 the art that the production of messenger RNA, that encodes the protein, is a necessary step in the production of the protein

ri itself. Thus, detection of high levels of messenger RNA by, for example, Northern blot, is a way of determining that the

protein itself is produced. The Northern blot technique is used as a routine procedure because it does not require the time

00 delays (as compared to Western blotting, immunoblotting or immunohistochemistry) involved in isolating or synthesizing the

Sprotein, preparing an immunological composition of the protein, eliciting a humoral immune response, harvesting the

Cr antibodies, and verifying the specificity thereof.

The Kozak consensus sequence for translation initiation CCACCATGG, where the ATG start codon is noted, is the

sequence with the highest established probability of initiating translation. This was confirmed by Peri and Pandey Trends in

Genetics (2001) 17: 685-687. The conclusion is consistent with the general knowledge in the art that, with rare exceptions,

expression of an mRNA is predictive of expression of its encoded protein. This is particularly true for mRNA with an open

reading frame and a Kozak consensus sequence for translation initiation.

It is understood in the art that the absolute levels of messenger RNA present and the amounts of protein produced

do not always provide a 1:1 correlation. In those instances where the Northern blot has shown mRNA to be present, it is

almost always possible to detect the presence of the corresponding protein in the tissue which provided a positive result in

the Northern blot. The levels of the protein compared to the levels of the mRNA may be differential, but generally, cells that

exhibit detectable mRNA also exhibit detectable corresponding protein and vice versa. This is particularly true where the

mRNA has an open reading frame and a good Kozak sequence (See, Peri and Pandey, supra.).

Occasionally those skilled in the art encounter a rare occurrence where there is no detectable protein in the

presence of corresponding mRNA. (See, Fu, L, et al., Embo. Journal, 15:4392-4401 (1996)). In many cases, a reported

lack of protein expression is due to technical limitations of the protein detection assay. These limitations are readily known to

those skilled in the art. These limitations include but are not limited to, available antibodies that only detect denatured

protein and not native protein present in a cell and unstable proteins with very short half-life. Short-lived proteins are still

functional and have been previously described to induce tumor formation. (See, Reinstein, et al., Oncogene, 19: 5944-

5950). In such situations, when more sensitive detection techniques are performed and/or other antibodies are generated,

protein expression Is detected. When studies fail to take these principles into account, they are likely to report artifactually

lowered correlations of mRNA to protein. Outside of these rare exceptions the use of Northern blot analysis is recognized to

those skilled in the art to be predictive and indicative of the detection of 251 P5G2 protein production.

Extensive expression of 191P4D12(b) in normal tissues is shown in Figure 15. Two multiple tissue northern blots

(Clontech) both with 2 ug of mRNAnane were probed with the 191P4D12(b) sequence. Size standards in kilobases (kb) are

indicated on the side. Results show expression of an approximately 4kb transcript in placenta and very weakly in prostate

but not in any other normal tissue tested. A smaller 191P4D12(b) transcript of approximately 2.5kb was detected in heart

and skeletal muscle.

Expression of 191P4D12(b) in bladder cancer patient specimens and human normal tissues is shown In Figure 16.

RNA was extracted from a pool of 3 bladder cancer patent specimens, as well as from normal prostate normal bladder

O normal kidney normal colon normal lung normal breast (NBr), normal ovary and normal

0 pancreas (NPa). Northern blot with 10 ug of total RNAlane was probed with 191P4D12(b) SSH sequence. Size standards

in kilobases (kb) are indicated on the side. The 191P4D12(b) transcript was detected in the bladder cancer specimens, but

not in the normal tissues tested.

Analysis of individual bladder cancer patient specimens Is depicted in Figure 17. RNA was extracted from bladder

cancer cell lines normal bladder and bladder cancer patient tumors Northern blots with 10 ug of total RNA

were probed with the 191P4D12(b) SSH fragment. Size standards in kilobases are on the side. Results show expression of

the approximately 4kb 191P4D12(b) transcript in the bladder tumor tissues but not in normal bladder. A smaller transcript

was detected in the HT1197 cell line but not in the other cancer cell lines tested.

t^ Expression of 191P4D12(b) was also detected in prostate cancer xenograft tissues (Figure 18). RNA was

extracted from normal prostate, and from the prostate cancer xenografts LAPC-4AD, LAPC-4AI, LAPC-9AD, and LAPC-9AI.

00 Northern blots with 10 ug of total RNA were probed with the 191P4D12(b) SSH fragment. Size standards In kilobases are on

the side. Results show expression of the approximately 4kb 191P4D12(b) transcript in all the LAPC xenograft tissues but not

in normal prostate.

Figure 19 shows expression of 191P4D12(b) In cervical cancer patient specimens. RNA was extracted from

normal cervix, Hela cancer cell line, and 3 cervix cancer patient tumors Northern blots with 10 ug of total RNA were

probed with the 191P4D12(b) SSH fragment. Size standards in kilobases are on the side. Results show expression of the

approximately 4kb 191P4D12(b) transcript in 2 out of 3 cervix tumors tested but not in normal cervix nor in the Hela cell line.

191P4D12(b) was also expressed in lung cancer patient specimens (Figure 20). RNA was extracted from lung

cancer cell lines normal lung bladder cancer patient tumors and normal adjacent tissue (Nat). Northem blots

with 10 ug of total RNA were probed with the 191P4D12(b). Size standards in kilobases are on the side. Results show

expression of the approximately 4kb 191P4D12(b) transcript in the lung tumor tissues but not in normal lung nor in the cell

lines tested.

191P4D12(b) expression was tested in a panel of individual patient cancer specimens (Figure 21). First strand

cDNA was prepared from a panel of lung cancer specimens bladder cancer specimens prostate cancer specimens

colon cancer specimens uterus cancer specimens and cervix cancer specimens Normalization was

performed by PCR using primers to actin. Semi-quantitative PCR, using primers to 191P4D12(b) SSH fragment, was

performed at 26 and 30 cycles of amplification. Expression level was recorded as 0 no expression detected; 1 weak

expression, 2 moderate expression; 3 strong expression. Results show expression of 191P4D12(b) in 97% of the 31

lung cancer patient specimens tested, 94% of 18 bladder cancer patient specimens, 100% of 20 prostate cancer patient

specimens, 100% of 22 colon cancer patient specimens, 100% of 12 uterus cancer patient specimens, and 100% of 14

cervix cancer patient specimens tested.

The restricted expression of 191P4D12(b) in normal tissues and the expression detected in cancer patient

specimens suggest that 191P4D12(b) is a potential therapeutic target and a diagnostic marker for human cancers.

Example 5: Transcript Variants of 191P4D12(b)

Transcript variants are variants of mature mRNA from the same gene which arise by alternative transcription or

altemative splicing. Alternative transcripts are transcripts from the same gene but start transcription at different points. Splice

variants are mRNA variants spliced differently from the same transcript. In eukaryotes, when a multi-exon gene is

transcribed from genomic DNA, the initial RNA Is spliced to produce functional mRNA, which has only exons and is used for

translation into an amino acid sequence. Accordingly, a given gene can have zero to many alternative transcripts and each

transcript can have zero to many splice variants. Each transcript variant has a unique exon makeup, and can have different

00 coding and/or non-coding or 3' end) portions, from the original transcript. Transcript variants can code for similar or

S different proteins with the same or a similar function or can encode proteins with different functions, and can be expressed in

CN the same tissue at the same time, or in different tissues at the same time, or in the same tissue at different times, or in

different tissues at different times. Proteins encoded by transcript variants can have similar or different cellular or

S extracellular localizations, secreted versus Intracellular.

STranscript variants are identified by a variety of art-accepted methods. For example, alternative transcripts and

splice variants are identified by full-length cloning experiment, or by use of full-length transcript and EST sequences. First,

all human ESTs were grouped into clusters which show direct or Indirect identity with each other. Second, ESTs in the same

cluster were further grouped into sub-clusters and assembled into a consensus sequence. The original gene sequence is

C1 compared to the consensus sequence(s) or other full-length sequences. Each consensus sequence is a potential splice

variant for that gene. Even when a variant is identified that is not a full-length clone, that portion of the variant is very useful

C for antigen generation and for further cloning of the full-length splice variant, using techniques known in the art.00

SMoreover, computer programs are available in the art that identify transcript variants based on genomic

sequences. Genomic-based transcript variant identification programs include FgenesH Salamov and V. Solovyev, "Ab

initio gene finding in Drosophila genomic DNA," Genome Research. 2000 April;10(4):516-22); Grail (URL

compbio.ornl.gov/Grail-bin/EmptyGrailForm) and GenScan (URL genes.mit.edu/GENSCAN.html). For a general discussion

of splice variant identification protocols see., Southan, A genomic perspective on human proteases, FEBS Lett.

2001 Jun 8; 498(2-3):214-8; de Souza, et al., Identification of human chromosome 22 transcribed sequences with ORF

expressed sequence tags, Proc. Natl Acad Sci U S A. 2000 Nov 7; 97(23):12690-3.

To further confirm the parameters of a transcript variant, a variety of techniques are available in the art, such as

full-length cloning, proteomic validation, PCR-based validation, and 5' RACE validation, etc. (see Proteomic Validation:

Brennan, et al., Albumin banks peninsula: a new termination variant characterized by electrospray mass spectrometry,

Biochem Biophys Acta. 1999 Aug 17;1433(1-2):321-6; Ferranti P, et al., Differential splicing of pre-messenger RNA produces

multiple forms of mature caprine alpha(sl)-casein, Eur J Biochem. 1997 Oct 1;249(1):1-7. For PCR-based Validation:

Wellmann S, et Specific reverse transcription-PCR quantification of vascular endothelial growth factor (VEGF) splice

variants by LightCycler technology, Clin Chem. 2001 Apr,47(4):654-60; Jia, et al., Discovery of new human beta-

defensins using a genomics-based approach, Gene. 2001 Jan 24; 263(1-2):211-8. For PCR-based and 5' RACE Validation:

Brigle, et al., Organization of the murine reduced folate carrier gene and identification of variant splice forms, Biochem

Biophys Acta. 1997 Aug 7; 1353(2): 191-8).

It is known in the art that genomic regions are modulated in cancers. When the genomic region to which a gene

maps is modulated in a particular cancer, the alternative transcripts or splice variants of the gene are modulated as well.

Disclosed herein is that 191P4D12(b) has a particular expression profile related to cancer. Alternative transcripts and splice

variants of 191P4D12(b) may also be involved in cancers in the same or different tissues, thus serving as tumor-associated

markers/antigens.

Using the full-length gene and EST sequences, four additional transcript variants were identified, designated as

191P4D12(b) v.6, v.7, v.8 and v.9 as shown in Figure 12. The boundaries of exons in the original transcript, 191P4D12(b) v.1

were shown in Table LI. Compared with 191P4D12(b) v.1, variant v.6 spliced out 202-321 from the first exon of v.1 while

variant v.8 spliced out 63 bases from the last exon of v.1. Variant v.7 spliced out exon 8 of v.1. Variant 9 was part of the last

exon of v.1. Theoretically, each different combination of exons in spatial order, e.g. exons 2, 3, 5, 7 and 9 of v.1, is a

potential splice variant.

Tables LlI through LV are set forth on a variant-by-variant bases. Tables LII shows nucleotide

sequence of the transcript variants. Tables LIII shows the alignment of the transcript variant with nucleic acidOO0 sequence of 191P4D12(b) v.l. Tables LIV lays out amino acid translation of the transcript variant for the identified

i reading frame orientation. Tables LV displays alignments of the amino acid sequence encoded by the splice variant

with that of 191P4D12(b) v.1.

Example 6: Single Nucleotide Polymorphisms of 191P4D12(b)

C A Single Nucleotide Polymorphism (SNP) is a single base pair variation in a nucleotide sequence at a specific

location. At any given point of the genome, there are four possible nucleotide base pairs: A/T, C/G, G/C and T/A. Genotype

refers to the specific base pair sequence of one or more locations in the genome of an individual. Haplotype refers to the

base pair sequence of more than one location on the same DNA molecule (or the same chromosome in higher organisms),

CN often in the context of one gene or in the context of several tightly linked genes. SNP that occurs on a cDNA Is called cSNP.

This cSNP may change amino acids of the protein encoded by the gene and thus change the functions of the protein. Some

o SNP cause inherited diseases; others contribute to quantitative variations In phenotype and reactions to environmental

S factors including diet and drugs among individuals. Therefore, SNP and/or combinations of alleles (called haplotypes) have

many applications, including diagnosis of inherited diseases, determination of drug reactions and dosage, identification of

genes responsible for diseases, and analysis of the genetic relationship between individuals Nowotny, J. M. Kwon and A.

M. Goate, "SNP analysis to dissect human traits," Curr. Opin. Neurobiol. 2001 Oct; 11(5):637-641; M. Pirmohamed and B. K.

Park, "Genetic susceptibility to adverse drug reactions," Trends Pharmacol. Sci. 2001 Jun; 22(6):298-305; J. H. Riley, C. J.

Allan, E. Lai and A. Roses, "The use of single nucleotide polymorphisms in the isolation of common disease genes,"

Pharmacogenomics. 2000 Feb; 1(1):39-47; R. Judson, J. C. Stephens and A. Windemuth, "The predictive power of

haplotypes in clinical response," Pharmacogenomics. 2000 feb; 1(1):15-26).

SNP are identified by a variety of art-accepted methods Bean, "The promising voyage of SNP target discovery,"

Am. Clin. Lab. 2001 Oct-Nov; 20(9):18-20; K. M. Weiss, "In search of human variation," Genome Res. 1998 Jul; 8(7):691-

697; M. M. She, "Enabling large-scale pharmacogenetic studies by high-throughput mutation detection and genotyping

technologies," Clin. Chem. 2001 Feb; 47(2):164-172). For example, SNP can be identified by sequencing DNA fragments

that show polymorphism by gel-based methods such as restriction fragment length polymorphism (RFLP) and denaturing

gradient gel electrophoresis (DGGE). They can also be discovered by direct sequencing of DNA samples pooled from

different individuals or by comparing sequences from different DNA samples. With the rapid accumulation of sequence data

in public and private databases, one can discover SNP by comparing sequences using computer programs Gu, L. Hillier

and P. Y. Kwok, "Single nucleotide polymorphism hunting in cyberspace," Hum. Mutat. 1998; 12(4):221-225). SNP can be

verified and genotype or haplotype of an individual can be determined by a variety of methods including direct sequencing

and high throughput microarrays Y. Kwok, "Methods for genotyping single nucleotide polymorphisms," Annu. Rev.

Genomics Hum. Genet. 2001; 2:235-258; M. Kokoris, K. Dix, K. Moynihan, J. Mathis, B. Erwin, P. Grass, B. Hines and A.

Duesterhoeft, "High-throughput SNP genotyping with the Masscode system," Mol. Diagn. 2000 Dec; 5(4):329-340).

Using the methods described above, seven SNP and one insertion/deletion of three bases were identified in the original

transcript, 191P4D12(b) v.1, at positions 420 2184 2341 2688 367 699 1590

and insertion of GCA in between 1262 and 12631. The transcripts or proteins with alternative allele were designated as

variant 191P4D12(b) v.2 through v.5 and v.10 through v.13, as shown in Figure 10. Figure 11 shows the schematic

alignment of protein variants, corresponding to nucleotide variants. Nucleotide variants that code for the same amino acid

sequence as v.1 are not shown in Figure 11. These alleles of the SNP, though shown separately here, can occur in different

combinations (haplotypes) and in any one of the transcript variants (such as 191P4D12(b) v.9) that contains the site of the

SNP. The SNP at 2688 of v.1 occurs also in transcript variant v.9 and contributed to one codon change of v.9 at amino acid

64 from Ala to Asp (Figure 11).

000 Example 7: Production of Recombinant 191P4D12(b) in Prokarvotic Systems

C To express recombinant 191P4D12(b) and 191P4D12(b) variants in prokaryotic cells, the full or partial length

191P4D12(b) and 191 P4D12(b) variant cDNA sequences are cloned into any one of a variety of expression vectors known in

the art. One or more of the following regions of 191P4D12(b) variants are expressed: the full length sequence presented in

Figures 2 and 3, or any 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more

Cr contiguous amino acids from 191P4D12(b), variants, or analogs thereof.

A. In vitro transcription and translation constructs:

pDRII: To generate 191P4D12(b) sense and anti-sense RNA probes for RNA in situ investigations, pCRII

Ci constructs (Invitrogen, Carlsbad CA) are generated encoding either all or fragments of the 191P4D12(b) cDNA. The pCRII

vector has Sp6 and T7 promoters flanking the insert to drive the transcription of 191P4D12(b) RNA for use as probes in RNA

C in situ hybridization experiments. These probes are used to analyze the cell and tissue expression of 191 P4D12(b) at the00

RNA level. Transcribed 191P4D12(b) RNA representing the cDNA amino acid coding region of the 191P4012(b) gene is

used in in vitro translation systems such as the TnTTM Coupled Reticulolysate System (Promega, Corp., Madison, WI) to

synthesize 191 P4D12(b) protein.

B. Bacterial Constructs:

pGEX Constructs: To generate recombinant 191P4D12(b) proteins in bacteria that are fused to the Glutathione S-

transferase (GST) protein, all or parts of the 191P4D12(b) cDNA protein coding sequence are cloned into the pGEX family of

GST-fusion vectors (Amersham Pharmacia Biotech, Piscataway, NJ). These constructs allow controlled expression of

recombinant 191P4D12(b) protein sequences with GST fused at the amino-terminus and a six histidine epitope (6X His) at

the carboxyl-lerminus. The GST and 6X His tags permit purification of the recombinant fusion protein from induced bacteria

with the appropriate affinity matrix and allow recognition of the fusion protein with anti-GST and anti-His antibodies. The 6X

His tag is generated by adding 6 histidine codons to the cloning primer at the 3' end, of the open reading frame (ORF).

A proteolytic cleavage site, such as the PreScissionTM recognition site in pGEX-6P-1, may be employed such that it permits

cleavage of the GST tag from 191P4D12(b)-related protein. The ampicillin resistance gene and pBR322 origin permits

selection and maintenance of the pGEX plasmids in E. coli.

pMAL Constructs: To generate, in bacteria, recombinant 191P4D12(b) proteins that are fused to maltose-binding

protein (MBP), all or parts of the 191P4D12(b) cDNA protein coding sequence are fused to the MBP gene by cloning into the

pMAL-c2X and pMAL-p2X vectors (New England Biolabs, Beverly, MA). These constructs allow controlled expression of

recombinant 191P4D12(b) protein sequences with MBP fused at the amino-terminus and a 6X His epitope tag at the

carboxyl-terminus. The MBP and 6X His tags permit purification of the recombinant protein from induced bacteria with the

appropriate affinity matrix and allow recognition of the fusion protein with anti-MBP and anti-His antibodies. The 6X His

epitope tag is generated by adding 6 histidine codons to the 3' cloning primer. A Factor Xa recognition site permits cleavage

of the pMAL tag from 191P4D12(b). The pMAL-c2X and pMAL-p2X vectors are optimized to express the recombinant

protein in the cytoplasm or periplasm respectively. Periplasm expression enhances folding of proteins with disulfide bonds.

pET Constructs: To express 191P4D12(b) in bacterial cells, all or parts of the 191P4D12(b) cDNA protein coding

sequence are cloned into the pET family of vectors (Novagen, Madison, WI). These vectors allow tightly controlled

expression of recombinant 191P4D12(b) protein in bacteria with and without fusion to proteins that enhance solubility, such

as NusA and thioredoxin (Trx), and epitope tags, such as 6X His and S-Tag TM that aid purification and detection of the

recombinant protein. For example, constructs are made utilizing pET NusA fusion system 43.1 such that regions of the

191P4D12(b) protein are expressed as amino-terminal fusions to NusA.00

C. Yeast Constructs:

pESC Constructs: To express 191P4D12(b) in the yeast species Saccharomyces cerevlsiae for generation of

recombinant protein and functional studies, all or parts of the 191P4D12(b) cDNA protein coding sequence are cloned into

the pESC family of vectors each of which contain 1 of 4 selectable markers, HIS3, TRP1, LEU2, and URA3 (Stratagene, La

Jolla, CA). These vectors allow controlled expression from the same plasmid of up to 2 different genes or cloned sequences

containing either FlagTM or Myc epitope tags in the same yeast cell. This system is useful to confirm protein-protein

interactions of 191P4D12(b). In addition, expression in yeast yields similar post-translational modifications, such as

S glycosylations and phosphorylations, that are found when expressed in eukaryotic cells.

pESP Constructs: To express 191P4D12(b) in the yeast species Saccharomyces pombe, all or parts of the 191P4D12(b)

cDNA protein coding sequence are cloned into the pESP family of vectors. These vectors allow controlled high level of

expression of a 191P4D12(b) protein sequence that is fused at either the amino terminus or at the carboxyl terminus to GST

00 which aids purification of the recombinant protein. A FlagT epitope tag allows detection of the recombinant protein with anti-

SFlagTM antibody.

Example 8: Production of Recombinant 191P4D12(b) in Higher Eukaryotic Systems

A. Mammalian Constructs:

To express recombinant 191P4D12(b) in eukaryotic cells, the full or partial length 191P4012(b) cDNA sequences

can be cloned into any one of a variety of expression vectors known in the art. One or more of the following regions of

S191P4D12(b) are expressed in these constructs, amino adds 1 to 510, or any 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,

21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more contiguous amino acids from 191P4D12(b) v.1, v.2, v.10, v.11, v.12; amino

acids 1 to 511, or any 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more

contiguous amino acids from 191P4D12(b) v.13, variants, or analogs thereof.

The constructs can be transfected into any one of a wide variety of mammalian cells such as 293T cells.

Transfected 293T cell lysates can be probed with the anti-191P4D12(b) polyclonal serum, described herein.

pcDNA4/HisMax Constructs: To express 191P4D12(b) in mammalian cells, a 191P4D12(b) ORF, or portions

thereof, of 191P4D12(b) were cloned into pcDNA4/HisMax Version A (Invitrogen, Carlsbad, CA). Protein expression is

driven from the cytomegalovirus (CMV) promoter and the SP16 translational enhancer. The recombinant protein has

XpressTM and six histidine (6X His) epitopes fused to the amino-terminus. The pcDNA4/HisMax vector also contains the

bovine growth hormone (BGH) polyadenylation signal and transcription termination sequence to enhance mRNA stability

along with the SV40 origin for episomal replication and simple vector rescue in cell lines expressing the large T antigen. The

Zeocin resistance gene allows for selection of mammalian cells expressing the protein and the ampicillin resistance gene and

ColE1 origin permits selection and maintenance of the plasmid in E. coli.

pcDNA3.11MycHis Constructs: To express 191P4D12(b) in mammalian cells, a 191P4D12(b) ORF, or portions

thereof, of 191 P4D12(b) with a consensus Kozak translation initiation site was cloned into pcDNA3.1/MycHis Version A

(Invitrogen, Carlsbad, CA). Protein expression is driven from the cytomegalovlrus (CMV) promoter. The recombinant

proteins have the myc epitope and 6X His epitope fused to the carboxyl-terminus. The pcDNA3.1/MycHis vector also

contains the bovine growth hormone (BGH) polyadenylation signal and transcription termination sequence to enhance mRNA

stability, along with the SV40 origin for episomal replication and simple vector rescue in cell lines expressing the large T

antigen. The Neomycin resistance gene can be used, as it allows for selection of mammalian cells expressing the protein

and the ampicillin resistance gene and ColE1 origin permits selection and maintenance of the plasmid in E. coli. Figure 22

shows expression of 191P4D12(b).pcDNA3.1/MycHis following vector transfection into 293T cells. 293T cells were

transfected with either 191P4D12(b).pcDNA3.1/mychis or pcDNA3.11mychis vector control. Forty hours later cell lysates

00 were collected. Samples were run on an SDS-PAGE acrylamide gel, blotted and stained with anti-his antibody. The blot

was developed using the ECL chemiluminescence kit and visualized by autoradiography. Results show expression of

191P4D12(b) in the lysates of 191P4D12(b).pcDNA3.1/mychis transfected cells (Lane but not from the control

pcDNA3.1/mychis (Lane 4).

pcDNA3.11CT-GFP-TOPO Construct: To express 191P4D12(b) in mammalian cells and to allow detection of the

recombinant proteins using fluorescence, a 191P4D12(b) ORF, or portions thereof, with a consensus Kozak translation

initiation site are cloned into pcDNA3.1/CT-GFP-TOPO (Invitrogen, CA). Protein expression is driven from the

cytomegalovirus (CMV) promoter. The recombinant proteins have the Green Fluorescent Protein (GFP) fused to the

carboxyl-terminus facilitating non-invasive, in vivo detection and cell biology studies. The pcDNA3.1CT-GFP-TOPO vector

r also contains the bovine growth hormone (BGH) polyadenylation signal and transcription termination sequence to enhance

mRNA stability along with the SV40 origin for episomal replication and simple vector rescue in cell lines expressing the large

00 T antigen. The Neomycin resistance gene allows for selection of mammalian cells that express the protein, and the

Sampicillin resistance gene and ColE1 origin permits selection and maintenance of the plasmid in E. coli. Additional

N constructs with an amino-terminal GFP fusion are made in pcDNA3.1/NT-GFP-TOPO spanning the entire length of a

191P4D12(b) protein.

PAPta: A 191P4D12(b) ORF, or portions thereof, is cloned into pAPtag-5 (GenHunter Corp. Nashville, TN). This

construct generates an alkaline phosphatase fusion at the carboxyl-terminus of a 191P4D12(b) protein while fusing the IgGK

signal sequence to the amino-terminus. Constructs are also generated in which alkaline phosphatase with an amino-terminal

IgGK signal sequence is fused to the amino-terminus of a 191P4D12(b) protein. The resulting recombinant 191P4D12(b)

proteins are optimized for secretion into the media of transfected mammalian cells and can be used to identify proteins such

as ligands or receptors that interact with 191 P4D12(b) proteins. Protein expression is driven from the CMV promoter and the

recombinant proteins also contain myc and 6X His epitopes fused at the carboxyl-terminus that facilitates detection and

purification. The Zeocin resistance gene present in the vector allows for selection of mammalian cells expressing the

recombinant protein and the ampicillin resistance gene permits selection of the plasmid in E coli.

A 191P4D12(b) v.1 extracellular domain was cloned into pTag-5 plasmid. This vector is similar to pAPtag

but without the alkaline phosphatase fusion. This construct generates 191P4D12(b) protein with an amino-terminal IgGK

signal sequence and myc and 6X His epitope tags at the carboxyl-terminus that facilitate detection and affinity purification.

The resulting recombinant 191P4D12(b) protein is optimized for secretion into the media of transfected mammalian cells, and

is used as immunogen or ligand to identify proteins such as ligands or receptors that interact with the 191P4D12(b) proteins.

Protein expression is driven from the CMV promoter. The Zeocin resistance gene present in the vector allows for selection

of mammalian cells expressing the protein, and the ampicillin resistance gene permits selection of the plasmid in E. coli.

Figure 22 shows expression and secretion of the extracellular domain of 191P4D12(b) following 191P4D12(b).pTag5 vector

transfection into 293T cells. 293T cells were transfected with 191P4D12(b) .pTag5. Forty hours later, cell lysate and

supematant were collected. Samples were run on an SDS-PAGE acrylamide gel, blotted and stained with anti-his antibody.

The blot was developed using the ECL chemiluminescence kit and visualized by autoradiography. Results show expression

from 191P4D12(b).pTag5 plasmid of 191P4D12(b) extracellular domain in the lysate (Lane 2) and secretion in the culture

supematant (Lane 1).

191P4D12(b) ORF, or portions thereof, is also cloned into pTag-5 plasmid.

PsecFc: A 191P4D12(b) ORF, or portions thereof, is also cloned into psecFc. The psecFc vector was assembled

by cloning the human immunoglobulin G1 (IgG) Fc (hinge, CH2, CH3 regions) into pSecTag2 (Invitrogen, California). This

construct generates an IgG1 Fc fusion at the carboxyl-terminus of the 191P4D12(b) proteins, while fusing the IgGK signal

sequence to N-terminus. 191P4D12(b) fusions utilizing the murine IgG1 Fc region are also used. The resulting recombinant

0o 191P4D12(b) proteins are optimized for secretion Into the media of transfected mammalian cells, and can be used as

0 immunogens or to identify proteins such as ligands or receptors that interact with 191P4D12(b) protein. Protein expression is

driven from the CMV promoter. The hygromycin resistance gene present in the vector allows for selection of mammalian

cells that express the recombinant protein, and the ampicillin resistance gene permits selection of the plasmid in E. coli.

pSRa Constructs: To generate mammalian cell lines that express 191P4D12(b) constitutively, 191P4D12(b)

ORF, or portions thereof, of 191P4D12(b) were cloned into pSRa constructs. Amphotropic and ecotropic retroviruses were

generated by transfection of pSRa constructs into the 293T-10A1 packaging line or co-transfection of pSRa and a helper

plasmid (containing deleted packaging sequences) into the 293 cells, respectively. The retrovirus is used to infect a variety

of mammalian cell lines, resulting in the integration of the cloned gene, 191P4D12(b), into the host cell-lines. Protein

C expression is driven from a long terminal repeat (LTR). The Neomycin resistance gene present in the vector allows for

p selection of mammalian cells that express the protein, and the ampicillin resistance gene and ColE1 origin permit selection0 0 and maintenance of the plasmid in E. coli. The retroviral vectors can thereafter be used for infection and generation of

various cell lines using, for example, PC3, NIH 3T3, TsuPrl, 293 or rat-1 cells.

Figure 23 shows stable expression of 191P4D12(b) following 191P4D12(b).pSRa transduction into 3T3 cells. 3T3

cells were transduced with the pSRa retroviral vector encoding the 191P4D12(b) gene. Following selection with neomycin,

the cells were expanded and RNA was extracted. Northern blot with 10 ug of total RNAlane was probed with the

191P4D12(b) SSH sequence. Size standards In kilobases (kb) are indicated on the side. Results show expression of the

191P4D12(b) transcript driven from the retroviral LTR, which migrates slower than the endogenous 4 kb 191P4D12(b)

transcript detected in the positive control LAPC-4AD.

Additional pSRa constructs are made that fuse an epitope tag such as the FLAGTM tag to the carboxyl-terminus of

191P4D12(b) sequences to allow detection using anti-Flag antibodies. For example, the FLAGTM sequence 5' gat tac aag

gat gac gac gat aag 3' (SEQ ID NO: 60) is added to cloning primer at the 3' end of the ORF. Additional pSRa constructs

are made to produce both amino-terminal and carboxyl-terminal GFP and myc/6X His fusion proteins of the full-length

191P4D12(b) proteins.

Additional Viral Vectors: Additional constructs are made for viral-mediated delivery and expression of

191P4012(b). High virus titer leading to high level expression of 191P4D12(b) is achieved in viral delivery systems such as

adenoviral vectors and herpes amplicon vectors. A 191P4D12(b) coding sequences or fragments thereof are amplified by

PCR and subcloned into the AdEasy shuttle vector (Stratagene). Recombination and virus packaging are performed

according to the manufacturer's instructions to generate adenoviral vectors. Alternatively, 191P4D12(b) coding sequences

or fragments thereof are cloned into the HSV-1 vector (Imgenex) to generate herpes viral vectors. The viral vectors are

thereafter used for infection of various cell lines such as PC3, NIH 3T3, 293 or rat-1 cells.

Regulated Expression Systems: To control expression of 191P4D12(b) in mammalian cells, coding sequences

of 191P4D12(b), or portions thereof, are cloned into regulated mammalian expression systems such as the T-Rex System

(Invitrogen), the GeneSwitch System (Invitrogen) and the tightly-regulated Ecdysone System (Sratagene). These systems

allow the study of the temporal and concentration dependent effects of recombinant 191P4D12(b). These vectors are

thereafter used to control expression of 191P4D12(b) in various cell lines such as PC3, NIH 3T3, 293 or rat-1 cells.

B. Baculovirus Expression Systems

To generate recombinant 191P4D12(b) proteins in a baculovirus expression system, 191P4D12(b) ORF, or

portions thereof, are cloned into the baculovirus transfer vector pBlueBac 4.5 (Invitrogen), which provides a His-tag at the N-

terminus. Specifically, pBlueBac-191P4D12(b) Is co-transfected with helper plasmid pBac-N-Blue (Invitrogen) into SF9

(Spodoptera frugiperda) insect cells to generate recombinant baculovirus (see Invitrogen instruction manual for;details).

Baculovirus is then collected from cell supernatant and purified by plaque assay.

00 Recombinant 191P4D12(b) protein is then generated by infection of HighFive insect cells (Invitrogen) with purified

S baculovirus. Recombinant 191P4D12(b) protein can be detected using anti-191P4D12(b) or anti-His-tag antibody.

Cr 191P4012(b) protein can be purified and used in various cell-based assays or as immunogen to generate polyclonal and

monoclonal antibodies specific for 191P4D12(b).

Example 9: Antigenicity Profiles and Secondary Structure

c Figure Figure Figure Figure and Figure 9(A-C) depict graphically five amino acid

profiles of 191P4D12(b) variants 1, 7, and 9, each assessment available by accessing the ProtScale website located on the

S World Wide Web at (.expasy.ch/cgi-bin/protscale.pl) on the ExPasy molecular biology server.

C1 These profiles: Figure 5, Hydrophilicity, (Hopp Woods 1981. Proc. Natl. Acad. Sci. U.S.A. 78:3824-

3828); Figure 6, Hydropathicity, (Kyte Doolittle 1982. J. Mol. Biol. 157:105-132); Figure 7, Percentage Accessible

Residues (Janin 1979 Nature 277:491-492); Figure 8, Average Flexibility, (Bhaskaran and Ponnuswamy 1988.00

Int. J. Pept. Protein Res. 32:242-255); Figure 9, Beta-turn (Deleage, Roux B. 1987 Protein Engineering 1:289-294); and

C optionally others available in the art, such as on the ProtScale website, were used to identify antigenic regions of each of the

191P4D12(b) variant proteins. Each of the above amino acid profiles of 191P4D12(b) variants were generated using the

following ProtScale parameters for analysis: 1) A window size of 9; 2) 100% weight of the window edges compared to the

window center; and, 3) amino acid profile values normalized to lie between 0 and 1.

Hydrophilicity (Figure Hydropathicity (Figure 6) and Percentage Accessible Residues (Figure 7) profiles were

used to determine stretches of hydrophilic amino acids values greater than 0.5 on the Hydrophilicity and Percentage

Accessible Residues profile, and values less than 0.5 on the Hydropathicity profile). Such regions are likely to be exposed to

the aqueous environment, be present on the surface of the protein, and thus available for immune recognition, such as by

antibodies.

Average Flexibility (Figure 8) and Beta-turn (Figure 9) profiles determine stretches of amino acids values

greater than 0.5 on the Beta-tur profile and the Average Flexibility profile) that are not constrained in secondary structures

such as beta sheets and alpha helices. Such regions are also more likely to be exposed on the protein and thus accessible

to immune recognition, such as by antibodies.

Antigenic sequences of the 191P4D12(b) variant proteins indicated, by the profiles set forth in Figure

Figure Figure Figure andlor Figure 9(A-C) are used to prepare immunogens, either peptides or

nucleic acids that encode them, to generate therapeutic and diagnostic anti-191P4D12(b) antibodies. The immunogen can

be any 5, 6, 7, 8, 9, 10, 11, 12,13,14,15,16,17,18,19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50 or more than

contiguous amino acids, or the corresponding nucleic acids that encode them, from the 191P4D12(b) protein variants listed

in Figures 2 and 3, of which the amino acid profiles are shown in Figure 9, or are identical to the variant sequences that are

the same as a variant depicted in figure 9. In particular, peptide immunogens of the invention can comprise, a peptide region

of at least 5 amino acids of Figures 2 and 3 in any whole number increment that includes an amino acid position having a

value greater than 0.5 in the Hydrophilicity profiles of Figure 5; a peptide region of at least 5 amino acids of Figures 2 and 3

in any whole number increment that includes an amino acid position having a value less than 0.5 in the Hydropathicity profile

of Figures 6; a peptide region of at least 5 amino acids of Figures 2 and 3 in any whole number increment that includes an

amino acid position having a value greater than 0.5 in the Percent Accessible Residues profiles of Figure 7; a peptide region

of at least 5 amino acids of Figures 2 and 3 in any whole number increment that includes an amino acid position having a

value greater than 0.5 in the Average Flexibility profiles on Figure 8 and, a peptide region of at least 5 amino acids of

Figures 2 and 3 In any whole number increment that includes an amino acid position having a value greater than 0.5 in the

Beta-turn profile of Figures 9. Peptide immunogens of the invention can also comprise nucleic acids that encode any of the

0 forgoing.

All immunogens of the invention, peptide or nucleic acid, can be embodied in human unit dose form, or comprised

by a composition that includes a pharmaceutical excipient compatible with human physiology.

The secondary structure of 191P4D12(b) protein variants 1,7, and 9, namely the predicted presence and location

of alpha helices, extended strands, and random coils, is predicted from the primary amino acid sequence using the HNN

Hierarchical Neural Network method (Guermeur, 1997, http://pbil.ibcp.fr/cgi-bin/npsa_automat.pl?page=npsann.html),

accessed from the ExPasy molecular biology server located on the World Wide Web at (.expasy.ch/tools/). The analysis

indicates that 191P4D12(b) variant 1 is composed of 24.90% alpha helix, 18.63% extended strand, and 56.47% random coil

(Figure 13A). Variant 6 is composed of 28.47% alpha helix, 19.32% extended strand, and 52.20% random coil (Figure 13B).

Variant 7 is composed of 26.19% alpha helix, 18.76% extended strand, and 55.05% random coil (Figure 13C). Variant 7 is

C composed of 56.20% alpha helix, 8.76% extended strand, and 35.04% random coil (Figure 13D).

0 Analysis for the potential presence of transmembrane domains in the 191P4D12(b) variant proteins was carried out

0 using a variety of transmembrane prediction algorithms accessed from the ExPasy molecular biology server located on the

World Wide Web at (.expasy.ch/tools/). Shown graphically in figure 13E and 13F are the results of analysis of variant 1

depicting the presence and location of 1 transmembrane domain using the TMpred program (Figure 13E) and 1

transmembrane domain using the TMHMM program (Figure 13F). Shown graphically In figure 13G and 13H are the results

of analysis of variant 6 depicting the presence and location of 1 transmembrane domains using the TMpred program (Figure

13G) and 1 transmembrane domain using the TMHMM program (Figure 13H). Shown graphically in figure 131 and 13J are

the results of analysis'of variant 7 depicting the presence and location of 1 transmembrane domain using the TMpred

program (Figure 131) and 1 transmembrane domain using the TMHMM program (Figure 13J). Shown graphically in figure

13K and 13L are the results of analysis of variant 9 depicting the presence and location of 2 transmembrane domains using

the TMpred program (Figure 1K) and 1 transmembrane domain using the TMHMM program (Figure 13L). The results of

each program, namely the amino acids encoding the transmembrane domains are summarized in Table VI and Table L.

Example 10: Generation of 191P4D12(b) Polyclonal Antibodies

Polyclonal antibodies can be raised in a mammal, for example, by one or more injections of an immunizing agent

and, if desired, an adjuvant. Typically, the immunizing agent and/or adjuvant will be injected in the mammal by multiple

subcutaneous or intraperitoneal injections. In addition to immunizing with a full length 191P4D12(b) protein variant,

computer algorithms are employed in design of immunogens that, based on amino acid sequence analysis contain

characteristics of being antigenic and available for recognition by the immune system of the immunized host (see the

Example entitled "Antigenicity Profiles and Secondary Structures"). Such regions would be predicted to be hydrophilic,

flexible, in beta-turn conformations, and be exposed on the surface of the protein (see, Figure Figure 6(A C),

Figure Figure 8(A or Figure 9(A-C) for amino acid profiles that indicate such regions of 191P4D12(b) protein

variants).

For example, recombinant bacterial fusion proteins or peptides containing hydrophilic, flexible, beta-turn regions of

191P4D12(b) protein variants are used as antigens to generate polyclonal antibodies in New Zealand White rabbits or

monoclonal antibodies as described in Example 11. For example, in 191P4D12(b) variant 1, such regions include, but are

not limited to, amino acids 27-39, amino acids 93-109, and amino acids 182-204. In sequence unique to variant 7, such

regions include, but are not limited to, amino acids 400-420. In sequence specific for variant 9, such regions include, but are

not limited to, amino acids 80-94. It is useful to conjugate the immunizing agent to a protein known to be immunogenic in the

mammal being immunized. Examples of such immunogenic proteins include, but are not limited to, keyhole limpet

hemocyanin (KLH), serum albumin, bovine thyroglobulin, and soybean trypsin inhibitor. In one embodiment, a peptide

00 encoding amino acids 52-63 of 191P4D12(b) variant 1 and amino acids 179-197 were each conjugated to KLH and used to

S immunize separate rabbits. Alternatively the immunizing agent may include all or portions of the 191P4D12(b) variant

C proteins, analogs or fusion proteins thereof. For example, the 191P4D12(b) variant 1 amino acid sequence can be fused

using recombinant DNA techniques to any one of a variety of fusion protein partners that are well known in the art, such as

glutathione-S-transferase (GST) and HIS tagged fusion proteins. In another embodiment, amino acids 2-349 of

C 191P4D12(b) variant 1 was fused to GST using recombinant techniques and the pGEX expression vector, expressed,

purified and used to immunize a rabbit Such fusion proteins are purified from induced bacteria using the appropriate affinity

matrix.

Other recombinant bacterial fusion proteins that may be employed include maltose binding protein, LacZ,

N thioredoxin, NusA, or an immunoglobulin constant region (see the section entitled "Production of 191P4D12(b) in Prokaryotic

Systems" and Current Protocols In Molecular Biology, Volume 2, Unit 16, Frederick M. Ausubul et al. eds., 1995; Linsley,

Brady, Urnes, Grosmaire, Damle, and Ledbetter, L.(1991) J.Exp. Med. 174, 561-566).00

SIn addition to bacterial derived fusion proteins, mammalian expressed protein antigens are also used. These

c antigens are expressed from mammalian expression vectors such as the Tag5 and Fc-fusion vectors (see the section

entitled "Production of Recombinant 191P4D12(b) in Eukaryotic Systems"), and retain post-translational modifications such

as glycosylations found in native protein. In one embodiment, amino acids 31-347 of variant 1, encoding the extracellular

domain, was doned into the Tag5 mammalian secretion vector, and expressed in 293T cells resulting in a soluble secreted

protein (Figure 22). The recombinant protein is purified by metal chelate chromatography from tissue culture supernatants of

293T cells stably expressing the recombinant vector. The purified Tag5 191P4D12(b) protein is then used as immunogen.

During the immunization protocol, it is useful to mix or emulsify the antigen in adjuvants that enhance the immune

response of the host animal. Examples of adjuvants include, but are not limited to, complete Freund's adjuvant (CFA) and

MPL-TDM adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate).

In a typical protocol, rabbits are initially immunized subcutaneously with up to 200 pg, typically 100-200 pg, of

fusion protein or peptide conjugated to KLH mixed in complete Freund's adjuvant (CFA). Rabbits are then injected

subcutaneously every two weeks with up to 200 pg, typically 100-200 pg, of the immunogen in incomplete Freund's adjuvant

(IFA). Test bleeds are taken approximately 7-10 days following each immunization and used to monitor the titer of the

antiserum by ELISA.

To test reactivity and specificity of immune serum, such as the rabbit serum derived from immunization with the

-191P4D12(b) variant 1 protein, the full-length 191P4D12(b) variant 1 cDNA is cloned into pCDNA 3.1 myc-his

expression vector (Invitrogen, see the Example entitled "Production of Recombinant 191P4D12(b) in Eukaryotic Systems").

After transfection of the constructs into 293T cells, cell lysates are probed with the anti-191P4D12(b) serum and with anti-His

antibody (Santa Cruz Biotechnologies, Santa Cruz, CA) to determine specific reactivity to denatured 191P4D12(b) protein

using the Western blot technique. In addition, the Immune serum is tested by fluorescence microscopy, flow cytometry and

immunoprecipitation against 293T (Figure 22) and other recombinant 191P4D12(b)-expressing cells to determine specific

recognition of native protein. Western blot, immunoprecipitation, fluorescent microscopy, and flow cytometric techniques

using cells that endogenously express 191P4D12(b) are also carried out to test reactivity and specificity.

Anti-serum from rabbits immunized with 191P4D12(b) variant fusion proteins, such as GST and MBP fusion proteins, are

purified by depletion of antibodies reactive to the fusion partner sequence by passage over an affinity column containing the

fusion partner either alone or in the context of an irrelevant fusion protein. For example, antiserum derived from a GST-

191P4D12(b) variant 1 fusion protein is first purified by passage over a column of GST protein covalently coupled to AffiGel

1

matrix (BioRad, Hercules, Calif.). The antiserum is then affinity purified by passage over a column composed of a MBP-

191P4D12(b) fusion protein covalently coupled to Affigel matrix. The serum is then further purified by protein G affinityS chromatography to isolate the IgG fraction. Sera from other His-tagged antigens and peptide immunized rabbits as well as

0 fusion partner depleted sera are affinity purified by passage over a column matrix composed of the original protein

immunogen or free peptide.

Example 11: Generation of 191P4D12(b) Monoclonal Antibodies (mAbs)

In one embodiment, therapeutic mAbs to 191P4D12(b) variants comprise those that react with epitopes specific for

each variant protein or specific to sequences in common between the variants that would disrupt or modulate the biological

function of the 191P4D12(b) variants, for example those that would disrupt the interaction with ligands and binding partners.

Immunogens for generation of such mAbs include those designed to encode or contain the entire 191P4D12(b) protein

S variant sequence, regions of the 191P4D12(b) protein variants predicted to be antigenic from computer analysis of the amino

acid sequence (see, Figure Figure Figure Figure or Figure and the Example

00 entitled "Antigenicity Profiles"). Immunogens include peptides, recombinant bacterial proteins, and mammalian expressed

Tag 5 proteins and human and murine IgG FC fusion proteins. In addition, cells engineered to express high levels of aC respective 191P4D12(b) variant, such as 293T-191P4D12(b) variant 1 or 300.19-191P4D12(b) variant Imurine Pre-B cells,

are used to immunize mice.

To generate mAbs to a 191P4D12(b) variant, mice are first immunized intraperitoneally (IP) with, typically, 10-50

pg of protein immunogen or 107 191P4D12(b)-expressing cells mixed in complete Freund's adjuvant. Mice are then

subsequently immunized IP every 2-4 weeks with, typically, 10-50 pg of protein immunogen or 107 cells mixed in incomplete

Freund's adjuvant. Alternatively, MPL-TDM adjuvant is used in immunizations. In addition to the above protein and cell-

based immunization strategies, a DNA-based immunization protocol is employed in which a mammalian expression vector

encoding a 191P4D12(b) variant sequence is used to immunize mice by direct injection of the plasmid DNA. For example,

amino acids 31-347 was cloned into the Tag5 mammalian secretion vector and the recombinant vector will then be used asimmunogen. In another example the same amino acids are cloned into an Fc-fusion secretion vector in which the

191P4D12(b) variant 1 sequence is fused at the amino-terminus to an IgK leader sequence and at the carboxyl-terminus tothe coding sequence of the human or murine IgG Fc region. This recombinant vector is then used as immunogen. The

plasmid immunization protocols are used in combination with purified proteins expressed from the same vector and with cellsexpressing the respective 191P4D12(b) variant

During the immunization protocol, test bleeds are taken 7-10 days following an injection to monitor titer and

specificity of the immune response. Once appropriate reactivity and specificity is obtained as determined by ELISA, Western

blotting, immunoprecipitation, fluorescence microscopy, and flow cytometric analyses, fusion and hybridoma generation isthen carried out with established procedures well known in the art (see, Harlow and Lane, 1988).

In one embodiment for generating 191P4D12(b) monoclonal antibodies, a Tag5-191P4D12(b) variant 1 antigen

encoding amino acids 31-347, was expressed (Figure 22) and then purified from stably transfected 293T cells. Balb C mice

are initially immunized intraperitoneally with 25 jg of the Tag5-191P4D12(b) variant 1 protein mixed in complete Freund's

adjuvant. Mice are subsequently immunized every two weeks with 25 pig of the antigen mixed in incomplete Freund's

adjuvant for a total of three immunizations. ELISA using the Tag5 antigen determines the titer of serum from immunized

mice. Reactivity and specificity of serum to full length 191P4D12(b) variant 1 protein is monitored by Western blotting,immunoprecipitation and flow cytometry using 293T cells transfected with an expression vector encoding the 191P4D12(b)variant 1 cDNA (see the Example entitled "Production of Recombinant 191P4D12(b) in Eukaryotic Systems"and Figure 22). Other recombinant 191P4D12(b) variant 1-expressing cells or cells endogenously expressing 191P4D12(b)

variant 1 are also used. Mice showing the strongest reactivity are rested and given a final injection of Tag5 antigen in PBS

and then sacrificed four days later. The spleens of the sacrificed mice are harvested and fused to SPO/2 myeloma cells

00 using standard procedures (Harlow and Lane, 1988). Supernatants from HAT selected growth wells are screened by ELISA,

S Western blot, immunoprecipitation, fluorescent microscopy, and flow cytometry to identify 191P4D12(b) specific antibody-

Cl producing clones.

To generate monoclonal antibodies that are specific for each 191P4D12(b) variant protein, immunogens are

S designed to encode sequences unique for each variant. In one embodiment, a GST-fusion antigen encoding the full

sequence of 191P4D12(b) variant 9 (AA 1-137) is produced, purified, and used as immunogen to derive monoclonal

LC antibodies specific to 191P4D12(b) variant 2. In another embodiment, an antigenic peptide composed of amino acids 400-

420 of 191P4D12(b) variant 7 is coupled to KLH and used as immunogen. Hybridoma supematants are then screened on

the respective antigen and then further screened on cells expressing the specific variant and cross-screened on cells

C<l expressing the other variants to derive variant-specific monoclonal antibodies.

The binding affinity of a 191 P4D 12(b) variant monoclonal antibody Is determined using standard technologies.

r1 Affinity measurements quantify the strength of antibody to epitope binding and are used to help define which 191P4D12(b)00

variant monoclonal antibodies preferred for diagnostic or therapeutic use, as appreciated by one of skill in the art. The

S BIAcore system (Uppsala, Sweden) is a preferred method for determining binding affinity. The BIAcore system uses surface

plasmon resonance (SPR, Welford K. 1991, Opt. Quant. Elect. 23:1; Morton and Myszka, 1998, Methods in Enzymology 295:

268) to monitor biomolecular interactions in real time. BIAcore analysis conveniently generates association rate constants,

dissociation rate constants, equilibrium dissociation constants, and affinity constants.

Example 12: HLA Class I and Class II Binding Assays

HLA class I and class II binding assays using purified HLA molecules are performed in accordance with disclosed

protocols PCT publications WO 94/20127 and WO 94/03205; Sidney et al., Current Protocols in Immunology 18.3.1

(1998); Sidney, et al., J. Immunol. 154:247 (1995); Sette, et Mol. Immunol. 31:813 (1994)). Briefly, purified MHC

molecules (5 to 500 nM) are incubated with various unlabeled peptide inhibitors and 1-10 nM 1251-radiolabeled probe peptides

as described. Following incubation, MHC-peptide complexes are separated from free peptide by gel filtration and the fraction

of peptide bound is determined. Typically, in preliminary experiments, each MHC preparation is titered in the presence of

fixed amounts of radiolabeled peptides to determine the concentration of HLA molecules necessary to bind 10-20% of the

total radioactivity. All subsequent inhibition and direct binding assays are performed using these HLA concentrations.

Since under these conditions [label]<[HLA] and ICso_[HLA], the measured ICso 'values are reasonable

approximations of the true Ko values. Peptide inhibitors are typically tested at concentrations ranging from 120 p.g/ml to 1.2

ng/ml, and are tested in two to four completely independent experiments. To allow comparison of the data obtained in

different experiments, a relative binding figure is calculated for each peptide by dividing the ICso of a positive control for

inhibition by the ICso for each tested peptide'(typically unlabeled versions of the radiolabeled probe peptide). For database

purposes, and inter-experiment comparisons, relative binding values are compiled. These values can subsequently be

converted back into ICso nM values by dividing the ICs0 nM of the positive controls for inhibition by the relative binding of the

peptide of interest. This method of data compilation is accurate and consistent for comparing peptides that have been tested

on different days, or with different lots of purified MHC.

Binding assays as outlined above may be used to analyze HLA supermotif and/or HLA motif-bearing peptides (see

Table IV).

Example 13: Identification of HLA Supermotif- and Motif-Bearing CTL Candidate Epitopes

HLA vaccine compositions of the invention can include multiple epitopes. The multiple epitopes can comprise

multiple HLA supermotifs or motifs to achieve broad population coverage. This example illustrates the identification and0 0 confirmation of supermotif- and motif-bearing epitopes for the inclusion in such a vaccine composition. Calculation of

0 population coverage is performed using the strategy described below.

Computer searches and algorithms for identification of supermotif and/or motif-bearing epitopes

SThe searches performed to identify the motif-bearing peptide sequences in the Example entitled "Antigenicity

Profiles" and Tables VII-XXI and XXII-XLIX employ the protein sequence data from the gene product of 191P4D12(b) set

O forth in Figures 2 and 3, the specific search peptides used to generate the tables are listed in Table VII.

Computer searches for epitopes bearing HLA Class I or Class II supermotifs or motifs are performed as follows, All

translated 191P4D12(b) protein sequences are analyzed using a text string search software program to identify potential

peptide sequences containing appropriate HLA binding motifs; such programs are readily produced in accordance with

S information in the art in view of known motif/supermotif disclosures. Furthermore, such calculations can be made mentally.

SIdentified A2-, A3-, and DR-supermotif sequences are scored using polynomial algorithms to predict their capacity

00 to bind to specific HLA-Class I or Class II molecules. These polynomial algorithms account for the impact of different amino

acids at different positions, and are essentially based on the premise that the overall affinity (or AG) of peptide-HLA molecule

S interactions can be approximated as a linear polynomial function of the type:

"AG" aul x a2 x a x ani

where aji is a coefficient which represents the effect of the presence of a given amino acid at a given position (i)

along the sequence of a peptide of n amino acids. The crucial assumption of this method is that the effects at each position

are essentially independent of each other independent binding of Individual side-chains). When residue j occurs at

position i in the peptide, it is assumed to contribute a constant amount ji to the free energy of binding of the peptide

irrespective of the sequence of the rest of the peptide.

The method of derivation of specific algorithm coefficients has been described in Gulukota et al., J. Mol. Biol.

267:1258-126, 1997; (see also Sidney et al., Human Immunol. 45:79-93, 1996; and Southwood et al., J. Immunol. 160:3363-

3373, 1998). Briefly, for all i positions, anchor and non-anchor alike, the geometric mean of the average relative binding

(ARB) of all peptides carrying j is calculated relative to the remainder of the group, and used as the estimate of j. For Class

II peptides, if multiple alignments are possible, only the highest scoring alignment is utilized, following an iterative procedure.

To calculate an algorithm score of a given peptide in a test set, the ARB values corresponding to the sequence of the peptideare multiplied. If this product exceeds a chosen threshold, the peptide is predicted to bind. Appropriate thresholds are

chosen as a function of the degree of stringency of prediction desired.

Selection of HLA-A2 supertype cross-reactive peptides

Protein sequences from 191P4D12(b) are scanned utilizing motif identification software, to identify 9- 10- and11-mer sequences containing the HLA-A2-supermotif main anchor specificity. Typically, these sequences are then scoredusing the protocol described above and the peptides corresponding to the positive-scoring sequences are synthesized andtested for their capacity to bind purified HLA-A*0201 molecules in vitro (HLA-A*0201 is considered a prototype A2 supertypemolecule).

These peptides are then tested for the capacity to bind to additional A2-supertype molecules (A*0202, A*0203,A*0206, and A*6802). Peptides that bind to at least three of the five A2-supertype alleles tested are typically deemed A2-supertype cross-reactive binders. Preferred peptides bind at an affinity equal to or less than 500 nM to three or more HLA-A2 supertype molecules.

Selection of HLA-A3 supermotif-bearing epitopes

The 191P4D12(b) protein sequence(s) scanned above is also examined for the presence of peptides with the HLA-

c0 A3-supermotif primary anchors. Peptides corresponding to the HLA A3 supermotif-bearing sequences are then synthesized

0 and tested for binding to HLA-A*0301 and HLA-A*1101 molecules, the molecules encoded by the two most prevalent A3-

C supertype alleles. The peptides that bind at least one of the two alleles with binding affinities of <500 nM, often 200 nM,

are then tested for binding cross-reactivity to the other common A3-supertype alleles A*3101, A*3301, and A*6801) to

identify those that can bind at least three of the five HLA-A3-supertype molecules tested.

C Selection of HLA-B7 supermotif bearing epitopes

The 191P4D12(b) protein(s) scanned above is also analyzed for the presence of 9- 10-, or 11-mer peptides with

I the HLA-B7-supermotif. Corresponding peptides are synthesized and tested for binding to HLA-B*0702, the molecule

C encoded by the most common 87-supertype allele the prototype B7 supertype allele). Peptides binding B*0702 with

ICso of 500 nM are identified using standard methods. These peptides are then tested for binding to other common B7-

CK supertype molecules 8*3501, B*5101, B'5301, and B*5401). Peptides capable of binding to three or more of the five

B7-supertype alleles tested are thereby identified.

Selection of Al and A24 motif-bearing epitopes

To further increase population coverage, HLA-A1 and -A24 epitopes can also be incorporated into vaccine

compositions. An analysis of the 191P4D12(b) protein can also be performed to identify HLA-A1- and A24-motif-containing

sequences.

High affinity and/or cross-reactive binding epitopes that bear other motif and/or supermotifs are identified using

analogous methodology.

Example 14: Confirmation of Immunogenicity

Cross-reactive candidate CTL A2-supermotif-bearing peptides that are identified as described herein are selected

to confirm in vitro immunogenicity. Confirmation is performed using the following methodology:

Target Cell Lines for Cellular Screening:

The .221A2.1 cell line, produced by transferring the HLA-A2.1 gene into the HLA-A, -C null mutant human B-

lymphoblastoid cell line 721.221, is used as the peptide-loaded target to measure activity of HLA-A2.1-restridted CTL. This

cell line is grown in RPMI-1640 medium supplemented with antibiotics, sodium pyruvate, nonessential amino acids and

heat inactivated FCS. Cells that express an antigen of interest, or transfectants comprising the gene encoding the

antigen of interest, can be used as target cells to confirm the ability of peptide-specific CTLs to recognize endogenous

antigen.

Primary CTL Induction Cultures:

Generation of Dendritic Cells PBMCs are thawed in RPMI with 30 lpg/ml DNAse, washed twice and

resuspended in complete medium (RPMI-1640 plus 5% AB human serum, non-essential amino adds, sodium pyruvate, L-

glutamine and penicillin/streptomycin). The monocytes are purified by plating 10 x 106 PBMC/well in a 6-well plate. After 2

hours at 37"C, the non-adherent cells are removed by gently shaking the plates and aspirating the supernatants. The wells

are washed a total of three times with 3 ml RPMI to remove most of the non-adherent and loosely adherent cells. Three ml of

complete medium containing 50 ng/ml of GM-CSF and 1,000 U/ml of IL-4 are then added to each well. TNFa( is added to the

DCs on day 6 at 75 ng/ml and the cells are used for CTL induction cultures on day 7.

Induction of CTL with DC and Peptide: CD8+ T-cells are isolated by positive selection with Dynal immunomagnetic

beads (Dynabeads® M-450) and the detacha-bead@ reagent. Typically about 200-250x10 6 PBMC are processed to obtain

0 24x10 6 CD8* T-cells (enough for a 48-well plate culture). Briefly, the PBMCs are thawed In RPMI with 30pg/ml DNAse,

washed once with PBS containing 1% human AB serum and resuspended In PBS/1% AB serum at a concentration of

S 20xl06cells/ml. The magnetic beads are washed 3 times with PBS/AB serum, added to the cells (140pl beads/20x10 6 cells)

and Incubated for 1 hour at 4°C with continuous mixing. The beads and cells are washed 4x with PBS/AB serum to remove

the nonadherent cells and resuspended at 100x10 6 cells/ml (based on the original cell number) in PBS/AB serum containing

C 100pl/ml detacha-bead® reagent and 30 pg/ml DNAse. The mixture is incubated for 1 hour at room temperature with

continuous mixing. The beads are washed again with PBS/AB/DNAse to collect the CD8+ T-cells. The DC are collected and

centrifuged at 1300 rpm for 5-7 minutes, washed once with PBS with 1% BSA, counted and pulsed with 40pg/ml of peptide

at a cell concentration of 1-2x10/ml in the presence of 3pg/ml 112- microglobulin for 4 hours at 20°C. The DC are then

NC Irradiated (4,200 rads), washed 1 time with medium and counted again.

N Setting up induction cultures: 0.25 ml cytokine-generated DC (at 1x10 s cells/ml) are co-cultured with 0.25ml of

00 CD8+ T-cells (at 2x10 6 cell/ml) in each well of a 48-well plate in the presence of 10 ng/ml of IL-7. Recombinant human

0 is added the next day at a final concentration of 10 ng/ml and rhuman IL-2 is added 48 hours later at 10 IU/ml.

Restimulation of the induction cultures with peptide-pulsed adherent cells: Seven and fourteen days after the

primary induction, the cells are restimulated with peptide-pulsed adherent cells. The PBMCs are thawed and washed twice

with RPMI and DNAse. The cells are resuspended at 5x10 6 cells/ml and irradiated at -4200 rads. The PBMCs are plated at

2x10 6 in 0.5 ml complete medium per well and incubated for 2 hours at 370C. The plates are washed twice with RPMI by

tapping the plate gently to remove the nonadherent cells and the adherent cells pulsed with 10pg/ml of peptide in the

presence of 3 pg/ml 112 microglobulin in 0.25ml RPMI/5%AB per well for 2 hours at 37°C. Peptide solution from each well is

aspirated and the wells are washed once with RPMI. Most of the media is aspirated from the induction cullures (CD8+ cells)

and brought to 0.5 ml with fresh media. The cells are then transferred to the wells containing the peptide-pulsed adherent

cells. Twenty four hours later recombinant human IL-10 is added at a final concentration'of 10 ng/ml and recombinant

human IL2 is added the next day and again 2-3 days later at 501U/ml (Tsai et al., Critical Reviews in Immunology

18(1-2):65-75, 1998). Seven days later, the cultures are assayed for CTL activity in a 51Cr release assay. In some

experiments the cultures are assayed for peptide-specific recognition in the in situ IFNy ELISA at the time of the second

restimulation followed by assay of endogenous recognition 7 days later. After expansion, activity is measured in both assays

for a side-by-side comparison.

Measurement of CTL lytic activity by 5'Cr release.

Seven days after the second restimulation, cytotoxicity is determined in a standard (5 hr) s5 Cr release assay by

assaying individual wells at a single E:T. Peptide-pulsed targets are prepared by Incubating the cells with 10pg/ml peptide

overnight at 370C.

Adherent target cells are removed from culture flasks with trypsin-EDTA. Target cells are labeled with 200pCi of1Cr sodium chromate (Dupont, Wilmington, DE) for 1 hour at 370C. Labeled target cells are resuspended at 106 per ml and

diluted 1:10 with K562 cells at a concentration of 3.3x10 6/ml (an NK-sensitive erythroblastoma cell line used to reduce non-

specific lysis). Target cells (100 pl) and effectors (100pl) are plated in 96 well round-bottom plates and incubated for 5 hours

at 370C. At that time, 100 pl of supernatant are collected from each well and percent lysis is determined according to the

formula:

[(cpm of the test sample- cpm of the spontaneous slCr release sample)/(cpm of the maximal 51Cr release sample-

cpm of the spontaneous 51Cr release sample)] x 100.

Maximum and spontaneous release are determined by incubating the labeled targets with 1% Triton X-100 and

media alone, respectively. A positive culture is defined as one in which the specific lysis (sample- background) is 10% or

00 higher in the case of individual wells and is 15% or more at the two highest E:T ratios when expanded cultures are assayed.

SIn situ Measurement of Human IFNy Production as an Indicator of Peptide-specific and Endogenous Recognition

Cl Immulon 2 plates are coated with mouse anti-human IFNy monoclonal antibody (4 pg/ml 0.1M NaHCO3, pH8.2)

overnight at 4°C. The plates are washed with Ca2 Mg2 -free PBS/0.05% Tween 20 and blocked with PBS/10% FCS for two

hours, after which the CTLs (100 pl/well) and targets (100 pl/well) are added to each well, leaving empty wells for the

standards and blanks (which received media only). The target cells, either peptide-pulsed or endogenous targets, are used

l at a concentration of 1x10 6 cells/ml. The plates are incubated for 48 hours at 37°C with 5% CO2.

Recombinant human IFN-gamma is added to the standard wells starting at 400 pg or 1200pg/100 microliter/well

and the plate incubated for two hours at 37°C. The plates are washed and 100 pl of biotinylated mouse anti-human IFN-

S gamma monoclonal antibody (2 microgram/ml in PBS/3%FCS/0.05% Tween 20) are added and incubated for 2 hours at

room temperature. After washing again, 100 microliter HRP-streptavidin (1:4000) are added and the plates incubated for one

00 hour at room temperature. The plates are then washed 6x with wash buffer, 100 microliter/well developing solution (TMB

1:1) are added, and the plates allowed to develop for 5-15 minutes. The reaction is stopped with 50 microliter/well 1M H3P0 4

Cl and read at OD450. A culture is considered positive if it measured at least 50 pg of IFN-gammalwell above background and

is twice the background level of expression.

CTL Expansion.

Those cultures that demonstrate specific lytic activity against peptide-pulsed targets and/or tumor targets are

expanded over a two week period with anti-CD3. Briefly, 5x10 4 CD8+ cells are added to a T25 flask containing the following:

lx106 irradiated (4,200 rad) PBMC (autologous or allogeneic) per ml, 2x10 5 irradiated (8,000 rad) EBV- transformed cells per

ml, and OKT3 (anti-CD3) at 30ng per ml in RPMI-1640 containing 10% human AB serum, non-essential amino acids,

sodium pyruvate, 25pM 2-mercaptoethanol, L-glutamine and penicillin/streptomycin. Recombinant human IL2 is added 24

hours later at a final concentration of 2001U/ml and every three days thereafter with fresh media at 501U/ml. The cells are

split if the cell concentration exceeds lx10 6/ml and the cultures are assayed between days 13 and 15 at E:T ratios of 30,

3 and 1:1 in the s5 Cr release assay or at 1x10 6/ml in the in situ IFNy assay using the same targets as before the expansion.

Cultures are expanded in the absence of anti-CD3* as follows. Those cultures that demonstrate specific lytic

activity against peptide and endogenous targets are selected and 5x104 CD8* cells are added to a T25 flask containing the

following: 1x106 autologous PBMC per ml which have been peptide-pulsed with 10 pg/ml peptide for two hours at 37°C and

irradiated (4,200 rad); 2x10 5 irradiated (8,000 rad) EBV-transformed cells per ml RPMI-1640 containing 10%(v/v) human AB

serum, non-essential AA, sodium pyruvate, 25mM 2-ME, L-glutamine and gentamicin.

Immunogenicity of A2 supermotif-bearing peptides

A2-supermotif cross-reactive binding peptides are tested in the cellular assay for the ability to induce peptide-

specific CTL in normal individuals. In this analysis, a peptide Is typically considered to be an epitope if it induces peptide-

specific CTLs in at least individuals, and preferably, also recognizes the endogenously expressed peptide.

Immunogenicity can also be confirmed using PBMCs isolated from patients bearing a tumor that expresses

191P4D12(b). Briefly, PBMCs are isolated from patients, re-stimulated with peptide-pulsed monocytes and assayed for the

ability to recognize peptide-pulsed target cells as well as transfected cells endogenously expressing the antigen.

Evaluation of A*03/A11 immunoqenicity

HLA-A3 supermotif-bearing cross-reactive binding peptides are also evaluated for immunogenicity using

methodology analogous for that used to evaluate the immunogenicity of the HLA-A2 supermotif peptides.

Evaluation of B7 immunoqenicitv

Immunogenicity screening of the B7-supertype cross-reactive binding peptides identified as set forth herein are

confirmed in a manner analogous to the confirmation of A2-and A3-supermotif-bearing peptides.00

Peptides bearing other supermotifs/motifs, HLA-A1, HLA-A24 etc. are also confirmed using similar

S methodology

Example 15: Implementation of the Extended Supermotif to Improve the Binding Capacity of Native Epitopes byCreating Analogs

SHLA motifs and supermotifs (comprising primary and/or secondary residues) are useful in the identification and

preparation of highly cross-reactive native peptides, as demonstrated herein. Moreover, the definition of HLA motifs and

supermotifs also allows one to engineer highly cross-reactive epitopes by identifying residues within a native peptide

sequence which can be analoged to confer upon the peptide certain characteristics, e.g. greater cross-reactivity within the

S group of HLA molecules that comprise a supertype, and/or greater binding affinity for some or all of those HLA molecules.

Examples of analoging peptides to exhibit modulated binding affinity are set forth in this example.

00 Analoqing at Primary Anchor Residues

Peptide engineering strategies are implemented to further increase the cross-reactivity of the epitopes. ForS example, the main anchors of A2-supermotif-bearing peptides are altered, for example, to introduce a preferred L, I, V, or M

at position 2, and I or V at the C-terminus.

To analyze the cross-reactivity of the analog peptides, each engineered analog is initially tested for binding to theprototype A2 supertype allele A*0201, then, if A*0201 binding capacity Is maintained, for A2-supertype cross-reactivity.

Alternatively, a peptide is confirmed as binding one or all supertype members and then analoged to modulatebinding affinity to any one (or more) of the supertype members to add population coverage.

The selection of analogs for immunogenicity in a cellular screening analysis is typically further restricted by thecapacity of the parent wild type (WT) peptide to bind at least weakly, bind at an ICso of 5000nM or less, to three of moreA2 supertype alleles. The rationale for this requirement is that the WT peptides must be present endogenously in sufficientquantity to be biologically relevant. Analoged peptides have been shown to have Increased immunogenicity and cross-reactivity by T cells specific for the parent epitope (see, Parkhurst et al., J. Immunol. 157:2539, 1996; and Pogue et a.,Proc. Natl. Acad. Sci. USA 92:8166, 1995).

In the cellular screening of these peptide analogs, it is important to confirm that analog-specific CTLs are also ableto recognize the wild-type peptide and, when possible, target cells that endogenously express the epitope.

Analoqing of HLA-A3 and B7-supermotif-bearing peptides

Analogs of HLA-A3 supermotif-bearing epitopes are generated using strategies similar to those employed inanaloging HLA-A2 supermotif-bearing peptides. For example, peptides binding to 3/5 of the A3-supertype molecules areengineered at primary anchor residues to possess a preferred residue S, M, or A) at position 2.

The analog peptides are then tested for the ability to bind A*03 and A*11 (prototype A3 supertype alleles). Thosepeptides that demonstrate 500 nM binding capacity are then confirmed as having A3-supertype cross-reactivity.

Similarly to the A2- and A3- motif bearing peptides, peptides binding 3 or more B7-supertype alleles can beimproved, where possible, to achieve increased cross-reactive binding or greater binding affinity or binding half life. B7supermotif-bearing peptides are, for example, engineered to possess a preferred residue I, L, or F) at the C-terminalprimary anchor position, as demonstrated by Sidney et al. Immunol. 157:3480-3490, 1996).

Analoging at primary anchor residues of other motif and/or supermotif-bearing epitopes is performed in a likemanner.

The analog peptides are then be confirmed for immunogenicity, typically in a cellular screening assay. Again, it is

generally important to demonstrate that analog-specific CTLs are also able to recognize the wild-type peptide and, when

OO possible, targets that endogenously express the epitope.

O

CN Analoging at Secondary Anchor Residues

Moreover, HLA supermotifs are of value in engineering highly cross-reactive peptides andlor peptides that bind

HLA molecules with increased affinity by identifying particular residues at secondary anchor positions that are associated

with such properties. For example, the binding capacity of a B7 supermotif-bearing peptide with an F residue at position 1 is

S analyzed. The peptide is then analoged to, for example, substitute L for F at position 1. The analoged peptide is evaluated

for increased binding affinity, binding half life and/or increased cross-reactivity. Such a procedure identifies analoged

peptides with enhanced properties.

C Engineered analogs with sufficiently improved binding capacity or cross-reactivity can also be tested for

Immunogenicity in HLA-B7-transgenic mice, following for example, IFA immunization or lipopeptide immunization. Analoged

r1 peptides are additionally tested for the ability to stimulate a recall response using PBMC from patients with 191P4D12(b)-00

expressing tumors.

SOther analoging strategies

Another form of peptide analoging, unrelated to anchor positions, involves the substitution of a cysteine with cc-

amino butyric acid. Due to its chemical nature, cysteine has the propensity to form disulfide bridges and sufficiently alter the

peptide structurally so as to reduce binding capacity. Substitution of ct-amino butyric acid for cysteine not only alleviates this

problem, but has been shown to improve binding and crossbinding capabilities in some instances (see, the review by

Sette et al., In: Persistent Viral Infections, Eds. R. Ahmed and I. Chen, John Wiley Sons, England, 1999).

Thus, by the use of single amino acid substitutions, the binding properties and/or cross-reactivity of peptide ligands

for HLA supertype molecules can be modulated.

Example 16: Identification and confirmation of 191P4D12(b)-derived sequences with HLA-DR binding motifs

Peptide epitopes bearing an HLA class II supermotif or motif are identified and confirmed as outlined below using

methodology similar to that described for HLA Class I peptides.

Selection of HLA-DR-supermotif-bearinq epitopes.

To identify 191P4D12(b)-derived, HLA class II HTL epitopes, a 191P4D12(b) antigen is analyzed for the presence

of sequences bearing an HLA-DR-motif or supermotif. Specifically, 15-mer sequences are selected comprising a DR-

supermotif, comprising a 9-mer core, and three-residue N- and C-terminal flanking regions (15 amino acids total).

Protocols for predicting peptide binding to DR molecules have been developed (Southwood et al., J. Immunol.

160:3363-3373, 1998). These protocols, specific for individual DR molecules, allow the scoring, and ranking, of 9-mer core

regions. Each protocol not only scores peptide sequences for the presence of DR-supermotif primary anchors at

position 1 and position 6) within a 9-mer core, but additionally evaluates sequences for the presence of secondary anchors.

Using allele-specific selection tables (see, Southwood et al., ibid.), it has been found that these protocols efficiently

select peptide sequences with a high probability of binding a particular DR molecule. Additionally, it has been found that

performing these protocols in tandem, specifically those for DR1, DR4w4, and DR7, can efficiently select DR cross-reactive

peptides.

The 191P4D12(b)-derived peptides identified above are tested for their binding capacity for various common HLA-

DR molecules. All peptides are initially tested for binding to the DR molecules in the primary panel: DR1, DR4w4, and DR7.

Peptides binding at least two of these three DR molecules are then tested for binding to DR2w2 p1, DR2w2 02, DR6w19,

and DR9 molecules in secondary assays. Finally, peptides binding at least two of the four secondary panel DR molecules,

and thus cumulatively at least four of seven different DR molecules, are screened for binding to DR4w15, DR5w11, and00

S DR8w2 molecules in tertiary assays. Peptides binding at least seven of the ten DR molecules comprising the primary,

secondary, and tertiary screening assays are considered cross-reactive DR binders. 191P4D12(b)-derived peptides found to

S bind common HLA-DR alleles are of particular interest.

Selection of DR3 motif peptides

Because HLA-DR3 is an allele that is prevalent in Caucasian, Black, and Hispanic populations, DR3 binding

LC capacity is a relevant criterion In the selection of HTL epitopes. Thus, peptides shown to be candidates may also be

assayed for their DR3 binding capacity. However, in view of the binding specificity of the DR3 motif, peptides binding only to

DR3 can also be considered as candidates for inclusion in a vaccine formulation.

To efficiently identify peptides that bind DR3, target 191P4D12(b) antigens are analyzed for sequences carrying

CK1 one of the two DR3-specific binding motifs reported by Geluk et al. Immunol. 152:5742-5748, 1994). The corresponding

LC peptides are then synthesized and confirmed as having the ability to bind DR3 with an affinity of 1 LM or better, less than

0 1 pM. Peptides are found that meet this binding criterion and qualify as HLA class II high affinity binders.

SDR3 binding epitopes identified in this manner are included in vaccine compositions with DR supermotif-bearing

peptide epitopes.

Similarly to the case of HLA class I motif-bearing peptides, the class II motif-bearing peptides are analoged to

improve affinity or cross-reactivity. For example, aspartic acid at position 4 of the 9-mer core sequence is an optimal residue

for DR3 binding, and substitution for that residue often improves DR 3 binding.

Example 17: Immunogenicity of 191P4D12(b)-derived HTL epitopes

This example determines immunogenic DR supermotif- and DR3 motif-bearing epitopes among those identified

using the methodology set forth herein.

Immunogenicity of HTL epitopes are confirmed in a manner analogous to the determination of immunogenicity of

CTL epitopes, by assessing the ability to stimulate HTL responses and/or by using appropriate transgenic mouse models.

Immunogenicity is determined by screening for: in vitro primary induction using normal PBMC or recall responses from

patients who have 191P4D12(b)-expressing tumors.

Example 18: Calculation of phenotypic frequencies of HLA-supertypes in various ethnic backgrounds to determine

breadth of population coverage

This example illustrates the assessment of the breadth of population coverage of a vaccine composition comprised

of multiple epitopes comprising multiple supermotifs and/or motifs.

In order to analyze population coverage, gene frequencies of HLA alleles are determined. Gene frequencies for

each HLA allele are calculated from antigen or allele frequencies utilizing the binomial distribution formulae gf=1-(SQRT(1-

at)) (see, Sidney et al., Human Immunol. 45:79-93, 1996). To obtain overall phenotypic frequencies, cumulative gene

frequencies are calculated, and the cumulative antigen frequencies derived by the use of the inverse formula [af=1-(1-Cgf) 2

Where frequency data is not available at the level of DNA typing, correspondence to the serologically defined

antigen frequencies is assumed. To obtain total potential supertype population coverage no linkage disequilibrium is

assumed, and only alleles confirmed to belong to each of the supertypes are included (minimal estimates). Estimates of total

potential coverage achieved by inter-loci combinations are made by adding to the A coverage the proportion of the non-A

covered population that could be expected to be covered by the B alleles considered total=A+B*(1-A)). Confirmed

members of the A3-like supertype are A3, All, A31, A*3301, and A*6801. Although the A3-like supertype may also include

A34, A66, and A'7401, these alleles were not included in overall frequency calculations. Likewise, confirmed members of

the A2-like supertype family are A*0201, A*0202, A*0203, A*0204, A*0205, A*0206, A*0207, A*6802, and A*6901. Finally,

Sthe B7-like supertype-confirmed alleles are: B7, B83501-03, 851, B*5301, B*5401, B*5501-2, B*5601, B*6701, and B7801

0 (potentially also 8*1401, B*3504-06, 8*4201, and B*5602).

CPopulation coverage achieved by combining the A2-, A3- and B7-supertypes is approximately 86% in five major

S ethnic groups. Coverage may be extended by including peptides bearing the Al and A24 motifs. On average, Al is present

in 12% and A24 in 29% of the population across five different major ethnic groups (Caucasian, North American Black,

Chinese, Japanese, and Hispanic). Together, these alleles are represented with an average frequency of 39% in these

C same ethnic populations. The total coverage across the major ethnicities when Al and A24 are combined with the coverage

of the A2-, A3- and B7-supertype alleles is see, Table IV An analogous approach can be used to estimate

population coverage achieved with combinations of class II motif-bearing epitopes.

Immunogenicity studies in humans Bertoni et at., J. Clin. Invest. 100:503,1997; Doolan et al., Immunity 7:97,c 1997; and Threlkeld et J. Immunol. 159:1648, 1997) have shown that highly cross-reactive binding peptides are almost

CN always recognized as epitopes. The use of highly cross-reactive binding peptides is an important selection criterion in000 identifying candidate epitopes for inclusion in a vaccine that is immunogenic in a diverse population.

With a sufficient number of epitopes (as disclosed herein and from the art), an average population coverage is

predicted to be greater than 95% in each of five major ethnic populations. The game theory Monte Carlo simulation analysis,

which is known in the art (see Osborne, M.J. and Rubinstein, A. "A course in game theory" MIT Press, 1994), can be

used to estimate what percentage of the individuals in a population comprised of the Caucasian, North American Black,

Japanese, Chinese, and Hispanic ethnic groups would recognize the vaccine epitopes described herein. A preferred

percentage is 90%. A more preferred percentage is

Example 19: CTL Recognition Of Endogenously Processed Antigens After Priming

This example confirms that CTL induced by native or analoged peptide epitopes identified and selected as

described herein recognize endogenously synthesized, native antigens.

Effector cells isolated from transgenic mice that are immunized with peptide epitopes, for example HLA-A2

supermotif-bearing epitopes, are re-stimulated in vitro using peptide-coated stimulator cells. Six days later, effector cells are

assayed for cytotoxicity and the cell lines that contain peptide-specific cytotoxic activity are further re-stimulated. An

additional six days later, these cell lines are tested for cytotoxic activity on 51Cr labeled Jurkat-A2.1/Kb target cells in the

absence or presence of peptide, and also tested on 5'Cr labeled target cells bearing the endogenously synthesized antigen,i.e. cells that are stably transfected with 191P4D12(b) expression vectors.

The results demonstrate that CTL lines obtained from animals primed with peptide epitope recognize

endogenously synthesized 191P4D12(b) antigen. The choice of transgenic mouse model to be used for such an analysis

depends upon the epitope(s) that are being evaluated. In addilion to HLA-A*0201/Kb transgenic mice, several other

transgenic mouse models including mice with human All, which may also be used to evaluate A3 epitopes, and B7 alleles

have been characterized and others transgenic mice for HLA-A1 and A24) are being developed. HLA-DR1 and HLA-

DR3 mouse models have also been developed, which may be used to evaluate HTL epitdpes.

Example 20: Activity Of CTL-HTL Conjugated Epitopes In Transgenic Mice

This example illustrates the induction of CTLs and HTLs in transgenic mice, by use of a 191P4D12(b)-derived CTLand HTL peptide vaccine compositions. The vaccine composition used herein comprise peptides to be administered to apatient with a 191P4D12(b)-expressing tumor. The peptide composition can comprise multiple CTL and/or HTL epitopes.

The epitopes are identified using methodology as described herein. This example also illustrates that enhanced

S Immunogenicity can be achieved by inclusion of one or more HTL epitopes in a CTL vaccine composition; such a peptide

O composition can comprise an HTL epitope conjugated to a CTL epitope. The CTL epitope can be one that binds to multiple

HLA family members at an affinity of 500 nM or less, or analogs of that epitope. The peptides may be lipidated, if desired.

Immunization procedures: Immunization of transgenic mice is performed as described (Alexander et al., J.

Immunol. 159:4753-4761, 1997). For example, A2/Kb mice, which are transgenic for the human HLA A2.1 allele and are

used to confirm the immunogenicity of HLA-A*0201 motif- or HLA-A2 supermotif-bearing epitopes, and are primed

C1 subcutaneously (base of the tail) with a 0.1 ml of peptide in Incomplete Freund's Adjuvant, or if the peptide composition is a

lipidated CTL/HTL conjugate, in DMSO/saline, or if the peptide composition is a polypeptide, In PBS or Incomplete Freund's

S Adjuvant. Seven days after priming, splenocytes obtained from these animals are restimulated with syngenic irradiated LPS-

activated lymphoblasts coated with peptide.

Cell lines: Target cells for peptide-specific cytotoxicity assays are Jurkat cells transfected with the HLA-A2.1/Kb

CK chimeric gene Vitiello et al,, J. Exp. Med. 173:1007, 1991)

SIn vitro CTL activation: One week after priming, spleen cells (30x10 6 cells/flask) are co-cultured at 37*C with

O syngeneic, irradiated (3000 rads), peptide coated lymphoblasts (10x10 6 cells/flask) in 10 ml of culture medium/T25 flask.

After six days, effector cells are harvested and assayed for cytotoxic activity.

Assay for cytotoxic activity: Target cells (1.0 to 1.5x106) are incubated at 37°C in the presence of 200 pl of s5 Cr.

After 60 minutes, cells are washed three times and resuspended in R10 medium. Peptide is added where required at a

concentration of 1 pg/ml. For the assay, 104 slCr-labeled target cells are added to different concentrations of effector cells

(final volume of 200 pl) in U-bottom 96-well plates. After a six hour incubation period at 37°C, a 0.1 ml aliquot of supernatant

is removed from each well and radioactivity is determined in a Micromedic automatic gamma counter. The percent specific

lysis is determined by the formula: percent specific release 100 x (experimental release spontaneous release)/(maximum

release spontaneous release). To facilitate comparison between separate CTL assays run under the same conditions,

s Cr release data is expressed as lytic units/106 cells. One lytic unit is arbitrarily defined as the number of effector cells

required to achieve 30% lysis of 10,000 target cells in a six hour 51Cr release assay. To obtain specific lytic units/10 6 the

lytic units/106 obtained in the absence of peptide is subtracted from the lytic units/106 obtained in the presence of peptide.

For example, if 30% 5'Cr release is obtained at the effector target ratio of 50:1 5x10 5 effector cells for 10,000

targets) in the absence of peptide and 5:1 5x10 4 effector cells for 10,000 targets) in the presence of peptide, the specific

lytic units would be: [(1/50,000)-(1/500,000)] x 106 18 LU.

The results are analyzed to assess the magnitude of the CTL responses of animals injected with the immunogenic

CTL/HTL conjugate vaccine preparation and are compared to the magnitude of the CTL response achieved using, for

example, CTL epitopes as outlined above in the Example entitled "Confirmation of Immunogenicity." Analyses similar to this

may be performed to confirm the immunogenicity of peptide conjugates containing multiple CTL epitopes and/or multiple HTL

epitopes. In accordance with these procedures, It is found that a CTL response is induced, and concomitantly that an HTL

response is induced upon administration of such compositions.

Example 21: Selection of CTL and HTL epitopes for Inclusion in a 191P4D12(b)-specific vaccine.

This example illustrates a procedure for selecting peptide epitopes for vaccine compositions of the invention. The

peptides in the composition can be in the form of a nucleic acid sequence, either single or one or more sequences

minigene) that encodes peptide(s), or can be single and/or polyepitopic peptides.

The following principles are utilized when selecting a plurality of epitopes for inclusion in a vaccine composition.

Each of the following principles is balanced in order to make the selection.

Epitopes are selected which, upon administration, mimic immune responses that are correlated with 191P4D12(b)

clearance. The number of epitopes used depends on observations of patients who spontaneously clear 191P4D12(b). For

00 example, if it has been observed that patients who spontaneously clear 191P4D12(b)-expressing cells generate an immune

response to at least three epitopes from 191P4D12(b) antigen, then at least three epitopes should be included for HLA

class 1. A similar rationale is used to determine HLA class II epitopes.

Epitopes are often selected that have a binding affinity of an ICso of 500 nM or less for an HLA class I molecule, or

for class 11, an ICso of 1000 nM or less; or HLA Class I peptides with high binding scores from the BIMAS web site, at URL

0 bimas.dcrt.nih.govl.

In order to achieve broad coverage of the vaccine through out a diverse population, sufficient supermotif bearing

peptides, or a sufficient array of allele-specific motif bearing peptides, are selected to give broad population coverage. In

S one embodiment, epitopes are selected to provide at least 80% population coverage. A Monte Carlo analysis, a statistical

evaluation known in the art, can be employed to assess breadth, or redundancy, of population coverage.

O When creating polyepitopic compositions, or a minigene that encodes same, it is typically desirable to generate the

00 smallest peptide possible that encompasses the epitopes of interest. The principles employed are similar, if not the same, as

O those employed when selecting a peptide comprising nested epitopes. For example, a protein sequence for the vaccine

Cl composition is selected because It has maximal number of epitopes contained within the sequence, it has a high

concentration of epitopes. Epitopes may be nested or overlapping frame shifted relative to one another). For example,

with overlapping epitopes, two 9-mer epitopes and one 10-mer epitope can be present in a 10 amino acid peptide. Each

epitope can be exposed and bound by an HLA molecule upon administration of such a peptide. A multi-epitopic, peptide can

be generated synthetically, recombinantly, or via cleavage from the native source. Alternatively, an analog can be made of

this native sequence, whereby one or more of the epitopes comprise substitutions that alter the cross-reactivity and/or

binding affinity properties of the polyepitopic peptide. Such a vaccine composition is administered for therapeutic or

prophylactic purposes. This embodiment provides for the possibility that an as yet undiscovered aspect of immune system

processing will apply to the native nested sequence and thereby facilitate the production of therapeutic or prophylactic

immune response-inducing vaccine compositions. Additionally such an embodiment provides for the possibility of motif-

bearing epitopes for an HLA makeup that is presently unknown. Furthermore, this embodiment (absent the creating of any

analogs) directs the immune response to multiple peptide sequences that are actually present in 191P4D12(b), thus avoiding

the need to evaluate any junctional epitopes. Lastly, the embodiment provides an economy of scale when producing nucleic

acid vaccine compositions. Related to this embodiment, computer programs can be derived in accordance with principles in

the art, which identify in a target sequence, the greatest number of epitopes per sequence length.

A vaccine composition comprised of selected peptides, when administered, is safe, efficacious, and elicits an

immune response similar in magnitude to an immune response that controls or clears cells that bear or overexpress

191P4D12(b).

Example 22: Construction of "Minigene" Multi-Epltope DNA Plasmids

This example discusses the construction of a minigene expression plasmid. Minigene plasmids may, of course,

contain various configurations of B cell, CTL and/or HTL epitopes or epitope analogs as described herein.

A minigene expression plasmid typically includes multiple CTL and HTL peptide epitopes. In the present example,

HLA-A2, -A3, -B7 supermotif-bearing peptide epitopes and HLA-A1 and -A24 motif-bearing peptide epitopes are used in

conjunction with DR supermotif-bearing epitopes and/or DR3 epitopes. HLA class I supermotif or motif-bearing peptide

epitopes derived 191P4D12(b), are selected such that multiple supermotifs/motifs are represented to ensure broad

population coverage. Similarly, HLA class II epitopes are selected from 191P4D12(b) to provide broad population coverage,

i.e. both HLA DR-1-4-7 supermotif-bearing epitopes and HLA DR-3 motif-bearing epitopes are selected for inclusion in the

minigene construct The selected CTL and HTL epitopes are then incorporated into a minigene for expression in an00

S expression vector.

Such a construct may additionally include sequences that direct the HTL epitopes to the endoplasmic reticulum.

For example, the li protein may be fused to one or more HTL epitopes as described in the art, wherein the CLIP sequence of

the li protein is removed and replaced with an HLA class II epitope sequence so that HLA class II epitope is directed to the

endoplasmic reticulum, where the epitope binds to an HLA class II molecules.

This example illustrates the methods to be used for construction of a minigene-bearing expression plasmid. Other

expression vectors that may be used for minigene compositions are available and known to those of skill in the art.

The minigene DNA plasmid of this example contains a consensus Kozak sequence and a consensus murine kappa

Ig-light chain signal sequence followed by CTL and/or HTL epitopes selected in accordance with principles disclosed herein.

C-K The sequence encodes an open reading frame fused to the Myc and His antibody epitope tag coded for by the pcDNA 3.1

Myc-His vector.

00 Overlapping oligonucleotides that can, for example, average about 70 nucleotides in length with 15 nucleotide

0 overlaps, are synthesized and HPLC-purified. The oligonucleotides encode the selected peptide epitopes as well as

appropriate linker nucleotides, Kozak sequence, and signal sequence. The final multiepitope minigene is assembled by

extending the overlapping oligonucleotides in three sets of reactions using PCR. A Perkin/Elmer 9600 PCR machine is used

and a total of 30 cycles are performed using the following conditions: 95°C for 15 sec, annealing temperature (50 below the

lowest calculated Tm of each primer pair) for 30 sec, and 72*C for 1 min.

For example, a minigene is prepared as follows. For a first PCR reaction, 5 pig of each of two oligonucleotides are

annealed and extended: In an example using eight oligonucleotides, four pairs of primers, oligonucleotides 1+2, 3+4,

5+6, and 7+8 are combined in 100 p1 reactions containing Pfu polymerase buffer (1x= 10 mM KCL, 10 mM (NH4)2S04,

mM Tris-chloride, pH 8.75, 2 mM MgSO4, 0.1% Triton X-100, 100 gg/ml BSA), 0.25 mM each dNTP, and 2.5 U of Pfu

polymerase. The full-length dimer products are gel-purified, and two reactions containing the product of 1+2 and 3+4, and

the product of 5+6 and 7+8 are mixed, annealed, and extended for 10 cycles. Half of the two reactions are then mixed, and

cycles of annealing and extension carried out before flanking primers are added to amplify the full length product. The full-

length product is gel-purified and cloned into pCR-blunt (Invitrogen) and Individual clones are screened by sequencing.

Example 23: The Plasmid Construct and the Degree to Which It Induces Immunogenicity.

The degree to which a plasmid construct, for example a plasmid constructed in accordance with the previous

Example, is able to induce immunogenicity is confirmed in vitro by determining epitope presentation by APC following

transduction or transfection of the APC with an epitope-expressing nucleic acid construct. Such a study determines

"antigenicity" and allows the use of human APC. The assay determines the ability of the epitope to be presented by the APC

in a context that is recognized by a T cell by quantifying the density of epitope-HLA class I complexes on the cell surface.

Quantitation can be performed by directly measuring the amount of peptide eluted from the APC (see, Sijts et al., J.

Immunol. 156:683-692, 1996; Demotz etal., Nature 342:682-684, 1989); or the number of peptide-HLA class I complexes

can be estimated by measuring the amount of lysis or lymphokine release induced by diseased or transfected target cells,

and then determining the concentration of peptide necessary to obtain equivalent levels of lysis or lymphokine release (see,

Kageyama et al., J. Immunol. 154:567-576, 1995).

Alternatively, Immunogenicity is confirmed through in vivo injections into mice and subsequent in vitro assessment

of CTL and HTL activity, which are analyzed using cytotoxicity and proliferation assays, respectively, as detailed in

Alexander et al., Immunity 1:751-761, 1994.

For example, to confirm the capacity of a DNA minigene construct containing at least one HLA-A2 supermotif

peptide to induce CTLs in vivo, HLA-A2.1/Kb transgenic mice, for example, are immunized intramuscularly with 100 .g of

00 naked cDNA. As a means of comparing the level of CTLs Induced by cDNA immunization, a control group of animals is also

immunized with an actual peptide composition that comprises multiple epitopes synthesized as a single polypeptide as they

C would be encoded by the minigene.

Splenocytes from immunized animals are stimulated twice with each of the respective compositions (peptide

epitopes encoded in the minigene or the polyepitopic peptide), then assayed for peptide-specific cytotoxic activity in a 51Cr

release assay. The results indicate the magnitude of the CTL response directed against the A2-restricted epitope, thus

indicating the in vivo immunogenicity of the minigene vaccine and polyepitopic vaccine.

It is, therefore, found that the minigene elicits immune responses directed toward the HLA-A2 supermotif peptide

S epitopes as does the polyepitopic peptide vaccine. A similar analysis is also performed using other HLA-A3 and HLA-B7

transgenic mouse models to assess CTL induction by HLA-A3 and HLA-B7 motif or supermotif epitopes, whereby it is also

found that the minigene elicits appropriate immune responses directed toward the provided epitopes.

C To confirm the capacity of a class II epitope-encoding minigene to induce HTLs in vivo, DR transgenic mice, or for

those epitopes that cross react with the appropriate mouse MHC molecule, I-Ab-restricted mice, for example, are immunized

1 intramuscularly with 100 pg of plasmid DNA. As a means of comparing the level of HTLs induced by DNA immunization, a

group of control animals is also immunized with an actual peptide composition emulsified in complete Freund's adjuvant.

CD4+ T cells, i.e. HTLs, are purified from splenocytes of immunized animals and stimulated with each of the respective

compositions (peptides encoded in the minigene). The HTL response is measured using a 3H-thymidine incorporation

proliferation assay, (see, Alexander et al. Immunity 1:751-761, 1994). The results indicate the magnitude of the HTL

response, thus demonstrating the in vivo immunogenicity of the minigene.

DNA minigenes, constructed as described in the previous Example, can also be confirmed as a vaccine in

combination with a boosting agent using a prime boost protocol. The boosting agent can consist of recombinant protein

Barnett at al., Aids Res. and Human Retroviruses 14, Supplement 3:S299-S309, 1998) or recombinant vaccinia, for

example, expressing a minigene or DNA encoding the complete protein of interest (see, Hanke et al, Vaccine 16:439-

445,1998; Sedegah et al., Proc. Natl. Acad. Sci USA 95:7648-53, 1998; Hanke and McMichael, Immunol. Letters 66:177-

181, 1999; and Robinson etal., Nature Med. 5:526-34, 1999).

For example, the efficacy of the DNA minigene used in a prime boost protocol is initially evaluated in transgenic

mice. In this example, A2.1/Kb transgenic mice are immunized IM with 100 jig of a DNA minigene encoding the

'immunogenic peptides including at least one HLA-A2 supermotif-bearing peptide. After an incubation period (ranging from 3-

9 weeks), the mice are boosted IP with 107 pfu/mouse of a recombinant vaccinia virus expressing the same sequence

encoded by the DNA minigene. Control mice are immunized with 100 ig of DNA or recombinant vaccinia without the

minigene sequence, or with DNA encoding the minigene, but without the vaccinia boost. After an additional incubation

period of two weeks, splenocytes from the mice are immediately assayed for peptide-specific activity in an ELISPOT assay.

Additionally, splenocytes are stimulated in vitro with the A2-restricted peptide epitopes encoded in the minigene and

recombinant vaccinia, then assayed for peptide-specific activity In an alpha, beta and/or gamma IFN ELISA.

It Is found that the minigene utilized in a prime-boost protocol elicits greater immune responses toward the HLA-A2

supermotif peptides than with DNA alone. Such an analysis can also be performed using HLA-A11 or HLA-B7 transgenic

mouse models to assess CTL induction by HLA-A3 or HLA-B7 motif or supermotif epitopes. The use of prime boost

protocols in humans is described below in the Example entitled "Induction of CTL Responses Using a Prime Boost Protocol."

Example 24: Peptide Compositions for Prophylactic Uses

Vaccine compositions of the present invention can be used to prevent 191P4D12(b) expression in persons who are

at risk for tumors that bear this antigen. For example, a polyepitopic peptide epitope composition (or a nucleic acid

S comprising the same) containing multiple CTL and HTL epitopes such as those selected in the above Examples, which are

0 also selected to target greater than 80% of the population, is administered to individuals at risk for a 191P4D12(b)-

associated tumor.

For example, a peptide-based composition is provided as a single polypeptide that encompasses multiple epitopes.

The vaccine Is typically administered in a physiological solution that comprises an adjuvant, such as Incomplete Freunds

Ci Adjuvant. The dose of peptide for the initial immunization is from about 1 to about 50,000 pg, generally 100-5,000 pg, for a

kg patient. The initial administration of vaccine is followed by booster dosages at 4 weeks followed by evaluation of the

S magnitude of the immune response in the patient, by techniques that determine the presence of epitope-specific CTL

populations in a PBMC sample. Additional booster doses are administered as required. The composition is found to be both

C= safe and efficacious as a prophylaxis against 191P4D12(b)-associated disease.

SAlternatively, a composition typically comprising transfecting agents is used for the administration of a nucleic acid-

00 based vaccine in accordance with methodologies known in the art and disclosed herein.

Example 25: Polyepitopic Vaccine Compositions Derived from Native 191P4012(b) Sequences

A native 191P4D12(b) polyprotein sequence is analyzed, preferably using computer algorithms defined for each

class I and/or class II supermotif or motif, to identify "relatively short" regions of the polyprotein that comprise multiple

epitopes. The "relatively short" regions are preferably less in length than an entire native antigen. This relatively short

sequence that contains multiple distinct or overlapping, "nested" epitopes can be used to generate a minigene construct.

The construct is engineered to express the peptide, which corresponds to the native protein sequence. The "relatively short"

peptide is generally less than 250 amino acids in length, often less than 100 amino acids in length, preferably less than

amino acids in length, and more preferably less than 50 amino acids in length. The protein sequence of the vaccine

composition is selected because it has maximal number of epitopes contained within the sequence, it has a high

concentration of epitopes. As noted herein, epitope motifs may be nested or overlapping frame shifted relative to one

another). For example, with overlapping epitopes, two 9-mer epitopes and one 10-mer epitope can be present in a 10 amino

acid peptide. Such a vaccine composition is administered for therapeutic or prophylactic purposes.

The vaccine composition will include, for example, multiple CTL epitopes from 191P4D12(b) antigen and at least

one HTL epitope. This polyepitopic native sequence is administered either as a peptide or as a nucleic acid sequence which

encodes the peptide. Alternatively, an analog can be made of this native sequence, whereby one or more of the epitopes

comprise substitutions that alter the cross-reactivity and/or binding affinity properties of the polyepitopic peptide.

The embodiment of this example provides for the possibility that an as yet undiscovered aspect of immune system

processing will apply to the native nested sequence and thereby facilitate the production of therapeutic or prophylactic

immune response-inducing vaccine compositions. Additionally, such an embodiment provides for the possibility of motif-

bearing epitopes for an HLA makeup(s) that is presently unknown. Furthermore, this embodiment (excluding an analoged

embodiment) directs the immune response to multiple peptide sequences that are actually present in native 191P4D12(b),

thus avoiding the need to evaluate any junctional epitopes. Lastly, the embodiment provides an economy of scale when

producing peptide or nucleic acid vaccine compositions.

Related to this embodiment, computer programs are available in the art which can be used to identify in a target

sequence, the greatest number of epitopes per sequence length.

Example 26: Polyepitopic Vaccine Compositions from Multiple Antigens

The 191P4D12(b) peptide epitopes of the present invention are used in conjunction with epitopes from other target

tumor-associated antigens, to create a vaccine composition that is useful for the prevention or treatment of cancer that

00 expresses 191P4D12(b) and such other antigens. For example, a vaccine composition can be provided as a single

O polypeptide that incorporates multiple epitopes from 191P4D12(b) as well as tumor-associated antigens that are often

C1 expressed with a target cancer associated with 191P4D12(b) expression, or can be administered as a composition

comprising a cocktail of one or more discrete epitopes. Alternatively, the vaccine can be administered as a minigene

S construct or as dendritic cells which have been loaded with the peptide epitopes in vitro.

S Example 27: Use of peptides to evaluate an immune response

Peptides of the invention may be used to analyze an immune response for the presence of specific antibodies,

S CTL or HTL directed to 191P4D12(b). Such an analysis can be performed in a manner described by Ogg et al., Science

CKl 279:2103-2106, 1998. In this Example, peptides in accordance with the invention are used as a reagent for diagnostic or

prognostic purposes, not as an immunogen.

In this example highly sensitive human leukocyte antigen tetrameric complexes ("tetramers") are used for a cross-00

sectional analysis of, for example, 191P4D12(b) HLA-A*0201-specific CTL frequencies from HLA A*0201-positive individuals

c- at different stages of disease or following immunization comprising a 191P4D12(b) peptide containing an A*0201 motif.

Tetrameric complexes are synthesized as described (Musey et al., N. Engl. J. Med. 337:1267, 1997). Briefly, purified HLA

heavy chain (A*0201 in this example) and p2-microglobulin are synthesized by means of a prokaryotic expression system.

The heavy chain is modified by deletion of the transmembrane-cytosolic tail and COOH-terminal addition of a sequence

containing a BirA enzymatic biotinylation site. The heavy chain, p2-microglobulin, and peptide are refolded by dilution. The

refolded product is isolated by fast protein liquid chromatography and then biotinylated by BirA in the presence of

biotin (Sigma, St. Louis, Missouri), adenosine 5' triphosphate and magnesium. Streptavidin-phycoerythrin conjugate is

added in a 1:4 molar ratio, and the tetrameric product is concentrated to 1 mg/ml. The resulting product is referred to as

tetramer-phycoerythrin.

For the analysis of patient blood samples, approximately one million PBMCs are centrifuged at 300g for 5 minutes

and resuspended in 50 pl of cold phosphate-buffered saline. Tri-color analysis is performed with the tetramer-phycoerythrin,

along with anti-CD8-Tricolor, and anti-CD38. The PBMCs are incubated with tetramer and antibodies on ice for 30 to 60 min

and then washed twice before formaldehyde fixation. Gates are applied to contain >99.98% of control samples. Controls for

the tetramers include both A*0201-negative individuals and A*0201-positive non-diseased donors. The percentage of cells

stained with the tetramer is then determined by flow cytometry. The results indicate the number of cells in the PBMC sample

that contain epitope-restricted CTLs, thereby readily indicating the extent of immune response to the 191P4D12(b) epitope,

and thus the status of exposure to 191P4D12(b), or exposure to a vaccine that elicits a protective or therapeutic response.

Example 28: Use of Peptide Epitopes to Evaluate Recall Responses

The peptide epitopes of the invention are used as reagents to evaluate T cell responses, such as acute or recall

responses, in patients. Such an analysis may be performed on patients who have recovered from 191P4D12(b)-associated

disease or who have been vaccinated with a 191P4D12(b) vaccine.

For example, the class I restricted CTL response of persons who have been vaccinated may be analyzed. The

vaccine may be any 191P4D12(b) vaccine. PBMC are collected from vaccinated individuals and HLA typed. Appropriate

peptide epitopes of the invention that, optimally, bear supermotifs to provide cross-reactivity with multiple HLA supertype

family members, are then used for analysis of samples derived from Individuals who bear that HLA type.

PBMC from vaccinated individuals are separated on Ficoll-Histopaque density gradients (Sigma Chemical Co., St.

Louis, MO), washed three times in HBSS (GIBCO Laboratories), resuspended in RPMI-1640 (GIBCO Laboratories)

O supplemented with L-glutamine (2mM), penicillin (50U/ml), streptomycin (50 pg/ml), and Hepes (10mM) containing

c heat-inactivated human AB serum (complete RPMI) and plated using microculture formats. A synthetic peptide comprising

S an epitope of the invention is added at 10 .g/ml to each well and HBV core 128-140 epltope is added at 1 p.g/ml to each well

as a source of T cell help during the first week of stimulation.

In the microculture format, 4 x 105 PBMC are stimulated with peptide in 8 replicate cultures In 96-well round bottom

r plate In 100 pl/well of complete RPMI. On days 3 and 10, 100 pl of complete RPMI and 20 U/ml final concentration of rlL-2

are added to each well. On day 7 the cultures are transferred into a 96-well flat-bottom plate and restimulated with peptide,

r- rlL-2 and 10s irradiated (3,000 rad) autologous feeder cells. The cultures are tested for cytotoxlc activity on day 14. A

N positive CTL response requires two or more of the eight replicate cultures to display greater than 10% specific 61Cr release,

based on comparison with non-diseased control subjects as previously described (Rehermann, et al., Nature Med.

C 2:1104,1108, 1996; Rehermann et al., J. Clin. Invest. 97:1655-1665, 1996; and Rehermann et a. J. Clin. Invest. 98:1432-000 1440, 1996).

Target cell lines are autologous and allogeneic EBV-transformed B-LCL that are either purchased from the

American Society for Histocompatibility and Immunogenetics (ASHI, Boston, MA) or established from the pool of patients as

described (Guilhot, et al. J. Virol. 66:2670-2678, 1992).

Cytotoxicity assays are performed in the following manner. Target cells consist of either allogeneic HLA-matched

or autologous EBV-transformed B lymphoblastoid cell line that are incubated overnight with the synthetic peptide epitope of

the invention at 10 pM, and labeled with 100 iCi of S5 Cr (Amersham Corp., Arlington Heights, IL) for 1 hour after which they

are washed four times with HBSS.

Cytolytic activity is determined in a standard 4-h, split well s5 Cr release assay using U-bottomed 96 well plates

containing 3,000 targets/well. Stimulated PBMC are tested at effector/target ratios of 20-50:1 on day 14. Percent

cytotoxicity is determined from the formula: 100 x [(experimental release-spontaneous release)/maximum release-

spontaneous release)]. Maximum release is determined by lysis of targets by detergent Triton X-100; Sigma Chemical

Co., St. Louis, MO). Spontaneous release is <25% of maximum release for all experiments.

The results of such an analysis indicate the extent to which HLA-restricted CTL populations have been stimulated

by previous exposure to 191P4D12(b) or a 191P4D12(b) vaccine.

Similarly, Class II restricted HTL responses may also be analyzed. Purified PBMC are cultured in a 96-well flat

bottom plate at a density of 1.5x10 5 cells/well and are stimulated with 10 ig/ml synthetic peptide of the Invention, whole

191P4D12(b) antigen, or PHA. Cells are routinely plated in replicates of 4-6 wells for each condition. After seven days of

culture, the medium is removed and replaced with fresh medium containing 10U/ml IL-2. Two days later, 1 pCi 3H-thymldine

is added to each well and incubation is continued for an additional 18 hours. Cellular DNA is then harvested on glass fiber

mats and analyzed for 3H-thymidine incorporation. Antigen-specific T cell proliferation is calculated as the ratio of 3H-

thymidine incorporation in the presence of antigen divided by the 3H-thymidine incorporation in the absence of antigen.

Example 29: Induction Of Specific CTL Response In Humans

A human clinical trial for an immunogenic composition comprising CTL and HTL epitopes of the invention is set up

as an IND Phase I, dose escalation study and carried out as a randomized, double-blind, placebo-controlled trial. Such a

trial is designed, for example, as follows:

A total of about 27 individuals are enrolled and divided into 3 groups:

Group I: 3 subjects are injected with placebo and 6 subjects are injected with 5 pg of peptide composition;

Group II: 3 subjects are injected with placebo and 6 subjects are injected with 50 pg peptide composition;

Group III: 3 subjects are Injected with placebo and 6 subjects are injected with 500 pg of peptide composition.

00 After 4 weeks following the first injection, all subjects receive a booster inoculation at the same dosage.O

0The endpoints'measured in this study relate to the safety and tolerability of the peptide composition as well as its

immunogenicity. Cellular immune responses to the peptide composition are an index of the intrinsic activity of this the

t peptide composition, and can therefore be viewed as a measure of biological efficacy. The following summarize the clinical

and laboratory data that relate to safety and efficacy endpoints.

SSafety: The incidence of adverse events is monitored in the placebo and drug treatment group and assessed in

terms of degree and reversibility.

Evaluation of Vaccine Efficacy: For evaluation of vaccine efficacy, subjects are bled before and after injection.

Peripheral blood mononuclear cells are isolated from fresh heparinized blood by Ficoll-Hypaque density gradient

centrifugation, aliquoted In freezing media and stored frozen. Samples are assayed for CTL and HTL activity.

SThe vaccine is found to be both safe and efficacious.

00

Example 30: Phase II Trials In Patients Expressing 191P4D12(b)

r Phase II trials are performed to study the effect of administering the CTL-HTL peptide compositions to patients

having cancer that expresses 191P4D12(b). The main objectives of the trial are to determine an effective dose and regimen

for inducing CTLs in cancer patients that express 191P4D12(b), to establish the safety of inducing a CTL and HTL response

in these patients, and to see to what extent activation of CTLs improves the clinical picture of these patients, as manifested,

by the reduction and/or shrinking of lesions. Such a study is designed, for example, as follows:

The studies are performed in multiple centers. The trial design is an open-label, uncontrolled, dose escalation

protocol wherein the peptide composition is administered as a single dose followed six weeks later by a single booster shot

of the same dose. The dosages are 50, 500 and 5,000 micrograms per injection. Drug-associated adverse effects (severity

and reversibility) are recorded.

There are three patient groupings. The first group is injected with 50 micrograms of the peptide composition and

the second and third groups with 500 and 5,000 micrograms of peptide composition, respectively. The patients within each

group range in age from 21-65 and represent diverse ethnic backgrounds. All of them have a tumor that expresses

191P4D12(b).

Clinical manifestations or antigen-specific T-cell responses are monitored to assess the effects of administering the

peptide compositions. The vaccine composition is found to be bdth safe and efficacious in the treatment of 191P4D12(b)-

associated disease.

Example 31: Induction of CTL Responses Using a Prime Boost Protocol

A prime boost protocol similar in its underlying principle to that used to confirm the efficacy of a DNA vaccine in

transgenic mice, such as described above in the Example entitled "The Plasmid Construct and the Degree to Which It

Induces Immunogenicity," can also be used for the administration of the vaccine to humans. Such a vaccine regimen can

Include an initial administration of, for example, naked DNA followed by a boost using recombinant virus encoding the

vaccine, or recombinant protein/polypeptide or a peptide mixture administered in an adjuvant.

For example, the initial immunization may be performed using an expression vector, such as that constructed in the

Example entitled "Construction of "Minigene" Multi-Epitope DNA Plasmids" in the form of naked nucleic acid administered IM

(or SC or ID) in the amounts of 0.5-5 mg at multiple sites. The nucleic acid (0.1 to 1000 pg) can also be administered using

a gene gun. Following an incubation period of 3-4 weeks, a booster dose is then administered. The booster can be

recombinant fowlpox virus administered at a dose of 5-10 7 to 5x109 pfu. An altemative recombinant virus, such as an MVA,

canarypox, adenovirus, or adeno-associated virus, can also be used for the booster, or the polyepitopic protein or a mixture

0 of the peptides can be administered. For evaluation of vaccine efficacy, patient blood samples are obtained before

S immunization as well as at intervals following administration of the initial vaccine and booster doses of the vaccine.

S Peripheral blood mononuclear cells are isolated from fresh heparinized blood by Ficoll-Hypaque density gradient

centrifugation, aliquoted in freezing media and stored frozen. Samples are assayed for CTL and HTL activity.

Analysis of the results indicates that a magnitude of response sufficient to achieve a therapeutic or protective

immunity against 191P4D12(b) is generated.

Example 32: Administration of Vaccine Compositions Using Dendritic Cells (DC)

Vaccines comprising peptide epitopes of the invention can be administered using APCs, or "professional" APCs

CN such as DC. In this example, peptide-pulsed DC are administered to a patient to stimulate a CTL response in vivo. In this

C method, dendritic cells are isolated, expanded, and pulsed with a vaccine comprising peptide CTL and HTL epitopes of the

00 invention. The dendritic cells are infused back into the patient to elicit CTL and HTL responses in vivo. The induced CTL

0 and HTL then destroy or facilitate destruction, respectively, of the target cells that bear the 191P4D12(b) protein from which

the epitopes in the vaccine are derived.

For example, a cocktail of epitope-comprising peptides is administered ex vivo to PBMC, or isolated DC therefrom.

A pharmaceutical to facilitate harvesting of DC can be used, such as ProgenipoietinTM (Monsanto, St. Louis, MO) or GM-

CSF/IL-4. After pulsing the DC with peptides, and prior to reinfusion into patients, the DC are washed to remove unbound

peptides.

As appreciated clinically, and readily determined by one of skill based on clinical outcomes, the number of DC

reinfused into the patient can vary (see, Nature Med. 4:328, 1998; Nature Med. 2:52, 1996 and Prostate 32:272, 1997).

Although 2-50 x 106 DC per patient are typically administered, larger number of DC, such as 107 or 108 can also be provided.

Such cell populations typically contain between 50-90% DC.

In some embodiments, peptide-loaded PBMC are injected into patients without purification of the DC. For

example, PBMC generated after treatment with an agent such as ProgenipoietinTM are injected into patients without

purification of the DC. The total number of PBMC that are administered often ranges from 108 to 1010. Generally, the cell

doses injected into patients is based on the percentage of DC in the blood of each patient, as determined, for example, by

immunofluorescence analysis with specific anti-DC antibodies. Thus, for example, if ProgenipoletinTM mobilizes 2% DC in

the peripheral blood of a given patient, and that patient is to receive 5 x 106 DC, then the patient will be injected with a total of

x 108 peptide-loaded PBMC. The percent DC mobilized by an agent such as ProgenipoietinTM is typically estimated to

be between 2-10%, but can vary as appreciated by one of skill in the art.

Ex vivo activation of CTLHTL responses

Altematively, ex vivo CTL or HTL responses to 191P4D12(b) antigens can be induced by incubating, in tissue

culture, the patient's, or genetically compatible, CTL or HTL precursor cells together with a source of APC, such as DC, and

immunogenic peptides. After an appropriate incubation time (typically about 7-28 days), in which the precursor cells are

activated and expanded into effector cells, the cells are infused into the patient, where they will destroy (CTL) or facilitate

destruction (HTL) of their specific target cells, tumor cells.

Example 33: An Alternative Method of Identifying and Confirming Motif-Bearing Peptides

Another method of identifying and confirming motif-bearing peptides is to elute them from cells bearing defined

MHC molecules. For example, EBV transformed B cell lines used for tissue typing have been extensively characterized to

determine which HLA molecules they express. In certain cases these cells express only a single type of HLA molecule.

These cells can be transfected with nucleic acids that express the antigen of interest, e.g. 191P4D12(b). Peptides produced

00 by endogenous antigen processing of peptides produced as a result of transfection will then bind to HLA molecules within the

cell and be transported and displayed on the cell's surface. Peptides are then eluted from the HLA molecules by exposure to

CK1 mild acid conditions and their amino acid sequence determined, by mass spectral analysis Kubo et al., J.

Immunol. 152:3913,1994). Because the majority of peptides that bind a particular HLA molecule are motif-bearing, this is an

alternative modality for obtaining the motif-bearing peptides correlated with the particular HLA molecule expressed on the

cell.

Alternatively, cell lines that do not express endogenous HLA molecules can be transfected with an expression

construct encoding a single HLA allele. These cells can then be used as described, they can then be transfected with

S nucleic acids that encode 191P4D12(b) to isolate peptides corresponding to 191P4D12(b) that have been presented on the

CKl cell surface. Peptides obtained from such an analysis will bear motif(s) that correspond to binding to the single HLA allele

that is expressed in the cell.

OC) As appreciated by one in the art, one can perform a similar analysis on a cell bearing more than one HLA allele00

and subsequently determine peptides specific for each HLA allele expressed. Moreover, one of skill would also recognize

C=K that means other than transfection, such as loading with a protein antigen, can be used to provide a source of antigen to the

cell.

Example 34: Complementary Polynucleotldes

Sequences complementary to the 191P4D12(b)-encoding sequences, or any parts thereof, are used to detect,

decrease, or inhibit expression of naturally occurring 191P4D12(b). Although use of oligonucleotides comprising from about

to 30 base pairs is described, essentially the same procedure is used with smaller or with larger sequence fragments.

Appropriate oligonucleotides are designed using, OLIGO 4.06 software (National Biosciences) and the coding sequence

of 191P4D12(b). To inhibit transcription, a complementary oligonucleotide is designed from the most unique 5' sequence

and used to prevent promoter binding to the coding sequence. To inhibit translation, a complementary oligonucleotide is

designed to prevent ribosomal binding to a 191P4D12(b)-encoding transcript.

Example 35: Purification of Naturally-occurring or Recombinant 191P4D12(b) Using 191P4D12(b)-Specific

Antibodies

Naturally occurring or recombinant 191P4D12(b) is substantially purified by immunoaffinity chromatography using

antibodies specific for 191P4D12(b). An immunoaffinity column is constructed by covalently coupling anti-191P4D12(b)

antibody to an activated chromatographic resin, such as CNBr-activated SEPHAROSE (Amersham Pharmacia Biotech).

After the coupling, the resin is blocked and washed according to the manufacturers instructions.

Media containing 191P4D12(b) are passed over the immunoaffinity column, and the column is washed under

conditions that allow the preferential absorbance of 191P4D12(b) high ionic strength buffers in the presence of

detergent). The column is eluted under conditions that disrupt antibody/191P4D12(b) binding a buffer of pH 2 to pH 3,

or a high concentration of a chaotrope, such as urea or thiocyanate ion), and GCR.P is collected.

Example 36: Identification of Molecules Which Interact with 191P4D12(b)

191P4D12(b), or biologically active fragments thereof, are labeled with 121 1 Bolton-Hunter reagent. (See, e.g.,

Bolton et at. (1973) Biochem. J. 133:529.) Candidate molecules previously arrayed in the wells of a multi-well plate are

incubated with the labeled 191P4D12(b), washed, and any wells with labeled 191P4D12(b) complex are assayed. Data

obtained using different concentrations of 191P4D12(b) are used to calculate values for the number, affinity, and association

of 191P4D12(b) with the candidate molecules.00

S Example 37: In Vivo Assay for 191P4D12(b) Tumor Growth Promotion

S The effect of the 191P4D12(b) protein on tumor cell growth is evaluated in vivo by evaluating tumor development

and growth of cells expressing or lacking 191P4D12(b). For example, SCID mice are Injected subcutaneously on each flank

with 1 x 106 of either 3T3, prostate PC3 cells), bladder UM-UC3 cells), kidney CaKI cells), or lung A427

cells) cancer cell lines containing tkNeo empty vector or 191P4D12(b). At least two strategies may be used: Constitutive

191P4D12(b) expression under regulation of a promoter such as a constitutive promoter obtained from the genomes of

viruses such as polyoma virus, fowlpox virus (UK 2,211,504 published 5 July 1989), adenovirus (such as Adenovirus 2),

bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis-B virus and Simian Virus 40 (SV40), or

from heterologous mammalian promoters, the actin promoter or an immunoglobulin promoter, provided such promoters

are compatible with the host cell systems, and Regulated expression under control of an inducible vector system, such as

00 ecdysone, tetracycline, etc., provided such promoters are compatible with the host cell systems. Tumor volume Is then

monitored by caliper measurement at the appearance of palpable tumors and followed over time to determine if

C 191P4D12(b)-expressing cells grow at a faster rate and whether tumors produced by 191P4D12(b)-expressing cells

demonstrate characteristics of altered aggressiveness enhanced metastasis, vascularization, reduced responsiveness

to chemotherapeutic drugs).

Additionally, mice can be implanted with 1 x 105 of the same cells orthotopically to determine if 191P4D12(b) has

an effect on local growth in the prostate, and whether 191P4D12(b) affects the ability of the cells to metastasize, specifically

to lymph nodes, and bone (Miki T et al, Oncol Res. 2001;12:209; Fu X et al, Int J Cancer. 1991, 49:938). The effect of

191P4D12(b) on bone tumor formation and growth may be assessed by injecting tumor cells intratiblally.

The assay is also useful to determine the 191P4D12(b) inhibitory effect of candidate therapeutic compositions,

such as for example, 191P4D12(b) intrabodies, 191P4D12(b) antisense molecules and ribozymes.

Example 38: 191P4D12(b) Monoclonal Antibody-mediated Inhibition of Tumors In Vivo

The significant expression of 191 P4D12(b) in cancer tissues and surface localization, together with its restrictive

expression in normal tissues makes 191P4D12(b) a good target for antibody therapy. Similarly, 191P4D12(b) is a target for

T cell-based immunotherapy. Thus, the therapeutc efficacy of anti-191P4D12(b) mAbs in human cancer xenograft mouse

models, including prostate, lung, bladder, kidney and other -191P4D12(b)cancers listed in table 1, is evaluated by using

recombinant cell lines such as PC3-191P4D12(b), UM-UC3-191P4D12(b), CaKi-191P4D12(b), A427-191P4D12(b) and

3T3-191P4D12(b) (see, Kaighn, et Invest Urol, 1979. 17(1): 16-23), as well as human prostate, kidney and

bladder xenograft models such as LAPC 9AD, AGS-K3 and AGS-B1 (Saffran et al PNAS 1999,10:1073-1078).

Antibody efficacy on tumor growth and metastasis formation is studied, in a mouse orthotopic prostate,

kidney, bladder, and lung cancer xenograft models. The antibodies can be unconjugated, as discussed in this Example, or

can be conjugated to a therapeutic modality, as appreciated in the art. Anti-191P4D12(b) mAbs inhibit formation of tumors in

prostate kidney, bladder and lung xenografts. Anti-191P4012(b) mAbs also retard the growth of established orthotopic

tumors and prolonged survival of tumor-bearing mice. These results indicate the utility of anti-191P4D12(b) mAbs in the

treatment of local and advanced stages several solid tumors. (See, Saffran, et al., PNAS 10:1073-1078 or world

wide web URL pnas.org/cgildoi/10.1073/pnas.051624698).

Administration of the anti-191 P4D12(b) mAbs led to retardation of established orthotoplc tumor growth and

inhibition of metastasis to distant sites, resulting in a significant prolongation in the survival of tumor-bearing mice. These

studies indicate that 191P4D12(b) as an attractive target for immunotherapy and demonstrate the therapeutic potential of

anti-191P4D12(b) mAbs for the treatment of local and metastatic prostate cancer. This example indicates that unconjugated

0 191P4D12(b) monodonal antibodies are effective to inhibit the growth of human prostate, kidney, bladder and lung tumor

O xenografts grown In SCID mice; accordingly a combination of such efficacious monoclonal antibodies is also effective.

CK Tumor Inhibition using multiple unconjugated 191P4D12(b) mAbs

Materials and Methods

191P4D12(b) Monoclonal Antibodies:

Monoclonal antibodies are raised against 191P4D12(b) as described in the Example entitled "Generation of

1 191P4D12(b) Monoclonal Antibodies (mAbs)." The antibodies are characterized by ELISA, Western blot, FACS, and

immunoprecipitation for their capacity to bind 191P4D12(b). Epitope mapping data for the anti-191P4D12(b) mAbs, as

determined by ELISA and Western analysis, recognize epitopes on the 191P4D12(b) protein. Immunohistochemical analysis

C of prostate, kidney, bladder and lung cancer tissues and cells with these antibodies is performed.

SThe monoclonal antibodies are purified from ascites or hybridoma tissue culture supernatants by Protein-G

Cr Sepharose chromatography, dialyzed against PBS, filter sterilized, and stored at -20°C. Protein determinations are00

performed by a Bradford assay (Bio-Rad, Hercules, CA). A therapeutic monoclonal antibody or a cocktail comprising a

mixture of individual monoclonal antibodies is prepared and used for the treatment of mice receiving subcutaneous or

orthotopic injections of PC3, UM-UC3, CaKi and A427 tumor xenografts.

Cell Lines and Xenografts

The cancer cell lines, PC3, UM-UC3, CaKi, and A427 cell line as well as the fibroblast line NIH 3T3 (American

Type Culture Collection) are maintained in RPMI (PC3) and DMEM (UM-UC3, CaKi, and A427, 3T3) respectively,

supplemented with L-glutamine and 10% FBS.

PC3-191P4D12(b), UM-UC3-191P4D12(b), CaKi-191P4D12(b), A427-191P4D12(b) and 3T3-191P4D12(b) cell populations

are generated by retroviral gene transfer as described in Hubert, et al., Proc Natl Acad Sci U S A, 1999. 96(25): 14523.

The LAPC-9 xenograft, which expresses a wild-type androgen receptor and produces prostate-specific antigen (PSA), is

passaged in 6- to 8-week-old male ICR-severe combined immunodeficient (SCID) mice (Taconic Farms) by s.c. trocar

implant (Craft, et al., Nat Med. 1999, 5:280). Single-cell suspensions of LAPC-9 tumor cells are prepared as described in

Craft, et al. Similarly, kidney (AGS-K3) and bladder (AGS-B1) patient-derived xenografts are passaged in 6- to 8-week-old

male ICR-SCID mice.

Xenograft Mouse Models.

Subcutaneous tumors are generated by injection of 2 x 10 6 cancer cells mixed at a 1:1 dilution with Matrigel

(Collaborative Research) in the right flank of male SCID mice. To test antibody efficacy on tumor formation, i.e. antibody

injections are started on the same day as tumor-cell injections. As a control, mice are injected with either purified mouse IgG

(ICN) or PBS; or a purified monoclonal antibody that recognizes an irrelevant antigen not expressed in human cells. In

preliminary studies, no difference is found between mouse IgG or PBS on tumor growth. Tumor sizes are determined by

caliper measurements, and the tumor volume is calculated as length x width x height Mice with Subcutaneous tumors

greater than 1.5 cm in diameter are sacrificed.

Orthotopic injections are performed under anesthesia by using ketamine/xylazine. For prostate orthotopic studies, an

incision is made through the abdomen to expose the prostate and LAPC or PC3 tumor cells (5 x 105) mixed with Matrigel are

injected Into the prostate capsule in a 10-pl volume. To monitor tumor growth, mice are palpated and blood is collected on a

weekly basis to measure PSA levels. For kidney orthotopic models,.an incision is made through the abdominal muscles to

expose the kidney. AGS-K3 cells mixed with Matrigel are injected under the kidney capsule. The mice are segregated into

groups for the appropriate treatments, with anti-191P4D12(b) or control mAbs being injected i.p.00

SAnti-191P4D12(b) mAbs Inhibit Growth of 191P4D12(b)-Expressing Xenoqraft-Cancer Tumors

The effect of anti-191P4D12(b) mAbs on tumor formation is tested by using cell line PC3, UM-UC3, CaKI, A427, and

3T3) and patient-derived tumor LAPC9, AGS-K3, AGS-B1) orthotopic models. As compared with the s.c. tumor model,

the orthotopic model, which requires injection of tumor cells directly in the mouse organ, such as prostate, bladder, kidney or

S lung, results in a local tumor growth, development of metastasis in distal sites, deterioration of mouse health, and

subsequent death (Saffran, et al., PNAS supra). The features make the orthotoplc model more representative of human

disease progression and allowed us to follow the therapeutic effect of mAbs on clinically relevant end points.

For example, tumor cells are injected into the mouse prostate, and 2 days later, the mice are segregated into two groups and

CK" treated with either: a) 200-500pg, of anti-191P4D12(b) Ab, or b) PBS three times per week for two to five weeks.

A major advantage of the orthotopic cancer models is the ability to study the development of metastases.0 0 Formation of metastasis in mice bearing established orthotopic tumors is studies by IHC analysis on lung sections using an

0 antibody against a tumor-specific cell-surface protein such as anti-CK20 for prostate cancer (Lin S et al, Cancer Detect Prev.

2001;25:202).

Another advantage of xenograft cancer models is the ability to study neovascularization and angiogenesis. Tumor

growth is partly dependent on new blood vessel development. Although the capillary system and developing blood network

is of host origin, the initiation and architecture of the neovascular is regulated by the xenograft tumor (Davidoff AM et al, Clin

Cancer Res. 2001;7:2870; Solesvik O et al,, Eur J Cancer Clin Oncol. 1984, 20:1295). The effect of antibody and small

molecule on neovascularization is studied in accordance with procedures known in the art, such as by IHC analysis of tumor

tissues and their surrounding microenvironment.

Mice bearing established orthotopic tumors are administered 1000pg injections of either anti-191P4D12(b) mAb or

PBS over a 4-week period. Mice in both groups are allowed to establish a high tumor burden, to ensure a high frequency of

metastasis formation in mouse lungs. Mice then are killed and their bladders, livers, bone and lungs are analyzed for the

presence of tumor cells by IHC analysis. These studies demonstrate a broad anti-tumor efficacy of anti-191P4D12(b)

antibodies on initiation and progression of prostate cancer in xenograft mouse models. Anti-191P4D12(b) antibodies inhibit

tumor formation of tumors as well as retarding the growth of already established tumors and prolong the survival of treated

mice. Moreover, anti-191P4D12(b) mAbs demonstrate a dramatic inhibitory effect on the spread of local prostate tumor to

distal sites, even in the presence of a large tumor burden. Thus, anti-191P4D12(b) mAbs are efficacious on major clinically

relevant end points (tumor growth), prolongation of survival, and health.

Example 39: Therapeutic and Diagnostic use of Anti-191P4D12(b) Antibodies In Humans.

Anti-191 P4D12(b) monoclonal antibodies are safely and effectively used for diagnostic, prophylactic, prognostic

and/or therapeutic purposes in humans. Western blot and immunohistochemical analysis of cancer tissues and cancer

xenografts with anti-191P4D12(b) mAb show strong extensive staining in carcinoma but significantly lower or undetectable

levels in normal tissues. Detection of 191P4D12(b) in carcinoma and in metastatic disease demonstrates the usefulness of

the mAb as a diagnostic and/or prognostic indicator. Anti-191P4D12(b) antibodies are therefore used in diagnostic

applications such as immunohistochemistry of kidney biopsy specimens to detect cancer from suspect patients.

As determined by flow cytometry, anti-191P4D12(b) mAb specifically binds to carcinoma cells. Thus, anti-

191P4D12(b) antibodies are used in diagnostic whole body imaging applications, such as radioimmunoscintigraphy and

radioimmunotherapy, (see, Potamianos et. al. Anticancer Res 20(2A):925-948 (2000)) for the detection of localized

and metastatic cancers that exhibit expression of 191P4D12(b). Shedding or release of an extracellular domain of

191P4D12(b) into the extracellular milieu, such as that seen for alkaline phosphodiesterase B10 (Meerson, N. R.,

00 Hepatology 27:563-568 (1998)), allows diagnostic detection of 191P4D12(b) by anti-191P4D12(b) antibodies in serum

and/or urine samples from suspect patients.

ri Anti-191P4D12(b) antibodies that specifically bind 191P4D12(b) are used in therapeutic applications for the

treatment of cancers that express 191P4D12(b). Anti-191P4D12(b) antibodies are used as an unconjugated modality and as

conjugated form in which the antibodies are attached to one of various therapeutic or imaging modalities well known in the

art, such as a prodrugs, enzymes or radioisotopes. In preclinical studies, unconjugated and conjugated anti-191P4D12(b)

antibodies are tested for efficacy of tumor prevention and growth inhibition in the SCID mouse cancer xenograft models, e.g.,

kidney cancer models AGS-K3 and AGS-K6, (see, the Example entitled "191P4D12(b) Monoclonal Antibody-mediated

S Inhibition of Bladder and Lung Tumors In Vivo). Either conjugated and unconjugated anti-191P4D12(b) antibodies are used

CN as a therapeutic modality in human clinical trials either alone or in combination with other treatments as described in

following Examples.

00Example 40: Human Clinical Trials for the Treatment and Diagnosis of Human Carcinomas through use of Human

C Anti-191P4D12(b) Antibodies In vivo

Antibodies are used in accordance with the present invention which recognize an epitope on 191P4D12(b), and

are used in the treatment of certain tumors such as those listed in Table I. Based upon a number of factors, including

191P4D12(b) expression levels, tumors such as those listed in Table I are presently preferred indications. In connection with

each of these indications, three clinical approaches are successfully pursued.

Adjunctive therapy: In adjunctive therapy, patients are treated with anti-191P4D12(b) antibodies in

combination with a chemotherapeutic or antineoplastic agent andlor radiation therapy. Primary cancer targets, such as those

listed in Table I, are treated under standard protocols by the addition anti-191P4D12(b) antibodies to standard first and

second line therapy. Protocol designs address effectiveness as assessed by reduction in tumor mass as well as the ability to

reduce usual doses of standard chemotherapy. These dosage reductions allow additional and/or prolonged therapy by

reducing dose-related toxicity of the chemotherapeutic agent. Anti-191P4D12(b) antibodies are utilized in several adjunctive

clinical trials in combination with the chemotherapeutic or antineoplastic agents adriamycin (advanced prostrate carcinoma),

cisplatin (advanced head and neck and lung carcinomas), taxol (breast cancer), and doxorubicin (preclinical).

II.) Monotherapy: In connection with the use of the anti-191P4D12(b) antibodies in monotherapy of tumors,

the antibodies are administered to patients without a chemotherapeutic or antineoplastic agent. In one embodiment,

monotherapy is conducted clinically in end stage cancer patients with extensive metastatic disease. Patients show some

disease stabilization. Trials demonstrate an effect in refractory patients with cancerous tumors.

III.) Imaging Agent Through binding a radionuclide iodine or yttrium (1131, Y90 to anti-191P4D12(b)

antibodies, the radiolabeled antibodies are utilized as a diagnostic and/or imaging agent. In such a role, the labeled

antibodies localize to both solid tumors, as well as, metastatic lesions of cells expressing 191P4D12(b). In connection with

the use of the anti-191P4D12(b) antibodies as imaging agents, the antibodies are used as an adjunct to surgical treatment of

solid tumors, as both a pre-surgical screen as well as a post-operative follow-up to determine what tumor remains and/or

returns. In one embodiment, a (11' ln)-191P4D12(b) antibody is used as an imaging agent in a Phase I human clinical trial in

patients having a carcinoma that expresses 191P4D12(b) (by analogy see, Divgi etal. J. Natl. Cancer nst. 83:97-104

(1991)). Patients are followed with standard anterior and posterior gamma camera. The results indicate that primary lesions

and metastatic lesions are identified.

Dose and Route of Administration

As appreciated by those of ordinary skill in the art, dosing considerations can be determined through comparison

with the analogous products that are in the clinic. Thus, anti-191P4D12(b) antibodies can be administered with doses in the

00 range of 5 to 400 mg/m 2, with the lower doses used, In connection with safety studies. The affinity of anti-

191P4D12(b) antibodies relative to the affinity of a known antibody for its target is one parameter used by those of skill In the

art for determining analogous dose regimens. Further, anti-191P4D12(b) antibodies that are fully human antibodies, as

c compared to the chimeric antibody, have slower clearance; accordingly, dosing in patients with such fully human anti-

191P4D12(b) antibodies can be lower, perhaps in the range of 50 to 300 mg/m 2 and still remain efficacious. Dosing in

mg/m 2 as opposed to the conventional measurement of dose in mg/kg, is a measurement based on surface area and is a

convenient dosing measurement that is designed to include patients of all sizes from infants to adults.

Three distinct delivery approaches are useful for delivery of anti-191P4D12(b) antibodies. Conventional

intravenous delivery is one standard delivery technique for many tumors. However, in connection with tumors in the

CK peritoneal cavity, such as tumors of the ovaries, biliary duct, other ducts, and the like, intraperitoneal administration may

0 prove favorable for obtaining high dose of antibody at the tumor and to also minimize antibody clearance. In a similar

00 manner, certain solid tumors possess vasculature that is appropriate for regional perfusion. Regional perfusion allows for a

O high dose of antibody at the site of a tumor and minimizes short term clearance of the antibody.

NC Clinical Development Plan (CDP)

Overview: The CDP follows and develops treatments of anti-191P4D12(b) antibodies in connection with adjunctive

therapy, monotherapy, and as an imaging agent. Trials initially demonstrate safety and thereafter confirm efficacy in repeat

doses. Trails are open label comparing standard chemotherapy with standard therapy plus anti-191P4D12(b) antibodies. As

will be appreciated, one criteria that can be utilized in connection with enrollment of patients is 191P4D12(b) expression

levels in their tumors as determined by biopsy.

As with any protein or antibody infusion-based therapeutic, safety concerns are related primarily to cytokine

release syndrome, hypotension, fever, shaking, chills; (ii) the development of an immunogenic response to the material

development of human antibodies by the patient to the antibody therapeutic, or HAHA response); and, (iii) toxicity tonormal cells that express 191P4D12(b). Standard tests and follow-up are utilized to monitor each of these safety concerns.Anti-191P4D12(b) antibodies are found to be safe upon human administration.

Example 41: Human Clinical Trial Adjunctive Therapy with Human Anti-191P4D12(b) Antibody andChemotherapeutic Agent

A phase I human clinical trial is initiated to assess the safety of six intravenous doses of a human anti-191P4D12(b) antibody in connection with the treatment of a solid tumor, a cancer of a tissue listed in Table I. In thestudy, the safety of single doses of anti-191P4D12(b) antibodies when utilized as an adjunctive therapy to an antineoplastic

.or chemotherapeutic agent as defined herein, such as, without limitation: cisplatin, topotecan, doxorubicin, adriamycin, taxol,or the like, is assessed. The trial design includes delivery of six single doses of an anti-191P4D12(b) antibody with dosageof antibody escalating from approximately about 25 mg/m 2 to about 275 mg/m 2 over the course of the treatment inaccordance with the following schedule:

Day 0 Day 7 Day 14 Day 21 Day 28 Day

00 mAb Dose 25 75 125 175 225 275

mg/m 2 mg/m 2 mg/m 2 mg/m 2 mg/m2 mg/m 2

SChemotherapy

(standard dose)

O Patients are closely followed for one-week following each administration of antibody and chemotherapy. In

C particular, patients are assessed for the safety concerns mentioned above: cytokine release syndrome, hypotension,

fever, shaking, chills; (ii) the development of an immunogenic response to the material development of human

S antibodies by the patient to the human antibody therapeutic, or HAHA response); and, (iii) toxicity to normal cells that

CK express 191P4D12(b). Standard tests and follow-up are utilized to monitor each of these safety concerns. Patients are also

assessed for clinical outcome, and particularly reduction in tumor mass as evidenced by MRI or other imaging.

C The anti-191P4D12(b) antibodies are demonstrated to be safe and efficacious, Phase II trials confirm the efficacy

0 and refine optimum dosing.

Example 42: Human Clinical Trial: Monotherapy with Human Antl-191P4D12(b) Antibody

Anti-191P4D12(b) antibodies are safe in connection with the above-discussed adjunctive trial, a Phase II human

clinical trial confirms the efficacy and optimum dosing for monotherapy. Such trial is accomplished, and entails the same

safety and outcome analyses, to the above-described adjunctive trial with the exception being that patients do not receive

chemotherapy concurrently with the receipt of doses of anti-191P4D12(b) antibodies.

Example 43: Human Clinical Trial: Diagnostic Imaging with Anti-191P4D12(b) Antibody

Once again, as the adjunctive therapy discussed above is safe within the safety criteria discussed above, a human

clinical trial is conducted concerning the use of anti-191P4D12(b) antibodies as a diagnostic imaging agent. The protocol is

designed in a substantially similar manner to those described in the art, such as in Divgi et al. J. Natl. Cancer Inst. 83:97-104

(1991). The antibodies are found to be both safe and efficacious when used as a diagnostic modality.

Example 44: Homology Comparison of 191P4D12(b) to Known Sequences

The human 191P4D12(b) protein exhibit a high degree of homology to a known human protein, namely Ig

superfamily receptor LNIR (gi 14714574), also known as human nectin 4 (gi 16506807). Human LNIR shows 100% identity

to 191P4D12(b) at the protein level. The mouse homolog of 191P4D12(b) has been Identified as murine nectin 4 (gi

18874521). It shows strong homology to 191P4D12(b), exhibiting 92% identity and 95% homology to 191P4D12(b). (See,

Figure 4).

The prototype member of the 191P4D12(b) family, 191P4D12(b)v.1, Is a 510 amino acids protein, with the N-

terminus located extracellulary and intracellular C-terminus. Initial bioinformatics analysis using topology prediction

programs suggested that 191P2D14 may contain 2 transmembranes based on hydrophobicity profile. However, the first

hydrophobic domain was identified as a signal sequence, rendering 191P2D12 a type I membrane protein, with an

extracellular N-terminus.

The 191P4D12(b) gene has several variants, including one SNP represented in 191P4D12(b) v.2, an N-terminal

deletion variant represented in 191P4D12(b) v.6 and 191P4D12(b) v.7 which lacks 25 amino acids between amino acids 411

and 412 of 191P4D12(b) v.1.

Motif analysis revealed the presence of several protein functional motifs in the 191P4D12(b) protein (Table L).

Two immunoglobulin domains have been identified at positions 45-129 and 263-317. In addition, 191P4D12(b) contains a00 cadherin signature which includes and RGD sequence. Immunoglobulin domains are found in numerous proteins and

participate in protein-protein such including protein-ligand interactions (Weismann et al, J Mol Med 2000, 78:247). In

addition, Ig-domains function in cell adhesion, allowing the interaction of leukocytes and blood-born cells with the

ct endothelium (Wang and Springer, Immunol Rev 1998, 163:197). Cadherins are single transmembrane proteins containing

immunoglobulin like domains, and are involved in cell adhesion and sorting (Shan et al, Biophys Chem 1999, 82:157). They

mediate tissue-specific cell adhesion, such as adhesion of lymphocytes to the surface of epithelial cells. Finally, the closest

homolog to 191P4D12(b) is Nectin4, a known adhesion molecule that regulates epithelial and endothelial junctions, stronglysuggesting that 191P4D12(b) participates in cell adhesion (Reymond N et al, J Biol Chem 2001, 276:43205).

The motifs found in 191P4D12(b) can participate In tumor growth and progression by enhancing the initial stages oftumorigenesis, such as tumor take or establishment of a tumor, by allowing adhesion to basement membranes andsurrounding cells, by mediating cell communication and survival.

00 Accordingly, when 191P4D12(b) functions as a regulator of tumor establishment, tumor formation, tumor growth,cell signaling or as a modulator of transcription involved in activating genes associated with survival, invasion, tumorigenesis

Cl or proliferation, 191P4D12(b) is used for therapeutic, diagnostic, prognostic and/or preventative purposes. In addition, whena molecule, such as a variant or SNP of 191P4D12(b) is expressed in cancerous tissues, such as those listed in Table I, theyare used for therapeutic, diagnostic, prognostic and/or preventative purposes.

Example 45: Regulation of Transcription

The cell surface localization of 191P4D12(b) coupled to the presence of Ig-domains within its sequence indicatethat 191P4D12(b) modulates signal transduction and the transcriptional regulation of eukaryotic genes. Regulation of geneexpression is confirmed, by studying gene expression in cells expressing or lacking 191P4D12(b). For this purpose,two types of experiments are performed.

In the first set of experiments, RNA from parental and 191P4D12(b)-expressing cells are extracted and hybridizedto commercially available gene arrays (Clontech) (Smid-Koopman E et al. Br J Cancer. 2000. 83:246). Resting cells as wellas cells treated with FBS, androgen or growth factors are compared. Differentially expressed genes are identified inaccordance with procedures known in the art. The differentially expressed genes are then mapped to biological pathways(Chen K et al. Thyroid. 2001.11:41.).

In the second set of experiments, specific transcriptional pathway activation is evaluated using commerciallyavailable (Stratagene) luciferase reporter constructs including: NFkB-luc, SRE-luc, ELKI-luc, ARE-luc, p53-luc, and CRE-luc.These transcriptional reporters contain consensus binding sites for known transcription factors that lie downstream of well-characterized signal transduction pathways, and represent a good tool to ascertain pathway activation and screen forpositive and negative modulators of pathway activation.

Thus, 191P4D12(b) plays a role in gene regulation, and it is used as a target for diagnostic, prognostic, preventative and/ortherapeutic purposes.

Example 46: Identification and Confirmation of Potential Signal Transduction PathwaysMany mammalian proteins have been reported to interact with signaling molecules and to participate in regulating

signaling pathways. (J Neurochem. 2001; 76:217-223). Immunoglobulin-like molecules in particular has been associatedwith several tyrpsine klnases including Lyc, Blk, syk the MAPK signaling cascade that control cell mitogenesis and calciumflux (Vilen J et al, J Immunol 1997, 159:231; Jiang F, Jia Y, Cohen I. Blood. 2002, 99:3579). In addition, the 191P4D12(b)

protein contains several phosphorylation sites (see Table VI) indicating an association with specific signaling cascades.

Using immunoprecipitation and Western blotting techniques, proteins are identified that associate with 191P4D12(b) and

00 mediate signaling events. Several pathways known to play a role in cancer biology can be regulated by 191P4012(b),

including phospholipid pathways such as P13K, AKT, etc, adhesion and migration pathways, including FAK, Rho, Rac-1,

C icatenin, etc, as well as mitogenic/survival cascades such as ERK, p38, etc (Cell Growth Differ. 2000,11:279; J Biol Chem.

1999, 274:801; Oncogene. 2000, 19:3003, J. Cell Biol. 1997, 138:913.). In order to determine whether expression of

191P4D12(b) is sufficient to regulate specific signaling pathways not otherwise active in resting PC3 cells, the effect of these

genes on the activation of the p38 MAPK cascade was investigated in the prostate cancer cell line PC3 (Figure 21A-B).

Activation of the p38 kinase is dependent on its phosphorylation on tyrosine and serine residues. Phosphorylated p38 can be

distinguished from the non-phosphorylated state by a Phospho-p38 mAb. This phospho-specific Ab was used to study the

S phosphorylation state of p38 in engineered PC3 cell lines.

CK PC3 cells stably expressing 191P4D12(b) neo were grown overnight in either 1% or 10% FBS. Whole cell lysates

were analyzed by western blotting. PC3 cells treated with the known p38 activators, NaSal or TNF, were used as a positive

C control. The results show that while expression of the control neo gene has no effect on p38 phosphorylation, expression of

191P4D12(b) in PC3 cells is sufficient to induce the activation of the p38 pathway (Figure 21A). The results were verified

K using western blotting with an anti-p38 Ab, which shows equal protein loading on the gels (Figure 21B).

In another set of experiments, the sufficiency of expression of 191P4D12(b) in the prostate cancer cell line PC3 to activate

the mitogenic MAPK pathway, namely the ERK cascade, was examined (Figure 22A-B). Activation of ERK is dependent on

its phosphorylation on tyrosine and serine residues. Phosphorylated ERK can be distinguished from the non-phosphorylated

state by a Phospho-ERK mAb. This phospho-specific Ab was used to study the phosphorylation state of ERK in engineered

PC3 cell lines. PC3 cells, expressing an activated form of Ras, were used as a positive control.

The results show that while expression of the control neo gene has no effect on ERK phosphorylation, expression of

191P4D12(b) in PC3 cells Is sufficient to induce an increase in ERK phosphorylation (Figure 22A). These results were

verified using anti-ERK western blotting (Figure 22B) and confirm the activation of the ERK pathway by 191P4D12(b) and

STEAP-2.

Since FBS contains several components that may contribute to receptor-mediated ERK activation, we examined

the effect of 191P4D12(b) in low and optimal levels of FBS. PC3 cells expressing neo or 191P4D12(b) were grown in either

0.1% or 10% FBS overnight. The cells were analyzed by anti-Phospho-ERK western blotting. This experiment shows that

191P4D12(b) induces the phosphorylation of ERK in 0.1% FBS, and confirms that expression of 191P4D12(b) is sufficient to

induce activation of the ERK signaling cascade in the absence of additional stimuli.

To confirm that 191P4D12(b) directly or indirectly activates known signal transduction pathways in cells, luciferase

(luc) based transcriptional reporter assays are carried out in cells expressing individual genes. These transcriptional

reporters contain consensus-binding sites for known transcription factors that lie downstream of well-characterized signal

transduction pathways. The reporters and examples of these associated transcription factors, signal transduction pathways,

and activation stimuli are listed below.

1. NFkB-luc, NFkB/Rel; Ik-kinase/SAPK; growthlapoptosis/stress

2. SRE-luc, SRFfTCF/ELK1; MAPK/SAPK; growth/differentiation

3. AP-1-luc, FOS/JUN; MAPK/SAPK/PKC; growth/apoptosis/stress

4. ARE-luc, androgen receptor; sterolds/MAPK; growth/differentiation/apoptosis

p53-luc, p53; SAPK; growth/differentiation/apoptosis

6. CRE-luc, CREB/ATF2; PKAlp38; growth/apoptosis/stress

7. TCF-luc, TCF/Lef; 0-catenin, Adhesion/invasion

00 Gene-mediated effects can be assayed in cells showing mRNA expression. Luciferase reporter plasmids can be

0 introduced by lipid-mediated transfection (TFX-50, Promega). Luciferase activity, an indicator of relative transcriptional

activity, is measured by incubation of cell extracts with luciferin substrate and luminescence of the reaction is monitored in a

C' luminometer.

Signaling pathways activated by 191P4D12(b) are mapped and used for the identification and validation of

0 therapeutic targets. When 191P4D12(b) is involved in cell signaling, it is used as target for diagnostic, prognostic,

preventative and/or therapeutic purposes.

r"-Example 47: Involvement in Tumor Progression

Based on the role of Ig-domains and cadherin motifs in cell growth and signal transduction, the 191P4D12(b) gene

can contribute to the growth, invasion and transformation of cancer cells. The role of 191P4D12(b) in tumor growth is

00 confirmed in a variety of primary and transfected cell lines including prostate cell lines, as well as NIH 3T3 cells engineered

to stably express 191P4D12(b). Parental cells lacking 191P4D12(b) and cells expressing 191P4D12(b) are evaluated for cell

rC growth using a well-documented proliferation assay (Fraser SP, Grimes JA, Djamgoz MB. Prostate. 2000;44:61, Johnson

DE, Ochieng J, Evans SL. Anticancer Drugs. 1996, 7:288).

To confirm the role of 191P4D12(b) in the transformation process, its effect in colony forming assays is

investigated. Parental NIH-3T3 cells lacking 191P4D12(b) are compared to NIH-3T3 cells expressing 191P4D12(b), using a

soft agar assay under stringent and more permissive conditions (Song Z. et al. Cancer Res. 2000;60:6730).

To confirm the role of 191P4D12(b) in invasion and metastasis of cancer cells, a well-established assay is used,

a Transwell Insert System assay (Becton Dickinson) (Cancer Res. 1999; 59:6010). Control cells, including prostate,

breast and kidney cell lines lacking 191P4D12(b) are compared to cells expressing 191P4D12(b). Cells are loaded with the

fluorescent dye, calcein, and plated in the top well of the Transwell insert coated with a basement membrane analog.

Invasion Is determined by fluorescence of cells in the lower chamber relative to the fluorescence of the entire cell population.

191P4D12(b) can also play a role in cell cycle and apoptosis. Parental cells and cells expressing 191P4D12(b) are

compared for differences in cell cycle regulation using a well-established BrdU assay (Abdel-Malek ZA. J Cell Physiol.

1988, 136:247). In short, cells are grown under both optimal (full serum) and limiting (low serum) conditions are labeled with

BrdU and stained with anti-BrdU Ab and propidium iodide. Cells are analyzed for entry into the G1, S, and G2M phases of

the cell cycle. Alternatively, the effect of stress on apoptosis is evaluated in control parental cells and cells expressing

191P4D12(b), including normal and tumor prostate cells. Engineered and parental cells are treated with various

chemotherapeutic agents, such as etoposide, taxol, etc, and protein synthesis inhibitors, such as cycloheximide. Cells are

stained with annexin V-FITC and cell death is measured by FACS analysis. The modulation of cell death by 191P4D12(b)

can play a critical role in regulating tumor progression and tumor load.

When 191P4D12(b) plays a role in cell growth, transformation, invasion or apoptosis, it is used as a target for

diagnostic, prognostic, preventative and/or therapeutic purposes.

Example 48: Involvement In Anglogenesis

Angiogenesis or new capillary blood vessel formation is necessary for tumor growth (Hanahan D, Folkman J. Cell.

1996, 86:353; Folkman J. Endocrinology. 1998 139:441). Based on the effect of cadherins on tumor cell adhesion and

their Interaction with endothelial cells, 191P4012(b) plays a role In angiogenesis (Mareel and Leroy: Physiol Rev, 83:337;

DeFouw L et al, Microvasc Res 2001, 62:263). Several assays have been developed to measure anglogenesis in vitro and

in vivo, such as the tissue culture assays endothelial cell tube formation and endothelial cell proliferation. Using these

assays as well as in vitro neo-vascularization, the role of 191P4D12(b) in angiogenesis, enhancement or inhibition, is

confirmed.00

O For example, endothelial cells engineered to express 191P4D12(b) are evaluated using tube formation and

proliferation assays. The effect of 191P4D12(b) is also confirmed in animal models in vivo. For example, cells either

expressing or lacking 191P4D12(b) are implanted subcutaneously in immunocompromised mice. Endothelial cell migration

and angiogenesis are evaluated 5-15 days later using immunohistochemistry techniques. 191P4D12(b) affects

angiogenesis, and it is used as a target for diagnostic, prognostic, preventative and/or therapeutic purposes.

Example 49: Involvement in Protein-Protein Interactions

Ig-domains and cadherin motifs have been shown to mediate interaction with other proteins, including cell surface

protein. Using immunoprecipitation techniques as well as two yeast hybrid systems, proteins are identified that associate

C- with 191P4D12(b). Immunoprecipitates from cells expressing 191P4D12(b) and cells lacking 191P4D12(b) are compared for

CN specific protein-protein associations.

SStudies are performed to confirm the extent of association of 191P4D12(b) with effector molecules, such as

O nuclear proteins, transcription factors, kinases, phosphates etc. Studies comparing 191P4D12(b) positive and 191P4D12(b)

negative cells as well as studies comparing unstimulated/resting cells and cells treated with epithelial cell activators, such as

cytokines, growth factors, androgen and anti-integrin Ab reveal unique interactions.

In addition, protein-protein interactions are confirmed using two yeast hybrid methodology (Curr. Opin. Chem Biol.

1999, 3:64). A vector carrying a library of proteins fused to the activation domain of a transcription factor is introduced into

yeast expressing a 191P4D12(b)-DNA-binding domain fusion protein and a reporter construct. Protein-protein interaction is

detected by colorimetric reporter activity. Specific association with effector molecules and transcription factors directs one of

skill to the mode of action of 191P4D12(b), and thus identifies therapeutic, prognostic, preventative and/or diagnostic targets

for cancer. This and similar assays are also used to identify and screen for small molecules that interact with 191P4D12(b).

Thus it is found that 191P4D12(b) associates with proteins and small molecules. Accordingly, 191P4D12(b) and these

proteins and small molecules are used for diagnostic, prognostic, preventative and/or therapeutic purposes.

Example 50: Involvement of 191P4D12(b) in cell-cell communication.

Cell-cell communication is essential in maintaining organ Integrity and homeostasis, both of which become

deregulated during tumor formation and progression. Based on the presence of a cadherin motif in 191P4D12(b), a motif

known to be involved in cell interaction and cell-cell adhesion, 191P4D12(b) can regulate cell communication. Intercellular

communications can be measured using two types of assays Biol. Chem. 2000, 275:25207). In the first assay, cells

loaded with a fluorescent dye are incubated in the presence of unlabeled recipient cells and the cell populations are

examined under fluorescent microscopy. This qualitative assay measures the exchange of dye between adjacent cells. In

the second assay system, donor and recipient cell populations are treated as above and quantitative measurements of the

recipient cell population are performed by FACS analysis. Using these two assay systems, cells expressing 191P4D12(b)

are compared to controls that do not express 191P4D12(b), and it is found that 191P4D12(b) enhances cell communications.

Figure 19 and Figure 20 demonstrate that 191P4D12(b) mediates the transfer of the small molecule calcein between

adjacent cells, and thereby regulates cell-cell communication in prostate cancer cells. In this experiment, recipient PC3 cells

were labeled with dextran-Texas Red and donor PC3 cells were labeled with calcein AM (green). The donor (green) and

recipient (red) cells were co-cultured at 370C and analyzed by microscopy for the co-localization of Texas red and calcein.

The results demonstrated that while PC3 control cells (no detectable 191P4D12(b) protein expression) exhibit little calcein

transfer, the expression of 191P4D12(b) allows the transfer of small molecules between cells (Figure 19), whereby the

initially red recipient cells take on a brownish color, and co-localize the red and green molecules. Small molecules and/or

00 antibodies that modulate cell-cell communication mediated by 191P4D12(b) are used as therapeutics for cancers thatS express 191P4D12(b). When 191P4D12(b) functions in cell-cell communication and small molecule transport, it Is used as a

rCl target or marker for diagnostic, prognostic, preventative and/or therapeutic purposes.

Example 51: Modulation of 191P4D12(b) function.

Knock down of 191P4D12(b) expression

rli Several techniques can be used to knock down or knock out 191 P4D12(b) expression in vitro and in-vivo, includingRNA interference (RNAi) and other anti-sense technologies. RNAi makes use of sequence specific double stranded RNA toprevent gene expression. Small interfering RNA (siRNA) are transfected into mammalian cells and thereby mediate

S sequence specific mRNA degradation. (Elbashir, et al, Nature, 2001; vol. 411: 494-498). Using this approach, 191P4D12(b)-specific RNAi is introduced in 191P4D12(b)-expressing cells by transfection. The effect of knocking down the expression of

CN 191P4D12(b) protein is evaluated using the biological assays mentioned in examples 44 to 50 above.00

SReduction of 191P4D12(b) Protein expression is detected 24-48 hours after transfection by Immunostaining andS flow cytometry. The introduction of 191P4D12(b) specific RNAi reduced the expression of 191P4D12(b) positive cells and

reduce the biological effect of 191P4D12(b) on tumor growth and progression.

Accordingly, the RNA oligonucleotide sequences are used in therapeutic and prophylactic applications. Moreover,the RNA oligonucleotide sequences are used to assess how modulating the expression of a 191P4D12(b) gene affectsfunction of cancer cells and/or tissues.

Inhibition using small molecule and antibodies

Using control cell lines and cell lines expressing 191P4D12(b), inhibitors of 191P4D12(b) function are identified.For example, PC3 and PC3-191P4D12(b) cells can be incubated in the presence and absence of mAb or small moleculeinhibitors. The effect of these mAb or small molecule inhibitors are investigated using the cell communication, proliferationand signaling assays described above.

Signal transduction and biological output mediated by cadherins can be modulated through various mechanisms, includinginhibition of receptor binding, prevention of protein interactions, or affecting the expression of co-receptors and bindingpartners (Kamei et al, Oncogene 1999, 18:6776). Using control cell lines and cell lines expressing 191P4D12(b), modulators(inhibitors or enhancers) of 191P4D12(b) function are identified. For example, PC3 and PC3-191P4D12(b) cells areincubated in the presence and absence of mAb or small molecule modulators. When mAb and small molecules modulate,

inhibit, the Iransport and tumorigenic function of 191P4D12(b), they are used for preventative, prognostic, diagnosticand/or therapeutic purposes.

Throughout this application, various website data content, publications, patent applications and patents arereferenced. (Websites are referenced by their Uniform Resource Locator, or URL, addresses on the World Wide Web.)

The present invention is not to be limited in scope by the embodiments disclosed herein, which are intended assingle illustrations of individual aspects of the invention, and any that are functionally equivalent are within the scope of theinvention. Various modifications to the models and methods of the invention, in addition to those described herein, willbecome apparent to those skilled in the art from the foregoing description and teachings, and are similarly intended to fallwithin the scope of the invention. Such modifications or other embodiments can be practiced without departing from the truescope and spirit of the invention.

TABLES:

00TABLE 1: Tissues that Express 191NPDI 2(b):

a. Malianant Tissues

ProstateBladderKidneyColonLungPancreasOvaryBreastUterusCervix

TABLE ii: Amino AcId Abbreviations

SINGLE LETTER THREE LETTER FULL NAME

F Phe phenylalanineL Leu leucineS Ser serineY Tyr tyrosineC Cys cysteineW Trp tryptophanP Pro prolineH His histidineQ Gln glutamineR Arg arginine

Ilie isoleucineM Met methionineT Thr threonineN Asn asparagineK LYS lysineV Val valineA Ala aianlneD Asp aspartic acidE Glu glutamic acidG Gly glycine

TABLE III: Amino Acid Substitution Matrix

00 Adapted from the GCG Software 9.0 BLOSUM62 amino acid substitution matrix (block substitution matrix). The

S higher the value, the more likely a substitution is found in related, natural proteins. (See world wide web URLS ikp.unibe.ch/manual/blosum62.html)

A C D E F G H I K L M N P Q R S T V W Y.4 0 -2 -1 -2 0 -2 -1 -1 -1 -2 -1 -1 -1 1 0 0 -3 -2 A

9 -3 -4 -2 -3 -3 -1 -3 -1 -1 -3 -3 -3 -3 -1 -1 -1 -2 -2 C6 2 -3 -1 -1 -3 -1 -4 -3 1 -1 0 -2 0 -1 -3 -4 -3 D

-3 -2 0 -3 1 -3 -2 0 -1 2 0 0 1 -2 -3 -2 E6 -3 -1 0 -3 0 0 -3 -4 -3 -3 -2 -2 -1 1 3 F

6 -2 -4 -2 -4 -3 0 -2 -2 -2 0 -2 -3 -2 -3 G8 -3 -1 -3 -2 1 -2 0 0 -1 -2 -3 -2 2 H

4 -3 2 1 -3 -3 -3 -3 -2 -1 3 -3 -1 1-2 -1 0 1 1 2 0 -1 -2 -3 -2 K

CN14 2 -3-3 -2-2-2 -1 1 -2 -1 L-2 -2 0 -1 -1 -1 1 1 -1I M

00 6 -2 0 0 1 0 -3 -4-2 N7 -1 -2 -1 -1 -2 -4 -3 P

1 0 -1 -2 -2 -1 Q1 -1 -3 -3 -2 R4 1 -2 -3 -2 S

0 -2 -2 T4 -3 -1 V

1.1 2 W

7 Y

TABLE IV:HLA Class 1111 Mo~f slSupermotifs

00

00

TABLE IV HLA Class I SupermotifslMotifs

ISUPERMOTIF POSITION POSITION POSITION2 (Primary Anchor) 3 (Primary Anchor) C Terminus (Primary

Al TIL VMS FWYA2 LIVMATQ _____IVMATL

A3 VSMATLI RKA24 YFWIVLMT Fl YWLMB7 P VILFMWYA827 RHK

B44 ED ________FWYLIMVA

B58 ATS 862 QLIVMP FWYMIVL A

MOTIFS

Al TSM YAl IDEAS YA2.1 LMVQIAT VLIMATA3 LMVISATFCGD KYRHFAAllI VTMLISAGNCDF KRYHA24 YFWM FLIWA'3101 MVTAUIS A*3301 MVALFIST A*6801 AVTMSLI RK

B'*0702 p LMFWVfAIV8*3501 P LMFWYIVAB51 P _LIVF WYAMB*5301 P IMFWYALVB*5401 P ATIVLMFWY

Bolded residues are preferred, italicized residues are less preferred: A peptide is considered motif-bearing if it has primaryanchors at each primary anchor position for a motif or supermotif as specified in the above table.

TABLE IV HLA Class 11 Supermotif

TABLE IV HLA Class 11 Motifs

MOTIFS 1"a anchor 1 2 3 4 5 1 anchor 6 7 8 9DR4 preferred FMYUIVW M T I VSTCPALIM MH MH

deleterious W R WOE

DR1 preferred MFLIVWY PAMQ VMATSPUIC M AVMdeleterious C CH FD CWD GDE D

DR7 preferred MFLIVWY M W A IVMSACTPL M IVdeleterious C G GIRD N G

DR3 MOTIFS 1 0anchor 1 2 3 1 *anchor 4 5 1 *anchor 6Motif a preferred LIVMFY DMotif b preferred LIVMFAY DNQEST KRHDR Supermotif MFLIVWY VMSTACPU/

Italicized residues indicate less preferred or "tolerated" residues

TABLE IV HLA Class I Supermotifs

POSITION: 1 2 3 4 5 6 7 8 C-terminusSUPER-MOTIFSAl 1 a Anchor I' Anchor

TIL VMS FWYA2 10* Anchor 1 Anchor

LIVMATQ LIVMATA3 Preferred 1 0 Anchor YEW YFW YFW P 1 0 Anchor

VSMATL/ RKdeleterious DE DE

P A24 1' Anchor 1 o Anchor

YFV~1VLMT FlY WLMB7 Preferred FWY 10* Anchor FWY FWY 1 "Anchor

LIVM P VILFMWYAdeleterious DE DE G QN DE

G(415);

B27 1* Anchor I "AnchorRHK FYLWMIVA

B41 *Anchor 1 0 AnchorED FWYLIMVA

858 1 *Anchor 1" AnchorATS FWYLIVMA

B62 1 *Anchor 1" AnchorQUVMP FWYMIVLA

Italicized residues indicate less preferred or "tolerated" residues

TABLE IV HLA Class I Motifs

POSITION 1 3 4 5 6 7 8 9 C-00

00

terminusorC-terminus

Al preferred GFYW 1 0Anchor DEA YFW P DEQN YFW 1 *Anchor9-mer STM Y

deleterious DE RHKLIVMP A G AAl preferred GRHK ASTCLIVM 1 0Anchor GSTC ASTC LIVMV DE 1 0Anchor9-mer DEAS Y

deleterious A RHKDEPYFW DE PQN RHK PG GPAl preferred YFW 1 0Anchor DEAQIN A YFWQN PASTO GDE P 1 0Anchor

STM Ymer

deleterious GP RHKGLIVM DE RHK ONA RHKYFW RHK AAl preferred YFW STCLIVMV 1 0Anchor A YFW PG G YFW 1 0Anchor

IDEAS Ymer

deleterious RHK RHKDEPYFW P G PRHK QNA2.1 preferred YEW l0Anchor YFW STO YFW A P l0Anchor9-mer LMIVQAT VLMAT

deleterious DEP DERKH RKH DERKHPOSITION:l1 3 4 5 6 7 8 9 C-

TerminusA2.1 preferred AYFW l0Anchor LVIm G G FYWL l0Anctior

LMIVQAT vim VLMATmer

deleterious DEP DE RKHA P RKH DERKHRKHA3 preferred RHK l0Anctior YFW PRHKYF A YFW P 1*Anchor

LMVISATFCGD W KXRHFAdeleterious DEP DE

AllI preferred A 1*Anchor YEW YEW A YEW YEW P l0AnchorVTLMISAGN CD KRYHF

deleterious DEP A GA24 preferred YFWRHK l0*Anchor STC YEW YFW l0Anchor9-mer YFWM FLIW

deleterious DEG DE G QNP DERHKG AQNA24 Preferred 1 0Anchor P YFWP P 1 0Anchor

YFWM FLIWmer

Deleterious GDE QN RHK DE A QN DEAA3101 Preferred RHK l0Anctior YFW P YFW YFW AP I Anchor

MVTALIS RKDeleterious DEP DE ADE DE DE DE

A3301 Preferred 1 0Anctior YFW AYFW 1 0AnchorMVALFIST RK

Deleterious GP DEA6801 Preferred YFWSTC I *Anchor YFWLIV YEW P l0Anchor

AVTMSLI M RKdeleterious GP DEG RHK A

B30702 Preferred RHKFWY' 1 0Anchor RHK RHK RHK RHK PA 1 0AnchorP LMFWYAI

Vdeleterious DEQNP DEP DE DE GDE QN DE

B3501 Preferred FWYLIVM 1 0Anchor FWY FWY 1*AnchorP LMFWY/V

POSITION I POION1 2 3 4 5 6 7 8 9 0-

00

00

terinIIusor

Al peferedGFYW 1 Act~r DA YF P EON YFW C-terminusprf FW 8Aco DA YWP DQ F Anchor9-mer STM Y

deleterious DE RHKLIVMP A G AAl preferred GRHK ASTCLIVM J0Anchor GSTC ASTC LIVM DE IcAnchor9-mer IDEAS Ydeleterious A RHKDEPYFW DE PQN RHK PG GP

deleterious AGP G G

851 Preferred LIVMFWY l0Anchor FWY STC FWY G FWY l0AnchorP LIVFWYA

Mdeleterious AGPIDER IDE G IDEQN GDEHKSTC

B5301 preferred LIVMFWY 1 *Anchor F5"Y STC FWY LI VMFWYF WY 1 AnctiorP IMFWYAL

Vdeleterious AGPQN G RHKQN IDE85401 preferred FWY 1 Anchor FWYLIVM LIVM ALIVM FWYA 1 *AnchorP P AT! VLMF

WYdeleterious GPQNDE GDESTC RHKDE IDE QNIDGE DE

TABLE IV

00

0

Summary of HLA-supertypesOverall phenotypic frequencies of HLA-supertypes In different ethnic populations

Specificity Phenotypic frequencySupertype Position 2 C-Terminus Caucasian N.A. Black Japanese Chinese Hispanic AverageB7 P AILMVFWY43.2 55.1 57.1 43.0 49.3 49.5,3 ,LMVST RK 37.5 42.1 45.8 52.7 43.1 44.2A2 AILMVT AILMVT 45.8 39.0 42.4 45.9 43.0 42.224 F (WIVLMT) FI (YWLM) 23.9 38.9 58.6 0.1 8.3 0.0

B44_ E(D) .FWYLIMVA 3.0 21.2 42.9 39.1 39.0 37.01 I (LVMS) FWY 47.1 16.1 21.8 14.7 26.3 25.227 HK YL (WMI) 28.4 26.1 13.3 13.9 35.3 23.4

362 QL(IVMP) FWY (MIV) 12.6 .8 36.5 25.4 11.1 18.158 ATS FWY (LIV) 10.0 25.1 1.6 9.0 5.9 10.3

TABLE IV Calculated population coverage afforded by different HLA-supertype combinationsHLA-supertypes Phenotypic frequency

Caucasian N.A Blacks Japanese hinese Hispanic Average83.0 86.1 87.5 88.4 36.3 86.2

2, A3 and 87 99.5 98.1 100.0 99.5 99.4 99.32, A3, B7, A24, B44 99.9 99.6 100.0 99.8 99.9 99.8

and AlA2, A3, B7, A24,B44, A1,B27, B62,nd B 58otifs indicate the residues defining supertype specificites. The motifs incorporate residues determined on the basis ofublished data to be recognized by multiple alleles within the supertype. Residues within brackets are additional residuesaso predicted to be tolerated by multiple alleles within the supertype.

Fable

V: Frequently Occurring Motifs

Table V: Frequently Occurring Motifs

I

Name avrg.% Description Potential Functionidentity

Nucleic acid-binding protein functions astranscription factor, nuclear location

f-C2H2 34% Zinc finger, C2H2 type probable

Cytochrome b(N- membrane bound oxidase, generate;ytochrome_b_N 68% erminal)/b6/petB superoxide

domains are one hundred amino acidslong and include a conserved

Ig 19% Immunoglobulin domain intradomain disulfide bond.tandem repeats of about 40 residues,each containing a Trp-Asp motif.Function in signal transduction and

18% WD domain, G-beta repeat protein interaction

may function in targeting signalingPDZ 23% PDZ domain molecules to sub-membranous sitesLRR 28% -eucine Rich Repeat short sequence motifs involved in

protein-protein interactions

conserved catalytic core common toboth serine/threonine and tyrosineprotein kinases containing an ATP

Pkinase 23% Protein kinase domain binding site and a catalytic site

00O0O

pleckstrin homology involved inintracellular signaling or as constituents

PH 16% PH domain of the cytoskeleton30-40 amino-acid long found in theextracellular domain of membrane-

EGF 34% EGF-like domain bound proteins or in secreted proteins

Reverse transcriptase(RNA-dependent DNA

Rvt 49% polymerase)

Cytoplasmic protein, associates integralAnk 25% Ank repeat membrane proteins to the cytoskeleton

NADH- membrane associated. Involved inUbiquinone/plastoquinone proton translocation across the

Oxidored_qi 32% (complex various chains membranecalcium-binding domain, consists of a12residue loop flanked on both sides by a

Efhand 24% EF hand 12 residue alpha-helical domain

Retroviral aspartyl Aspartyl or acid proteases, centered onRvp 79% protease a catalytic aspartyl residue

extracellular structural proteins involvedin formation of connective tissue. The

Collagen triple helix repeat sequence consists of the G-X-Y and theCollagen 42% (20 copies) polypeptide chains forms a triple helix.

Located in the extracellular ligand-binding region of receptors and Is about200 amino acid residues long with twopairs of cysteines involved in disulfide

Fn3 20% Fibronectin type III domain )ondsseven hydrophobic transmembraneegions, with the N-terminus located

7 transmembrane receptor extracellularly while the C-terminus Is7tm_1 19% (rhodopsin family) cytoplasmic. Signal through G proteins

Table VI: Motifs and Post-translational Modifications of 191P4D12(b)

Table VI: Post-translational modifications of 191P4D12(b)

N-glycosylation site281 284 NWTR (SEQ ID NO: 61)430- 433 NSSC (SEQ ID NO: 62)489- 492 NGTL (SEQ ID NO: 63)

Tyrosine sulfatlon site118- 132 VQADEGEYECRVSTF (SEQ ID NO: 64)

Protein kinase C phosphorylation site26- 28 TGR

192-194 SSR195-197 SFK249-251 SVR322-324 SSR339- 341 SGK383-385 TQK397-399 SIR426-428 SLK450-452 TVR465-467 SGR491 493 TLR

Casein kinase II phosphorylation site

283 -286 TIRLD (SEQ ID NO: 322- 325 SSRD (SEQ ID NO: 66)410-413 SQPE (SEQ ID NO: 67)426 -429 SLKD (SEQ ID NO: 68)

00 450 453 TVRE (SEQ ID NO: 69)456-459 TQTE (SEQ ID NO:

N-myristoylaUon site.135-140 GSFQAR (SEQ ID NO: 71)162- 167 GQGLTL (SEQ ID NO: 72)164-169 GLTLAA (SEQ ID NO: 73)189-194 GTTSSR (SEQ ID NO: 74)

c-i218-223 GQPLTC (SEQ ID NO: 311 -316 GIYVCH (SEQ ID NO; 76)354 -359 GVIAAL (SEQ ID NO: 77)464 -469 GSGRAE (SEQ ID NO: 78)477 -482 GlKQAM (SEQ ID NO: 79)490- 495 GTLRAK (SEQ ID NO:

c-K1500- 505 WIING (SEQ ID NO: 81)

c-1 RGD Cell attachment sequence00 55 -57 RGD

ci Table VII:Search Peptides

191 P412(b) v.1 aal-.5109-mers, 10-mets and 15-mers (SEQ ID NO: 82)MPLSLGAEMW GPEAWLLLLL LLASFTGRCP AGELETSDVV TVVLGQDAKL PCFYRGDSGEQVGQVAWARV DAGEGAQELA LLHSKYGLHV SPAYEGRVEQ PPPPRNPLDG SVLLRNAVQADEGEYECRVS TFPAGSFQAR LRLRVLVPPL PSLNPGPALE EGQGLTLMAS CTAEGSPAPSVTWDTEVKGT TSSRSFKHSR SAAVTSEFHL VPSRSMNGQP LTCWVSHPGL LQDQRITHILHVSFLAEASV-RGLEDQNLWH IGREGAMLKC LSEGQPPPSY NWVTRLDGPLP SGVRVDGDTLGFPPLTTEHS GIYVCHVSNE FSSRDSQVTV DVLDPQEDSG KQVDLVSASV VVVGVIAALLFCLLVVVVVL MSRYHRRKAQ QMTQKYEEEL TLTRENSIRR LHSHHTDPRS QPEESVGLRAEGHPDSLKDN SSCSVMSEEP EGRSYSTLTT VREIETQTEL LSPGSGRAEE EEDQDEGIKQAMNHFVQENG TLRAKPTGNG IYINGRGHLV

v.2 aal -5109-mets 45-6 1 GQDAKLPCLYRGDSGEQ (SEQ ID NO: 83)

44-62 LGQDAKLPCLYRGDSGEQV (SEQ ID NO: 84)39-67 VVTVVLGQDAKLPCLYRGDSGEQVGQVAW (SEQ ID NO:

v. ORFR 264..1721 Frame +39-mets 403-418 SHHTDPRSQSEEPEGR (SEQ ID NO: 86)

402-419 HSHHTDPRSQSEEPEGRS (SEQ ID NO: 87)397-424 SIRRLHSHHTDPRSQSEEPEGRSYSTLT (SEQ ID NO: 88)

V.9: AA 1-137; 9-mets, 1O-mers, 15-mets (SEQ ID NO: 89)MRRELLAGIL LRITFNFFLF FFLPFPLVVF FIYFYFYFFL EMESHYVAQA GLELLGSSNPPASASLVAGT LSVHHCACFE SFTKRKKKLK KAFRFIQCLL LGLLKVRPLQ HQGVNSCDCERGYFQGIFMQ MAPWEGT

SNP variant9-mets 27-43 GRCPAGELGTSDVVTWV (SEQ ID NO: 1 0-mets 26-44 TGRCPAGELGTSDVVTWVL (SEQ ID NO: 91)

21-49 LLASFTGRCPAGELGTSDVVTVVLGQDAK (SEQ ID NO: 92)

v11 SNP variant9-mets 138-154 QARLRLRVMVPPLPSLN (SEQ ID NO: 93)

137-1 55 FQARLRLRVMVPPLPSLNP (SEQ ID NO: 94)132-1 60 FPAGSFQARLRLRVMVPPLPSLNPGPALE (SEQ ID NO:

7-

v.12 SNP variant9-mers 435-451 VMSEEPEGCSYSTLTTV (SEQ ID NO: 96)1 0-mers 434-452 SVMSEEPEGCSYSTLTTVRE (SEQ ID NO: 97)

00 15-mers 429-457 DNSSCSVMSEEPEGCSYSTLTTVREIETQ (SEQ ID NO: 98)

v.13 Insertion of one AA at 333-49-mers 426-442 SQVTVDVLADPQEDSGK (SEQ ID NO: 99)

S 10-mers 425-443 DSQVTVDVLADPQEDSGKQ (SEQ ID NO: 100)420-448 EFSSRDSQVTVDVLADPQEDSGKQVDLVS (SEQ ID NO: 101)

S 191P4Dl2(b)v.14: AA56-72; 9-mersGSSNPPASASLVAGTLS (SEQ ID NO: 102)

.191 P4DI 2(b) v.14: AA55-73; I 0-mersLGSSNPPASASLVAGTLSV (SEQ ID NO: 103)

c~I 191 P4DI 2(b) v.1 4: AA5O-78; riAGLELLGSSNPPASASLVAGTLSVHHCAC (SEQ ID NO: 104)

00

Tables VillI- XXI:

00

00

1Table VIII-VI-H LA-Al -9mers-_191P4D126

Each peptide is a portion ofSEQ ID NO: 3; each start

Iposition Is specified, the lengthof peptide is 9 amino acids,and the end position for eachpeptide Is the start positionJ

[StartjSu-bsequence 1STrei

,F437 SEEPEGRSYF22500 I

EfLRV~fEPPPP]j 1.000]

E7i LSGQPPPS! 21.700

107 PLDGq SVLLR -TI.FpjLEiELT LTR]L.3oF[41 qtEE§KyR I 2.2501

58FTE VKGTS~ 1.250]

F7-67PidAEM PEAI i9I

45:'TSVVTWL] 1.5001

IL 3611 MSEEPEGRS[ 1.350]LU1 LTTH SGIY[1.5I 405[ L!ZQPE T i-Lli.IIGPEWLLLL lLj.'zsi5

[84]1 RLDGLPSG f.00-0]

l[hVD2 =.P0158 I AL EGQ E0.0

li4 flL~~ G ooTJ7CL1RE HP I 0.900-

iIA TiEIE ELLJI 999_9,L486 IQNTR iiC9L 0.675

Lm.[ .I L. HLs

Lff Jl AVQA5EGY f[150Il EEDQDEGI _Kj [0.500

I31 ITILHVSF I 0.0

[Tble 111M Al9es191 P401 2B

Each peptide is a portion ofSEQ ID NO: 3; each start

position Is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight

7rt] Subsequence ifScoreF3675vvvWiR[ 0.500

L Y6 VLSIRYTTO500

1.71, LATL.LIKY IF-.67

F[7 87 QqM Tqll 0.500]Wf J[EYECRVSTF j 0.450

I~oi DEGEECR~0.450]

71 IL FPXCTj 0.450 IyGL( _HV SPYjIO.?50 1

318F§NEF SSDS 1I_0.225_1

PT 1LAG AQE o [.225L~E gEYCVI 0.225LU75I LEEGQGLTLIL2I

1GLETSDVj =0.225I 15ILPP_ LL I0200[Ti][SVTWDTEVK II 92901

[41]TVLQDAKII 0.20 0

Li7jLLLLLLASF 0T

QPEESVG T. 01 501N_2I1 S L AGS F 15 7i

K3.IDSK 0.1 2-5 7I L2].ITRENSIRR. ff. 25 I

'F T51 GQVJ I.ZF I jTrSSRSFK Lo.1i25

j353. VGILFI 125j

313fI[VSNEfF_0.100

Table Vlll-VI-HLA-A1-9mers-191P4D12B

Each peptide is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide is 9 amino acdds,

and the end position for eachpeptide is the start position

plus eight.Sia-rtl[utbseqencel -Score

6IQ-VGQVYAWAR iF0.100,F5 .ELLSPGSGR II 0100

Py?9 I TVDV-Y LDPQE [0.100

L20 LLLSFTGR L q

I Y MNJ .0.100]

1467 iRA~f9P I0.090

I.1[x D q__qLIYH-q~ 0.075I

F{j GS~_ FQARLRL1[_O.075 I

FE77I DPQDqEGIKQA 00751R[DGTLGFPP [o0762j

L1L,6~vI FH =_0.0501

[folLvPsRsmNG -2oA650

1.W9 I .iL P i 0.0501IU 1. _W LLLLL LLL50 I

L~.iL~~LT L0.050 1

ITable VIII-V2-HL11A-A-9mers-

00

00

Each peptide is a portion ofSEQ ID NO: 5; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight.Start ISubsequence i 17 [GQDAKLPCLj 0.1.50

FT AK-LPCLYRG IF 0--010

KF LqPCLRGDS Y IP003J

[JJ PCYRGDG 000VY1L P D L-qlF.oo1 DT-IEI CL YRGDSGE 0.000--oT

§1r~Y~5GEQ. (000Ta le il-V7-HLA-A1-9mers-

Eah 191P4D128 jEahpeptide is a p ortion of

SEQ ID NO: 15; each startposition Is specified, the length

of peptide is 9 amino acids,and the end position for each

pepplde is the start positionplus eight.

I. I J ubsequence [Score3[iiIHDPF q§j =.250

F--j SQSEEPEG-R .015

LI71 DP RSQ P P9:99T.

LJ [7DS QSE PEj 1009

Tiale Vill-V9-H LA-Al -9mers-191P4D128

Each peptide is a portion of1SEQ ID NO: 19; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight. [Strt jj ubsequencj ScorI

I IDq~ F [5 q0

L2IJLIFNf -F L Ff

7I LFFWFIYYF lf76of

[Table VI II-V9-HLA-A1-9mers-L- 191P4D12B

Each peptide is a portion ofSEQ ID NO: 19; each start

position Is specified, the lengthof peptide Is 9 amino acids,

and the end position for eachpeptide Is the start position

plus eight.

9--]FI GLLLGSSLa9J007o

[TI. 17ELLGLR0.0

~JZ..J~!.TfFFLF. 050

~IJ18 [~EGYFQGj 0.450

ESFTRK

Fj77]I1 TEJL01 7 q

F 991 LLGL vR 13 KJLGVNSCDCERI 0. 10 0

ACFESFTKR II0. 10]-qCLLLGL

1..GI_ GLLKV i 0.050

=6 JLWYYJ050][~jfWAQGLEL] 095049_ IF2GLELLGS[01

[I I SPPASSL .050'65. SLvAGTLSV 1=.5

56 GSNPS,03OJ

I IGTLSV~cA -0.025II 30 1L..FIXYFYF.0251

Table VIII-V9-HLA-A1-9mers-191P4D12B

Each pepUde Is a portion ofSEQ ID NO: 19; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide Is the start position

[par] SFubseq-uejco[(. E

[7-21L FFLPFPLYY 0.025

Fj .iIFFLEMESH'URI 0.25

TIY_ LLSN6~(.020]

fNFFL 1F6 i3

2= KVRqPWQJ 0.0201

LDD[ LALLRIT 11.0101

175- iFF HCAFFL'T!I0.1:3]

[i Yl L.o =-1

128 D NMPEGI .005i15-5 GSSNPPATJ0

K JI A1L_1

ILA Ij KKAFRI LP3

FUD21 YFQGIF9 0.010DI]326ILL FF LEMS0.0f3

DEBJ.TE FFPP I0.=005I7 5][TLSVHHC I 0.9035

00

00

1Table Vil jHA-l9esEach peptide Is a portion ofSEQ ID NO: 19; each startI

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

-plus ei1ght.

Stat Sbsqunc _03_

_93_FFFRFIQCLLL 10031[114 IVNSCDCERG!FO.003

QIFQ 0.003j

I JF .A I I F F F L 0.0p 03j

[107 RPLQHQGVN L0.003'

:F 7 VH 9 91 E 0.003j1 91RFIQCLLLG. 10P.003

'FI_ I.FLFFFLPFP 1[-0-002.

11081PLQHQVNS]0.002[

61 I1E.AL-Gl

I 17P9I -q~CLLLGLL1i021

L' iL 'AA 0.002j

~~10.00211

191P4D12BEach peptide is a portion ofSEQ ID NO: 21; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight.

Lstart [.Subsequence rLj[7AGELGTSDV :FP7. 5I

[7]GRCPAGELG J10.005[771 LGSDvvT7V 0.05

,able _VIII-V10-HLA-A-9mers-111412B I

Each pepide Is a portion of1SEQ ID NO: 21; each start

position is specified, the length~of peptide Is 9 amino acids,

and the end position for eachpeptide Is the start position

plus eight.

LStadr [-Subsequence1 LScorei

[T CPAGELGTS F70003

I[117 -1 G EL GT SDVV F0 .0 0E7I.PA _GGTS jFo.oooi,

TbeVIll-VI 1-HLA-A1-9mers-:191P4D12B

Each peptide Is a portion ofSEQ ID NO: 23; each start

Iposition is specified, the length;of peptide is 9 amino acids,

and theend position for eachpeptide Is the start position

1_____jpus eight_.. I

ILFrt j subsequence iscorelMV- P FP LL 11.1001

7 F R LVMVPPLPS 1 1:501

RLRV1VPL0.001.1

7T2 FLRLVMV 0.000

[Table VIII-Vi 2-HLA-A1 -9mers-

L191P34D12B3Each peptide is a portion of1SEQ ID NO: 25; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

plus et.

f77 SEPEGC 1Y22.5013 SEEEGCS 1301

7~ PEGOSYS O 04501

77] GCSYSTLTT 0.050;

17111 m_ EPEGC -0 _09 51

1Table AVII-V 2-HLA-A -9mers-19P4D12BJ

Each peptide is a portion ofSEQ ID NO: 25; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

plus eg t

[Start .1 Sbsequee FS'ore[T GCSYSTILT IO 0 3]

PEGSYSTL 1Fo

T~able ViW-V1 3-HLAA1-9rners-j191P4D12B

Each peptide is a porion ofSEQ ID NO: 27; each start

position is specified, the lengthof peptide is 9 amino acids,'

and the end position for eachIpeptide is the start position

1- plus eight.

L9 1 I2!L G~I 0.01e0[11[LAP~qEDS 5.00

DillADPED ?GKII.00

TVnDVLADPii00]V77 KD~vVI: 0.005

[Table VIIIAVi4-H LA-Al .9mers-jEach peptide is a portion ofSEQ ID NO: 29; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight.-gj_ l ubsequence [core]

71 FASASLVAGT, IO391G I

E7 S ASLVAGTL 0 .010

WI NPPASASLVj FO 003

00

00

Table ViII.V14.HLA-A1-9mers-191P4D12B

Each peptide is a portion ofSEQ ID NO: 29; each start

position Is specified, the lengthof peptide Is 9 amino acids,

and the end position for eachpeptide Is the start position

plus eight._

[T71 PASASLVAGi F50072

[aeIXi-Vl.HLAA1orers-

Each peptide Is a portion of1SEQ ID NO: 3; each start

position Is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

plus nine.,[.Start Subsequence ScreI 71 j[ GffPSK i 135.0001

F33 2 VLDPQEDSG 100.0001

43 MSEEPEGRS 7 Q

L4 EGHPDSL1 18.000

QA~~**DEGEYEC1 _.0

[453 J[ EIET-QTERLLS1[E 4.50[306 TEHGI VC 300 j

GQDAKLPCF 3.5

[86IQ ENGTLAI 2.70

[76 AELA7LHSKJ 2.700250

E [57

1457! QT-ELSPGSG L2:.5

I 18j D3TEKGTTSSj2fi

,IRVEQPPPP .0

.t2 TfAE-GSPAPSVJ {T0-*I SD VT V GI1

ITable IX.V1-HLA-A1mers-II 191 P40D12B

Each peptide Is a portion ofSEQ ID NO: 3; each start

position Is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

plus nine.

[1 QPEESVGLR 1125

F11 T[GEAWLLLLL][ 151251

F6Ij[GEQNWHJ)A [09001

NQADEGE

1_61 0.L500]YTVGDK)~0

[~HLVPSRSMN O[00

G4IL~ 9ILLL MS:jF.500

[12] EGEYECRVS 0.450

[47SEEPEGRSY 0.45

[1JRSQPEESVG 030

[]RGDSGEQVG [0.250.

3181 ISNEFSSRDSI .2

F 1[ t LPEGRSYSTL2 7

1i6 FL LLLLLSF F. 2O I

L Table I1X-V1-HLA-A1-lo0mers-191P4D12B

Each peptide is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

plus nine.____[Strt I Subsequenqcoe

3 67]KVLMSRYHJL [0.2001

36~VLMSRYHRRI 0,2001K I

L2 251 VSHPDGLLQD 0.150

WL .GSFQARLRRI_F §]RSYSTLTTVR L0.j

18) GTTSSRSFKH 0.12

L~qNS lL- 0.L92

05 LLTTEHSq2YYJ 0125)

1[400 RLHSHHTDPI 0.100o

11451 VLVPPLPSL iLO.100

E SVMSEEPEG 010

260] IHGEAj0100j

I9jHVSPAYEGIR 0.0

E4 QDEGIKQAME00901

[4 7RAEEE)oDI

731Ir IKQA~f 0.075]

RSNGQPLT~[0

357 MFAAUCLLWI 0.950

00

00

Table IXV1-1-L1A-Al1l0mers-

Each peptide Is a portion ofSEQ ID NO: 3; each start

position Is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start positionI

plus nine.

Itrt SubseqUence [Scre

I F4 ILQDKPI 0.050

lL188Ji G TTSSRFK 0.050

217 NG~QP LCW 0.0501

29,4j RVDGDT7LGF 0.05

[i7fjq CTEGSPAPS1 0050

447Z LTLTTVREIET L0050-221_ILTCWVSHPGLI 0.0sq0

S-S-R-DSQVTD 0

if 30D4WELTERSGjFY .0502~ FEGQPPPS~YN 0050

1146 L- 4 1L 9511 1485 WLLLQENGTLFL00 1

Table IX-V2-HLA-A10mers-___191 P4D12B

Each peptide is a portion of1SEQ ID NO: 5; each start

position Is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

plus nine.

Is tartj Subsequence IS-corej,'T G~QDAKLPCy [3.750

17] KLCLRGI d .0-10q'FI1 LGq9RKLPPL7Fq.005

Tabl IX-V2-HLA-A10mers-K 191 P4D12B

Each peptide is a portion ofSEQ ID NO: 5; eachstr

position is specified, the lengthof peptide is 10 amino acids,and the end position for each

peptide is the start position

I.L PA.9J[S:9.[7L LPCLYRGDSG 09-0O3

F' _CLYRGDSGEJL.00J

71LA ~S!~xGEQY10.000

,[Table IX-V7-HLA-A1 -1 Omers-191P4D128

Each peptide is a portion ofSEQ ID NO: 15; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

plus nine. jFsi.a7.I __*Subsequence~ Fs9L~I

FlHTDPRSQSEE~i[7ki R.SQSEEPEGR

SHTDPRQ 0.01.5,,I.§QSEEPEGIRS 10.02

f[ 7 (TDSQSEEP [0 000

~Table IX-V9-LA-1-0mers.-191 P4D1 2B

Each peptide is a portion of1SEQ ID NO: 19; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachIpeptide is the start position

pusnie Subsequence ScorejI

I 1 ITFNFFLFF 110I 281 VVFHYYY-10

[Table IX-V9-H11A-A1-1 Omers-

Each peptide is a portion ofSEQ ID NO: 19; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for each

peptide is the start positionplus nine.

Start I Subsequence. JFr

117~ SCDCERGYFQ _5.00I HOACFESFTK IF.00

L8_11

IA2f ILVVFHXYFYF .0.5o

Lii U±RTFNF [ii~ LAURT 0.5001

SSNPPASASL 0.-3 09TiRRELLAGILL P]L.2251

12.j FLPffPLVVFF. 19:-2091q101TLSVHHA9FiL.9

I 77J ACFESFKRK 112.290L9U .Q GL

b'5] NSCDCERGYF 1F0419I

1i!3 ILVNSCDCERGY L0:1

76~ CACFESFTKR F000

T I LLf 'FY.00]

LTI LLGLKV L0A-0IFq. J1

E74T! I GLELLGN 10.0501SV.HGT!fY [0.0750.

L31 IYFYYFFL 0.050

F 8 '1SNPPASASLV' 10.025]

Fl RELLAGILLR 0.0251[112! QGVNSCDCER-j9 110051

69 J~GTSVHHac. P7.251

LRITFNFFLF T9.025,,

00

00

Table IX-V9-HL11A-A-1-l0mers-191P4D12B

Each peptide is a portion ofSEQ ID NO: 19; each start

position Is specified, the lengthof peptidle is 10 amino acids,and the end position for each*peptide is the start position

plus nine.

I..821 -FKKKLKIK .2291 VFFIYF F 025

[16 1[ NFFtLFFlPF_ 25~YFFILEMEHY 005

LGSSNPPA _0.20I

1[ 62 ASASVAGT 10151J1ESFTKRKKKL [IE175

FL .IL NPPSALV 7t13[1'21 11 RGYFQGIFMQ 10.131

YARTLSYH FClaO~

11051 KVRPLQHQGV jf0.0101[1-ILLRITFNFFj 1ojI~FESFTKRKKK '10.010

I_49 1[QAGLELLSJ ~poi14 iFYVqAGLELL [.olol

I±!~1LVNSCDERG 0.1

I..LQCLL 0.010Dl. FIFYFEYFF 0.1

[F SLAGT LvH 161L1.90I LLLLK'RPL 0.oj

[4811 AQAGLELLGS 1000ffl GLLLKVRPLQH .005I

I 5LGSSNPPASA LO.005]I LGLILKVRPILQ 905

T73, VHHCACFESF_]KooSIQGIFMQMPW. jo.LLRITFNFFL I:2I

11767 R PLQ HQGVNS] FoKosiT'8ilFMQAAPWEGT .05I 61 KKLKKAFRF q0031F117,[ CDCERY FqGI0_3]

[Table IXHAA1-l10mers-L191P4D12B

Each peptide is a portion ofSEQ ID NO: 19; each start

position Is specified, the lengthof peptidle is 10 amino acids,and the end position for each

peptide is the start positionpLu nine.

lStartLubsqeneIsoeI93j FR FICLLILGF7:3

FLTiLYFYYFLEM 10. 00120j1 ERGYfqGIFM 10.00

L22 YF QGI F6.7003

FT.3 YFFLEMES [O.7090

D[jI HYVAQAGLEL 000[so I ALELLGSSN 110-003

I

I 7 LSVHHCA F O.7002j[1 1 FN F1F L H .i I

I LLVPFLHQ 10.001

FL[j ARFIQCLLGL o1

K..l GIKY 19 0.002EachAI petd i ortono

[fASE -DN:21 IahFtr

I _rtI Susqec .661

F ll GRCP--IAE LGT10m 0251

EachpAetid s p pono

ITable IX-V 0G-HLA-A1 1 Omers-191P4D12B

Each peptide is a portion ofSEQ ID NO: 21; each start

position is specified, the lengthof peptide Is 10 amino acids,and the end position for eachpeptide is the start position

plus nine.

M7LmLTSDVVT [EO1]L5ILGLTSPVE 10.0011

IK1TG-RCPALG 0.000

Table IX-Vi 1 -HLA-Al 1Omers-191P4D12B

Each peptidle is a portion ofSEQ ID NO: 23; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptidle is the start position

plus nine.Jrt LJ&bseqyence Ls coreIMI.7 VMVPPLPSLN

1i.9JI _vL sL MI LY__rT-L1o~oo

LE7 0RMPLS[.003j[DI1LW LLRVM lLp2j

lifli RLRLRVMVP] 0.000I

[IlLRLRVMVPPL 1[.7ooo

L Tble IX-VI 12-HILA-Al-I Diers-i191 P4D12B

Each peptide is a portion ofSEQ ID NO: 25; each start

position is specified, the lengthof peptidle is 10 amino acids,and the end position for eachpeptide is the start position

___.plus nine.

3 MSEEPEGCSYj jF SEEPEGCSYS_jo.450

F_7, [EPE GCSYSTL 0.22?

00

00

Table IX-V1 2-HLA-A1 -1 Omers-191P4D12B

Each peptide Is a portion ofSEQ ID NO: 25; each start

position is specified, the lengthof peptide Is 10 amino acids,and the end position for each

peptide is the start positionp lu s n in e

Lstartl Subsequence i[ScrelLull CgSYSTLTTVR]0.5

ITLE(CSSTIT_7 !EO 131

GCSY TLT j.010~

j*VMSEEPEGCSjO7.05J

1 Y! SYSTLTV 1EO [900~PEGCYSTT 10.0001

Tbe IX-V1 3-HLA-A 1lmers-191 P4D1 26

Each peptide Is a portion ofSEQ ID NO: 27; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

plus nine.

[Sj Subsequenice jlre

Lo-o1

F--1 DSqnTpy! J[ .03DO

i. WLDVLADPQDS110.10

W37LQYTYVDJLAP 0.002

110 51LAPQEDSG-K9 b01

ablIXV1 4-HL-A-Al1l0mers-1

I191P4D128

Each peptide is a portion ofSEQ ID NO: 29; each start

Iposition is specified, the lengthof peptide Is 10 amino acids,and the end position for eachpeptide is the start position

plus nine..

I..Start 11 Subsequence IS-core

[ale IX-14-H-1-1 mer-10,

Eahpeptide is a portion ofSEQ ID NO: 29; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide Is the start position

plus nine.

1.§t.qj Subs,!quence _L[coreI[i SSPPASSLJ [0,3001

=07I ASLV AG TL S V 1T NPPAAs_ LV T.0251

[T]LAS aAGTL. 0~.015S

[2 J[SNPASS0.-0105-

P77! LGSSN~PPSA 10.00951

Table X- V1.-HLA-A201 -9mers-l191P4D12B

Each peptide is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachppde Is the start position1_!plus eight.

q]1 Subsequenice. iL 9I ~LLL.F9!4 12.546~:

[T8 L LSF T F2 I59? -80I

[KT0_iIS~9L 1 [7ML0411

F1 EMWGPAWL L72§~

M)2~ VLLR NAV 11. Ii

742? WLGQDAKL 1111.7I203[_, _TFHLV 111.5631F341l SASM1114101 SQPEESVGL j18.880

Table X- V1-HLA-A201-9mers-'191 P4D12B_Each peptide is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight._

lPti Su. bsequence j L~or

S351j qVVIAAL i 7.309

LESVTJ .288

[10 jWGPEALLLJI4.471

1l32JELTDW 4.122

1± L SY STLTJ34

L24 I VLAAV _2.856IILLAFT GII.1

1253]ELL PPNLWHI L.9[i21GLLQDQRIT..2.261[Ifl7iL v~y9yil__~..2?22

L~jNLDGSVL 21151

jGY~Rsj1 .775jE2I[DNGQPLTCV 1

[5~5j RIETTEL 1.7036]

L87iGPLSGVRJI68023 1 FLQDQ0TH I

3 Th

L6 21EV 9AY1v Fl.32

I.1Z.LLLLLLA~L.I.P98Ll iLLLLLAL J[1P78

I3fl F _ALLEo~ILJA.7

[i2611REGALCL [_2A.

00

00

Table X- V1 -HLA-A201-9mers-L 191P4D12B

Each peptide is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide Is 9 amino acids,

and the end position for eachpeptide Is the start position

li tart Subsequence JF sre I

390 1 LT L. 9k I

j(M?8 FvQEN1LoF K I

I2661 AmL cLSEG] 1 0.8

IF'!6lsLTTA IiI__EAWLLLLL .425_I

(11IDGYEGRvj .1

113061[ TT EISG IYV [0O.340

Jj~ AEEQGL 025j

P~flI KQVDLVSAS

F18JMT-QKY)-EELIOa2747[1 3L iLnsyF-9,. FT2:4- I

14501 -T-!KV TT123 71THILHVSF 088P-1-71[ N9 9!!TpW 0.1861

1.20 j LLLA FTiO781

144811 LTTVEITJ 011112851 IDGq!PPSGV f( 0.164

Table X- V1-HLA-A201-9mers-I. 191 P4D1 2B

Each peptide Is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

iI plus eight.lq]aYtiusequencej score]

1.4 7 1 FDQ DEGI KQA1 0142

1L332JLSSRIDSQVTV][ 0.141]lR'Tfi 0LSRHR 1 41I

1z221TCWSHGL I0.139

1P2 L -H G!EG-I014JL~eII QLTLASC 0.120]

I ?3 ii ASFTGRP II 0 ]0j

[TbexV2-HLA-A201-9mers-}191P4D12B

Each peptide is a portion ofSEQ ID NO: 5; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight_____

jSaqtl Subsequence 11. ScoreFY]_QDALPC L93Jt1I'- -GE~j 0.048

177 LPLYRG~qDSJL0-.T0TJDAKLPC LYI 0.000

9 LyGDGQ] 0.90

Table X- W7-HLA-A201 -9mers-191 P40128 B

Each peptide is a portion ofISEQ ID NO: 15; each startposition Is specified, the length

of peptide is 9 amino acids,and the end position for eachpeptide is the start position

plus eight.

stq [Subsequence scrj

R-SQSEEPEG FP 796001

WTal -V-HLA-A201 -9mers-1f~be 191 P4D12B

Each peptide Is a portion ofSEQ ID NO: 15; each start

position Is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide Is the start position

plus eight.-itl Fsubsequenej1 S

FT1I TDPRSQSEI000

[LI SHTPRTSQ 0[,000

T~be 191P4D1281

Each peptide is a portion ofSEQ ID NO: 19; each start

position is specified, the lengthof peptide is 9 amino acids.

and the end position for eachpeptide is the start position

plus eight.

I1staiiq seq uence 1

s. Lo-HYiIJ

I[NJFIQC LLGL DLl~z

181 ~FLfFFLP 12.194j

LG7SNPPA] 8.4j6j

K- 2I Eff 1[IFTL

F7 ILLRFFI 2-7191

11281 MQMPWEG.85 LF1 FIfYFYFF !11.576

IEE7F1TLY I 59..FT [LLGLL [TK.57.[F 21 FFLPFPLW 1.

00

00

Table X- V9-HLA-A201-9mers-191 P40128

Each peptide is a portion ofSEQ 10 NO: 19; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight. [Startil ubsequence I Sor

9.1.IQCLLLGLL 1 1.io0j

F- 29QFM--EG-iL .09702407 LE ME S HYVAf 1.02

L1 RGYFQGIFM 0-.5-71]

L LVFFY-FY 0.337GLL R I TF N- Fi 8 0

L [NPPASASLV 0.454j[]jLL!SVRPL II 0403]

[42J[MS AQ [t IDL 15*3

Fj- ILGTLSV IPAJ 0.255158 II SNPPASASL. I F- 9-]

ULjRITFNFFLF II 0.113[L7LA-§LYAG. I 1lL!PiI. LLRITFNFF L0..

LYIYFFLEm-I 0.085 J

NE68 ILLRVy J 0 .055

FRFIQCLLL1Lo~

L 91. ffIYFYFYJ~4LzUL.Ly~IJI .039

i 31 ISASLVAGTL 10.0391F126 iIGIMQAPWI 0.387

PLW[ F-F 0037-

Ii[ HCACFESFT, .0395[Ti-f LAGILLRIT ij. 0.033-1

f119 q E RGYF QG 17 0029

ITbe X- V9-HLA-A201-9mers-9iP4D12B

Each peptide Is a portion ofSEQ ID NO: 19; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight.

F07] LLGLLK1VRP]F 0.025

Iii II V QGVD 0O.0167

Li F§ SFKRKKKL 0015_

M4 ITFNF _ff 0.010

QAgLELLG;I 0.008'qHCCFE1 0.007

[0.-006

L IELLG§SSNPPIf_0,004~I P.IIFFLEMESHYI LOP0 I

l.A 7 I qAGELS RI 0.003l.FI9J 5 IIL9 0.002j

L5TI LELLGSS NPLO.024 [i lL-VAP.1

EEEM2RKLL-A!9qGI[ .0.0021

I P8jLQHQGVN Sj 0.00211 .1 LFFLP ii1 0.002

RI ]GNCDCE RII. IFT6 F7fAC:2 EThI .001TO

§I51 GSP PA§, oFPo II x FflEMVE 0.001

K1LHA97 DL-9! 1F[T~i GILLRITF7F 00 0 0

Table X- V9-HLA-A201-9mers-191 P4D128

Each peptide is a portion ofSEQ ID NO: 19; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight.IStartI Subsequenc1.e.j 7

.LfZ I.S NPPAA F Oq-7Fl1177 Ic .9 F~ P000 1

Lu. ItKSCDCE9L 9.~

;fTable X- V1O-HLA-A201.9mers-1 91 P401 2B

Each peptide is a portion ofSEQ ID NO: 21; each start

Iposition is specified, the length1Iof peptide is 9 amino acids,and the end position for eachIpeptide is the start position

plseight.9

Seuence'1-r I

.7 RLRMVPPL 11.03

'F7iF RVMVP-PlPS K 0.2:4]

11 .000 IF-47 L VMVPPLPII *K0:00

Table X-Vi1 -HLA-A201

Each peptide is a portion ofSEQ ID NO: 23; each start

position is specified, the lengthof peptide is 9 amino acids,and the end position for eachpeptide is the start position

plus eight.lStart:l I Susqec _§roJ

LG TSDVT 11177K2

F5-- FAGELGqT S DV F0029.

00

00

Table X-V1 1-HLA-A201--9mers-191'P412B

Each peptide is a portion of1SEQ ID NO: 23; each start

position Is specified, the lengthof peptidle is 9 amino acids,

and the end position for eachpeptidle is the start position

*plus eight.StarJj ubequence 11[Score

SCPAGELGTS! 0.077P-AGELGTSD jj 000V[7R-CPAGELG 1. F.-0

9rers-191PQ12B3IEach peptide is a portion of

SEQ ID NO: 25; each startposition is specified, the length

of peptidle is 9 amino acids,and the end position for each

peptide Is the start positionpius eight.

jStart j Subsequence lScorei

[TF7jc GCSTLTT ILRm9PEG-CSYSTL 0.014 Jj

IDfEEGCOSY [000I

11.1 IIMSEPGCS [Eo007o

L Table X-V1 3-HLA-A201-9mers-191P4D1 2B_

Each peptide Is a portion ofSEQ ID NO: 27; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight.I !9rtII. ubsequenceJScr

1~ SQVTVDVLA 1[.0.50 Fl7 WA PQDJj.253FflVDVLADP 0j.003

LADPQEDS 0 II OOOJ

Table X-V13-HLA-A201-9nmers-191P4D12B

Each peptidle Is a portion ofSEQ ID NO: 27; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight.Star][SLs uence.1 _scoreI

[E[I[ADPEI 11 FOO9J

Table X-V14-HLA-A201-9mers-1 91P4D1 28

Each peptidle Is a portion ofSEQ ID NO: 29; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end positon for each

Lpeptide is the start positionplus eight.

[Start ffu Subequence F--iril-~F(7] NPP ASASLV jFO.ffl S nPA-sALjJO.- 13flJ

L17 GSSNPP-ASA1 T. 0q032]MI] ASLVAGTLS J[ .900

F1 L PA§V I 0.000

~fTable XI-V1-HLA-A201-l0mers-191p14Dl2B

Each peptide is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptidleis 10 amino acids,

Iand the end position for eachpeptide Is the start position

_plus nine.

I359.i LCLV\y 4256

358 j L-F-cLYY924. 6741244 LES~Ii2S230FL-LQDQRITHi 1167.2481

81 LLSYG9LHV IP 8.2381

215 1 SMNGQPLTC 115.534

IFTab-le XI-V1 -HLA-A201 I Omers-191 P4D12B

Each peptide Is a portion ofSEQ ID NO: 3; each start

position Is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

pRlus nine.ISta tisbsq u e[ 1.

ILHVS FL AE A 73. 8

L -PAW 72.031252_ GLEDQLHI~j4.2

[Y6j? civwvj[!:. FI3LT9T EH SG lY2Y9j.0

RLDGPLPSRL 27.821

3 5-4iIGv -IAA! L L124.93

L!441LYVPPLPSL 20 LL4LASFTGRCJ 15.4371

VTDTEVKG181] 1377

11Q .i VGALcL[.8I

IPE 8.453VI QDAKLP1

LP85[Z QENGTLR3.18

[381LT 7.560jI 447 _ILTYIEIET. Ji

350 VVVVGVIAL Fo9J

5L IALLFCLLV1 .4

[2 7 GQPPPSYNW 6.3

WGPEAWLLL .4

158 IALEEGQGLTL1 5.6095

NEFSSRDSQ

164j [LLAS T 96:8:]~

00

00

Table XI-V1-HLA-A201-10mers-191M4128

Each peptide is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

__._plus nine.

LS it. a-rtSubsequence I rF

1.34 IjLVSASVVV1L_49j9

[1 VQADEGEYE; 3.511

WVGVLL1[YV 31 78_

jLsIWLLU.LLLAs 112.917

1118 I LLLLLASFG ILZ.Z.!9.l[T2 IIYEqfRV§TtPAI 2.5771

t132] LFASQAL

L[7I LETSO) VV 2:16FSSRDSQVT

P21 r.RISQVT2.088

L1TTP2QRLLR.l 1.8- 79]iL. [M79w TWGQA L.891

FE ]Pj LALHSKYGfl .866

9KANHFVI

3J AvWG .775]211 M TSEFHIiIF.721]

Pii! 1:SV1 FN VJ=.608

[370 VGQA J 1.2220

~OjFMSR F 11 208

32 LGEETSDVTJ Pf991i

[T~f E LTLT TNSI I. 0.782

[39]1 VVTVVLGQD 0.739

Table XI-VI -HLA-A201 I Orers-1 91 P41 2B

Each peptide is; a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

LrtISubsquen~e] IS(creJ

(353]VG-VAALLFC.69YNWTRLD280]GL 0.692

[3:iT_QRiTH7IL'10.60471

IPTLTc vvSHPGti q. 5o04

6, VAWARVD 050

[I 2 F GQGTLAAS 0507TE I

[1 APSVTWDT I 0.454]

[T's EAWYLLLLLL I045[176PAS TW 0.365~

E1MNG Q PLT C V 1 [f8]qKYEEE-LTLj_ .3I

L~mi1CLSEGPPP~~0.306]L29JGL,_QDQR [.j0.276.

1501 PIWsLN PqtALj 0C.237

M GP 0.226

;112 IK VLLRNA V9QAD .216j

T6i 5GLTLAS~i .A§i

119 LL-LLASFTGR I. 9Y7..~1FTGRCPAGE [017

36J QE7DSGKQVDJ[0.6

9- E Q _P R N -1 2

'i 4_ YSTLTTVR~ 014

1 41SVRGLEDQ .4249 .S99i L.140

F Table XI-V1-HLA-A201-l0mers-191P4D12B.

Each pepfide is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for each

peptide is the start positionplus nine.

,[Sai Subs equnce SFcor e

[K][NPLDSL 0.1394]091 RSQ7PEESVG 1 0

FLk]GF9 LL 0.1391

156 GPALEEGQG 0.139

14511 IVLVPLp§SLN L:3Table X14V2-1-1LA-A201 -1

l0mers-191P4D12B_ Each peptide is a portion ofSEQ ID NO: 5; each start

Iposition is specified, the lengthof peptide is 10 amino acids,and the end position for each

peptide is the start positionIplus nine. I1

MIt Subsequence Score]

MIJL qAKLPCL1 2.23]

10 LYR DSGEQ]I o

FLQDKC R 10.0031V]L__LP CLYD [p j

[T7 DAKLPCLYR [0.000

Table XI-W-HLA-A201 F Imers-191P4D12B

Each peplide is a portion ofSEQ ID NO: 15; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

.usine..[t7 jj.Sy!bsequence. Score

[F_7!sQSEEPEGRSII 0.004_'

151

00

00

[Table XI-VW-HLA-A201 1 Omers-1 91 P4D1 28

Each peptide Is a portion ofSEQ ID NO: 15; each start

position. Is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

plus nine.

EStartjj Subsequence ScoreF iJ1lHHTDPRSQSJ, 0.0006 1

[TDP R-SQSE 0.0

F H HTql)s9 E LQOF T HSTPRSQ!:LPF0.PPJ

STable XI-V9-HLA-A201 -Inrs-194P 11

Each peptide is a portion ofSEQ ID) NO: 19; each start]

position is specified, the lengthof peptide is 10 aino aisand the end position for eachpeptide Is the start position

plus nine.-

IS LStub;sueq u e nce Sore

FI1YFYFFL1 7861.87

HFLFFFLPFPL 2108.811

FiEL LRITFNFFL[3.50PLYFF 1 .429

2] jFMQMAPWEG[F23[T3JIf FLEMESHYVI18.538

LGLVRPL1670

DC] IL ITFF J2- 4.898

157-1%12 K FPLV F Lt3 .j

I-T± IAL -VAGT7LVJ 1.680,105] IlfY!-LQH9 11161

ITable XI-V9-HLA-A201- 1l0mers-191 P4D12B

Each peptide Is a portion ofSEQ ID NO: 19; each start

position is specified, the lengthof peptide Is 10 amino acids,and the end position for eachpeptide is the start position

plus nine.

Subsequenlce IFssorei

II F53 ]LEL--GSNPPA7 9 .j

.1 3][LEMESffyV [:O600j

IF! f -T 171. 30 1

D I T FF fYfYLP.4 0T]

5 I jPWF lF[ 09.32 9I 102j[GLLKVRPL9 j F.276j

F7I. VAGTLSVI-IH 0.270GTLSVHHCA

08PLQHQGVNS [0.251.I

E-l[ Ii GILRIFNF I 17

[Tf]lLSSNPA I 0.127]

[5I FLDA. V F

I 126j GIFM(QAAPW[ .7042.

[4j MSY 0. 040]

F 80 -11 <RKKI I*09

LTable XI-V9-HLA-A201-l0mners-1 91 P4D12B

Each peptide is a portion ofSEQ ID NO: 19; each start

position Is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide Is the start position

plus nine.[S t artl FSu-e qu en~ 7ce .]e

F 2] .SVHHCACFE 00O38

AGTLSVHHC][ .032]62- 1IAS Y.iLp

R-0 ILEMEHYVA 0 01711

43J ESHYVAQAG

LM7.1 FF LF-FFLP]17 000FI KALE-LLGSSN [o.007Jf

FT 4]fY4jIFQGWAPfJI.O07liii AGILLR-FFN 0.006_

EF] JPA ASLY AGT

I121 [RGYFQGIFM 0L024_FELF7J C EGYF 0004]7 IHHCACFEFTJI. 97I

QQGVNSCD [0.003

GVNSgDCER J[0 ]0[I96][§L LLLGLLK .LP. 03I

19LQHQGVNSC .03

M4 J ESHYVAQ 002

G 0.002

00

00

Table XI-V9-HLA-A201-110mers-191P4012B3

Each peptide is a portion ofSEQ ID NO: 19; each start

position is specified, the length

Iof peptide is 10 amino acids,,and the end position for each

peptide is the start position

t[StaJl Subsequence lj SoRej

I !-flLLKVRPQHQL.992L-E-LLGSSNPPi0.00iI7 RPLQIIQGVN 0.002

[TFj LGILLRITF 0.002~

47 i GiLLL 0.002

tF iNCDCERGY 0.0

16jj NFLFFFL 1 0-q L71

FLj K zmi -EF~RIJ0.0 0 1I !P IIK2LKT< I 01 i

3 ]jASLVGTLSF 00 j

5~1. G1LELLGSSNP !LO.001 iFf71iISVHHqcACFEL.001 1F17Jlf-YFLEEHY LOO-jJ121 FfLFPLF A 001]II f9 LKKARFQC]qEL

F11 FLL /PwQ 0001

[125j FQGIFMQMAP 0 000

GSSPPAS 0.000

STable Xl.V1O-HLA-A201-mers-1 91 P4012B

Each peptide is a portion ofSEQ It) NO: 21; each start

position is specified, the lengthof peptide Is 10 amino acids,and the end position for eachpeptide is the start position

____plus nine.

WI9LGsDvy)vTYYJ AK?IJ9JlKIS0Y3 I 0.499

Table XI-VI 0-HLA-A201 L. lmers-191P4D12B JEach peptide is a portion ofSEQ ID NO: 21; each start

position is specified, the lengthof peplide Is 10 amino acids,and the end position for eachpeptide is the start position

pRlus nine.

MFWL-GTSpV\'il 0.2201MF]PAGELGTS-DV L92-L

0.006-

LLTGRCPGELGLoJ o

Table XI-V1 1-HLA-A201 I Omers-1 91 P4D12BEach peptide Is a portion ofSEQ ID NO: 23; each start

position Is specified, the lengthlIof peptide is 10 amino acids,1 ,Iand the end position for each

p eptide Is the start positionplus nine.

ttartjL:S9se 91Lnc 9 el

]VMV-PP LSLN I001ALRLRVMIVI 0.073

f05 LRVMvPP LI1j.043[-4IIR!LR,VMVPPII .00R3110 yPLPSLNPLT..2I

=6 LR YvPLP1I 0.1[7 ]LRVMVP.PLP.f7ULAR LLRVMVPI JB0000

I TbleXI-12HLA-A201 lms-19P4D1 26'

Each peptide is a portion ofSEQ ID NO: 25; each start

position is specified, the length,of peptide is 10 amino acids,and the end position for eachpeptide is the start position

p lus nine....-

Start Subsequence iiL.crEIGCSYSTLTIVJ 11.044.I

i MSEEPEGC1 .788, 1

Table XI-VI 2-HLA-A201 L 0mers-191P4D12BEach peptide is a portion ofSEQ ID NO: 25; each start

position is specified, the lengthof peptide Is 10 amino acids,and the end position for eachpeptide is the start position

~~plus nine.

L[Lta~j Su c eL~il!~Fs 049

FL- LJEEPEGOYSTj 04

]10LEC§T. =O901

Table XI-V13:-HLA-A201-L i mers-1 91 P412__ 1

Each peptide is a portion ofSEQ ID NO: 27; each start

Iposition is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

plus nine.Dart bequence.I[cofeJ

MLQFOVDVL- I~

[Wt~iSwoDVL 002J[I][vLADPQEDS]ffK]T

E4~I m'M =0001

D 1 PPQEGQ[ 0.0001

Table XI-V1 4-HLA-A201 -I

1 Omers-1 91 P401 2B--Each peptide is a portion ofSEQ ID NO: 29; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for each

peptide is the start positionplus nine.

00

00

LTable XI-V14-HLA-A201-I1 0mers-191P4D12B

Each peptide Is a portion ofSEQ ID NO: 29; each start

position is specified, the lengthiIof peptide Is 10 amino acids,and the end position for eachpeptide is the start position

plus nine.

1Startj ubsequencejj score.L1ull AS-L VA-GT LS L F15.6 F41 NPPASASLV L 0.541

L-Y 000=8

(Table XIlI-VI -HLA-A3-9mers-1F1-Z 191 P4D12B I

Each peptide is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide is 9 amino acids,and the end position for each

peptide is the start positionplus eight

[FLrtj[ seque ce I c r

L[7 LA F LG]~ 000JfTJ51VMSEEPER .000j

L~zo LM RYHR [aooo

1 IILLAF IL 4. 00L3~zL~~wvv.LjI .050j

L 92iLT LJI 4.OO

I L qY 99A~ 3.000

1)821 SVVWDTVK O 0IK L~YQVW I L1.800368]jIVVLMSRYHRII 1.800

Table XII-V1-HLA-A3-9mners-1191P4D12B

Each peptide is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide is 9 amino acids,

,and the end position for eachpeptide Is the start position

plus eight.[Start subseq-uenc~[ e

136-311 Y 5LLvL FE.350-.t1-61SNE-SS-R_]jF 120k[252 GLE-DQNL Vl_1.200q

IL 78 IL I1.200I[366Pj j WMSYL.900j9

T1Jl KckY.I m 900

:115 IL LL~LLfl=.900j89 I HVPAYER FL 6qT

[485 II FV-qENGTLR[-0F~TIREQPPP 1 0. 600

[392 q P.ENIR 6Lo 0

351 -j V V AL[ LLq I 0.3 040

31 =Y.vj039

1)12I yLRNAVA L .300L2T PCl FPPLnj 0

LL6!I.I =LLSJ .3q0

P EGVIL~ j 0- .270

FIf =51 F9 2~:70J1 5 51L qN--v H-1 0.21 6

fl~~ [yyV VIA 1- E2180I 1861 EK-GTTSSR II.p89

1y9. SFHYPRJ L0.1801

I ii L -LL LLA 0.150219I. 7 UQELALHSK i~:~i

I Table XII-VI-HLA-A3-9mers-1L: 19P4D12B

Each peptide is a portion of1SEQ ID NO: 3; each start

position Is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight.

378 IFL QA7TKYII 0.12035L~IL!YSFLE o

FT.1U p LLLASTG Y-290

P35 ]IGS FALRL 0.090

LFTII DLVASMVW Tn.00

L 4FEPLPsGJ[y68 jL--

IXJLI][PHSKYGLH ][0O760

[3lyji I I -9

[IJL 7SRSFK] 060j

121g. IILRAVQAD TLo C

I 345 LVSKsVVWJ[-=060_

LF7-iI 0\Y i 0=

1471 D KCFR [0054

PI 20 LTTESM 00460

D39 A1LTLT R 1 0.04

00

00

ITable XIll-VI -FL-3ges

Each peptide is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide Is 9 amino adds,

Iand the end position for eachpeptide is the start positionL pluseight

[StartI[ SLbsequence rej1.-8fllALEEGQGLT jt05j

L66 II.AMLKCLSEG =1..045

Fi--iRL ~n~ 2 J _0=640I? ISFPLKD NS S1 I 0 .0361

1276 EYI.?~jliI 0.036

F3~ I7fLFAAvR n 0.030 I

ITable XII-V2-HLA-A3-9mers-191P4D12B

Each peptide is a portion ofSEQ ID NO: 5; each start

position Is specified, the lengthof peptidle is 9 amino acids,

and the end position for eachpeptide Is the start position

plus eight.__

I Strtil Subsequence 11 Score jDi K[CYRjGDSGEI 0.100

Wi]E GQDAKL C L FI-m91i

LPCELYRGD ][1E0.]

g[III_LPCLYSI0.004

]L LYRGJ =0.000

L 7-1 LYRGDS9GE] .000]

ale XII-V7-HLA-A3-9mers-1191P4D12BEach peptide is a portion of1SEQ ID NO: 15; each start

position is specified, the lengthof peptide is 9 amino acids,and the end position for each1peptide is the start position I

p -__lus eight. _j

[E i aL squene[ScoreJ

1181 SQ: EEPE GRI .1809 j HDRQE[T.00 7I

Table XII-W7-HL-3mes191 P4D2

Each peptide is a portion ofSEQ ID NO: 15; each start

position is specified, the lengthof peptide is 9 amino adids,

and the end position for eachpeptide is the start position

plus eight.

[07 9SEPEG LoOOLg1l HHTDPRSQS EL.S7 I

lli R 9EEJ 0.000I]PRS QSEEPE 0~.001

M] SHHT D P RSQ 7000

TbeXII-V9-HLA-A3-9mers-]Tb 191P4D12B

Each peptide is a portion of1SEQ ID NO: 19; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight._1P Strt ubseqyence II Score

[ul_I1FFFF.000

PILL(Iu±LLKV~fl 6.750j

Liii LLRTFNFjL6.-0001

F] LFHY .500

P- ]EFPfFW j 4.50 0

WL. LI

'FiflKRITFNF=FLF 1.800 fL13[GN SCDCERI 1.200]

Fi-ffCLLLGLLKV0.0

]L o.54o982 j F KRKKKLK j 0.500

FTable XII-V9-HLA-A3-9mers191 P4D12B

Each peptide is a portion ofSEQ ID NO: 19; each start

position is specified, the lengthof peptide is 9 amino adids,

and the end position for eachpeptide is the start position

plus eight. Fs-taRt I[Subsequence IL cy

.1.1FLFFFLPFPI 0.450JL ]KFRffQCLI 0.405

0 F-.Tn

L ELGSNPP 0.2001

M12 I[ ql-LKyRPLj 10.1 '35 1FI~ 4 -IYyV 9L9 [0121]j[80:I ESTKRKKJ0.7

g69jj GlSVHHCW j 0.0680

F! -5I FFLFFLLF0.05417I[]LffFfFLPFI0.054I

[F.1L 5 f.945 1

[2KjFIFYFi[ 027

I FYFE E10.027]

=24I ff iL-24

FoFL 9 y 00ELGLV P 7201

Fj1 LSHCA NLO.0

FW~~1 L 1F oi[86l IFET-q KKLKF If_0 .012

11051 KVRPLQHQGI1 .0091191 LFFFLPFPL 'I 0.009-

00

00

ITable Xl-V9-HLA-A3-9mers-191P4D12B

Each peptide is a portion ofSEQ ID NO: 19; each start

position is specified, the lengthof peptidle Is 9 amino acids,and the end position for eachpeptidle is the start position

plus eight.

[L-t~q S-ubsequence _I Score

11.DFLRITFNFFL- 00896JLQCLLLGLL 8

1.741 HHCFF! F0- 0008]

LI~.ILMEHYV IF 0.006 1

IiN3LSFDER GYQ F T 9

RELAGILLjjt005[A21z N4 WEHY VAQI 0.005

I6.1GSSNPPAESA J6L-5-[lj.-IFFFLPFPL .0

I 40 EMESHYVA P0.041

F!7 L N AFRFQ II0004

LF i I HCACqFESFT jO.031

[T6i NFFFF!FLP 1.003]LI. I FFLFPW. =0.003

[63 ILSASLVAGTL I0.003

I T 67 VGTLSVHH 0.002ffl]K RGYQGIFM JLO02j

0.002

[47 II YFF LEMESH JR 0.99271621 ASSVG 002112 RLGFQGIFMQJ_0.001

.RKKKLKKAF Ii 0.001o

Table XII-V9-HLA-A3-9mers-L....191P4D12B

Each peptide is a portion ofSEQ ID NO: 19; each start

position is specified, the lengthof peptide Is 9 amino acids,

and the end position for eachpeptidle is the start position

plus eight.

F24jPFPLVVFHJ om

i 9jE RGYFQGIF L9f. i

1 Table XII-V1O-HLA-A3-Smers-I1P4D)12B3

Each peptide is a portion ofSEQ ID NO: 21; each start

position is specified, the lengthof peptide is 9 amino acids,and the end position for eachpeptidle is the statpsto

plus eight

I[Start ILSubsequence I Scorel

[T7 [GLGTSDWT I LO.oo437YJ] [OPELT][ 0.0041]

~1L ~!§YYTV CI01]

FT7171f-- I9~ D Ilq.99'EP GEL] 10.0001

able Xil-V1 I -HLA-A3-9mers-191 P4D128

Each peptide is a portion ofSEQ ID NO: 23; each start

position is specified, the lengthof peptide is 9 amino acids,and the end position for eachpeptidle is the start position

~us ight.

F1. tart Subsequenc L crelF±@PPLPSL 3.38J

Fl] K-RLVMVP 101

FT][ QARLRLRVM- 0-001

[Table I -I 1 -H LA -A 3 -9 me rs 191P4D12B

Each peptide is a portion ofSEQ ID NO: 23; each start

position Is specified, the lengthof peptidle Is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight.

FS-iart Subsequence][gTor

L FA 1LRLRVM7VL~]F .LLRVMVPPP [00

Table XII-V1 3-H LA-A3-9mers-.191P4D12B___

Each peptide is a portion ofSEQ ID NO: 27; each start

position is specified, the lengthof peptide is 9 amino acids,.

and the end position for eachpeptidle is the start position

plus eight.

WELLP9 Ps-J 0.020

F -1H1Ipy 9_Q .002_YALP Joo1j

4Y]LYPVLDPQE 0.0

Table XII-VI4-H L-A-9mers-1191 P4012B

Each peptide is a portion of1SEQ ID NO: 29; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide Is the start position

eight.

I tartj Su§ bsequence ;Iscr

7i7[GSSNPPAS II 000

NPP SSLV I 0.00[P LSNPPASAS[- KLO.

[77 L SLAGT Fjqq0002771 SSNPPASAS 11 OJ000

00

00

ILL LVAGTL S .09L~

lTalex XI-VI -HLA-A3-1 Omers-

Each peptide is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide, Is the start position

pius nine.

[Stalubsequence IIc e1K2 3jAI)LDDGK -LOM9 [ILLLSFTGR 18.0003

LMSRYHRRK][9.go![25211[9 GLD-QN ml I 181 100ofI II11 TLRENSIRR 18.000*F1 Ti~iLLLLLLLASFE1.500 IIF 81 M WqP wLLFl4-050 IKOC LRLHSHHTOPR[ 4 000

FC6 J[IGREAMLKJI 4.000][3s911 LLFCLLv~vyvVIL.0-001

U LE L7TL.80][L2LG~LLQIDq i] =1.809]

LYfl[WVLMS-RYR][ j-

[2[1VLnQDA[ L1.500[362] cL50

[L 754 GVIAALLFCL, FT .215112571 NLWHGREGA. II .0-j

:yLhv ;sRJ.F 0.9001[239 ILSLAEJ[0.

LE:CoiLTHR!. ii 90~p

F1674 STE I O.600L

P68j1 LVVLMS Y::R0]

t] RAEGtHPDSLK I 0.450]8 L FCLVk VY Y 0450

Table XIlI-V1-HLA-A3-lomers-191 P4D12B

Each peptide is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

Runine.

Ir W:Jj GVIMALLF1IOAOOI]

F4--flEQVGQVAWARf =.36o.

J[ 4[ R GPLs~ v] .300 1

I FT4ILPW-A-Mqi. ILT29KPq PI LDNSSCSVJI 0.270o

I[Fl?0j LA IGEIT 0.27001

llIF4!1L~VI LPQ0.19. I[-3IL11__h~qyENS I ]wO]

vSFLEASV il0.200

F51 LLL sFT10.81-9

T4]LMy 0.090]8

F A-L-LHSKY -T i~~

1789 G S I 0..120

Table XII-VI-HLA-A3-loers-1K191P4D12B

Each peptide is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide is 10 amino acids,ad the end position for eachpeptide is the start position

.jusnine.

Fi-irJtLy~eence [(Scre][±6!LQNGTL RA2KLo.09-0

[Th 11 'YqK- I -0[3D6[ IHIL

U28JLRsTFPAsfl 6.961

127011. CLSEGqPPPS j[N060I 47J[GIQAMNFV I0.060j

I. =jF~NTR I0.060g205) TSEFLVPSR] 0L.060

I-Ill GPEAWLLLLL 1[ITOR4][218 LGQPLTcYHI 615a41

L99LTh9?tPTTE] 0.045[272] QPPSY 1[0.045]

135 GFQARRLR 0.045I

a~j]LLLWWVL ]ff041][341 ]QYQLVSAS§ j 0.0413

N5][ EETLTR [36

Iq IT ILLEg. 3 61

I I cwOi 03

Trable XII-V2-A-A3 -1 mrt 191 P4D12B _i

00

0

*Each peptide is a portion ofSEQ ID NO: 5; each start

position is specified, the lengthI of pepfide Is 10 amino acids,

and the end position for eachpeptide is the start position

plus nine.

LStartll subsequence Score

[Z,.iU19CD ]L9L F366Q[6_7[!PLYRGDS 1v 8)

I77I PKC pYR 0,.012

1-I IGQALC II QID NYRO:GV 15; eachstar

Eapeptide Is ar poition o

plus Ine. 1

[st-art L ubsequenc ej[Scor e

[Z11]F SQSEE 00]

LFJ[]PSQSEEPEI 0p.0900j

,jffHHDPRSQS§E 0.0001

K]LRSQE EPEG IR 0.00

Table XIII-V9-Hla---I-mers-S191P4D12B

Each peptide is a portion ofSEQ ID NO: 19; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

plus nine.

I startI Su bsequence II.Sco~nI 8 I FY F 1L40001

18 II FLFFF P 9051

Table XIII-V9-HLA-A3 10mers-191 P4DI2B"

Each peptide is a portion ofSEQ ID NO: 19; each start

position is specified, the lengthof peplide Is 10 amino acids,and the end position for each

peptide Is the start positionplus nine,

M [ldqueneILF cor 900

I 6. LYVF:F .100

'IF GR-ILLRIT FF I4.050I 2! RFFLFF L3.600J

FL E S FTRKI .250O182 j FKRK KKLKJ[2.000_1

[T.iT9J:LT CACF [12:000F! t. FLLKVRPLqH] 800I

[911ICLLGLLKI i:20 I

qL 1.20

L-3_il F LVAThSVEIO7KP~J LLGLVP 1 o]

I 7[CCFSFTK

I LjjI HVA L.ELL I9130 II 7FFYF L001

FU I REGL] 0.54

69 ITLSVHC~c 0.45

Table XITI-V:9-HLA31Oer

Each peptide is a portion ofSEQ ID NO: 19; each start

position Is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

plus nine.

Lstartj I Subsequence]

1.103 !LL~v Lo745

I66jLVATLSVH± _L3 0

[Igj GIMQPAtWJl 0.030](~221 GYQGIFQA j0.027.

7EL.'GL iI 0.022I. 7]YFLEESH q[0.00

I181 CFYFELEJ[0.018

112l1y _±~~oo2

I 1!9]LfEPLFQGIF I 0.010

Ti]T2 R-KILJK.0079!j FFF c LPFP i[.O6 7I

r F TIbY G

F I Fgi 119A qE IL0

I 9iLL SfmHY( .006

I 8 L~KLKAFRII .004I..i PAALVAL 0.004 I

L 0.003]

5?UT -j ASL LSV 1115.1 t NSDEGF o07

00

00

Table XII-V9-LAA3Iomers-191P4Dl2B_._

Each peptidle is a portion ofSEQ ID NO: 19; each start

position Is specified, the lengthof peptide is 10 amino acids,and the end position for each

peptide Is the start position

1..art§Sbsequence JF7coeJ1 RFICLILqlGL 0.003]

32LYFYFFLE (0.0031

FT 80 EFTRKKKL- II 999ZFi! L 1ESF -RK FL.00[Z1[YAQGLEL 10.00f 61[ FFFEMESHtPO2

123 ['LQGlFMQAA.001

[6i[ASASLVAGT 10.001

[7 I2RELLAGLLJ[0.001]

8j _KKAFRFiQc 05.001

1l F2[AfRffqCLLL j 0.00111109 [LqtqGyNSqPIL01

FT ~jE§L Aq~q10.001

L87. !KKLKK FF 0.001j

[11[ IIVN C DC EYO. 01

W2 IIHQGVNSCD I EIP00-1]

[IO7JIP LqHQqGVNI 0.001]27[I 4IL FM QP 0.001

LFEMESH YvJ=000[iI FYF FFE]~ 0.000

ff.! 11 RGFQGI FMQ [L7O(?

ITable AX1l411IO-HLA-A3-

Each peptide is a portion ofSEQ ID NO: 21; each start

position is specified, the lengthIof peptidle is 10 amino acids,and the end position for eachIpeptide is the start position

plus nine.

[S-tarti Sub-sequence IKc2ReI F LTDVVIq.T8R

GSDVWTWL7 .13 5F71. iE-LGTsDVVTT L.001FT2 11F qiRcPAGEGT FO.0011

Table XIll-V1O-HL.A-A3--1 0mers-191P4D12B

Each peptide is a portion ofSEQ ID NO: 21; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

plus nine.

ELGTSDV-'0000I

[T AGELGTSDVV 9J1.0001[77RCPGLGTS ffYOjO

,[IfjGRCAGEj0. 02

fTable XIII-VI 1-HLA-A3-l10mers-191P14ID12B

Each peptide is a portion ofSEQ ID NO: 23; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

plus nine.

10JI fLVIPPL P F

[2Dl. QARLRLRVMV E0002L itFQARLRLRVM 19.0011

Table XllI-V12-H L-A-1 Omers-1 91 P4D1 28

Each peptide is a porton of 1SEQ ID NO: 25; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for each

peptide is the start positionplus nine. j

S _rtJ Subsequence I.r70ii:Ei CSYSTLTrvR Kio-oo-1IM SV.~MSEPEGq 10.030

V 1MSE EPS 10.030.1

5[

EEPEGCSYS]P7I990

LfLPEGCSYSThT.l.09

[T]1j E9STIIL9OOOI0001

STable XIII-V13.HLA-A3-110mers-191P4012B

Each peptide is a portion of1SEQ ID NO: 27; each start

position Is specified, the lengthof peptide is 10 amino acids,and the end position for each;peptide is the start position

plus nine.

Su_§bsequence7Lscrel

77 QV-TVRYLADP JO.0051I[77_ DL EDS 1O

[2 DYI Pi[.021

v RVLA D qoF f b v: L7J[ IPQEs ~ooo

900.0 I H ~llI .9

9~ I ~c~Xi IN01

0WMA~d 9LZ

F i66 iF ozi

I L~~Iiij ]F6v- I

1 N LP16

Z o6o II ij iL li-

I6~ Ii/TVi I

v~hiiii4Li

8 F Mildl

Foqlso pel VdaH1A si op9 1

4088 Jol U11sod e eql

'S8 Ouwe6] a1iddK i joto6i66a awoupsfls uoilso

*JBI p Peg d 3

jo uoipiod e sl apdad qosflZ 10d1lU-5JGW6

I 9ifoOI 1dF1 I [8Cr

I-2Z07 .1 r TA I-e6 i

z 00JNAAA__

F6Fo

F6i 1o dHA-1ie

F oeooi~i9~i L\7[*IAS0lAi1

r6o WA

1-646i~

1069, snid-uofllsod piels 941 sl opIjded

14058 iol uoI~fsod pua 9qi pue'Sp!Oe Ou!we 6 sl epijdad jo

q)Bue I~ peij'p9gods Sf uoqjfSOdIJ'Is qL059! :O 01 03 DS

jo uolljod e SI opqded 4083

S9- 1.OVd 1.6 1.-SJGw6

R601 9Wd6JA V6U

I oo*Q IIS.L!A 8.7091.0 MilmA 4H8SnA9

I 6E]IN V6 0 I jA]'6'

WJddd6AA R]

IO f ILOMIAS091

pea jol uoilsod pua 914) pueI'SP!02 Oulwe 6 Si opildod 'o

141Buaj 941 'peijpeds 5! uo, sod

jo uofljod esSi opn~ded qoea

L O0 _VVHU.-AX elqei

1b6oo Fi6VS 6_Ir I

F 6: Fiido If V§~rir ib& lv~s I~ 0-11

FJd6Y1 RXIVSdd] LI

etju snlduoilisod liesS 814) Si ap!ldad

14059 iol uolSod pue 914 pUeISJpi0 oufWe 01 sipided jo

lb 14! aqjpaIj!0ds si uoilsod)J8)s 408!6Z :ON 01 03Sjo uoilJod e si api~ded 14059

-CV-VIH-71A-IIIX Glqsj

00

00

00

00

Table XIV-V1-HLA-AI 101.9rers-9P4D2Bj

Each peptide Is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide Is the start position

plus eight.

Startj Subsequence 11 Score

69]RVDAGEGAQ~j 0.006

362 FCLWVVVL I .0

-131-1TFP7AGSQ .0

357-1 -AA'LLFCLLV 0.00 j1771(ULLLLLLASF i 0006

77"! FQENGTLRAKII .006iOYiI Fq FP PL -E HJI-O6

rTable XIV-V2-HL-A-A1 101-

Each peptide is a portion of1SEQ ID NO: 5; each start

position is specified, the lengthof peplide Is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight.[sar I Sbsquenc 11 Score7

D-]j DAPC P LYRILffO 24[9qDAKLPCL 0 .018

[T1LYRGDG T 180.00

LFLP G] E 000D] PQoc9E[oo

Table Xl V-V7-HLA-Al lol-

Each peptide is a portion ofSEQ ID NO: 15; each start

position is specified, the lengthof peptide Is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight.____

F{Start Susqyuencej[ Score

8,F§9I E P G R 0. 120Lo

Table XIV-W-HLA-A1IO01-L. 9mers-1 911P4DI283

Each peptide is a portion ofSEQ ID NO: 15; each start

position Is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

I Plus eight.

Start I .Sbsence I L e I

-TiJ TDRSQSEEE F TO.00

I- tHDP RFS-. 96

Table Xl V-V9-HLA-A1 1017I 9mers-1 91P4D1 2B___Each peptide is a portion ofSEQ ID NO: 19; each start

position is specified, the length1of peptide is 9 amino acids,

and the end position for eachipeptide is the start position

____plus eight.

I SusequnceSc-ore1:3 Jj GVNSCP9E III.200

L

1 77 I,1.ACFESFTKR 0.08

7-A7 ELL-GUR] 0.07

8L769 iIGVHCAI.045

L2. .1 DTT fLf 000I i YYA9

FL 24166 _LVAGTLV 921

31 I FIYF YF YF] 19.0161

ITable XIV-V9-HLA-AlI 01-9mers-1 911P4DI 28

Each peptide Is a portion ofSEQ ID NO: 19; each start

position is specified, the lengthof peptide Is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight.

LS!a rt.Subsequence j[ScoreF86 IFKKKLKKAFRJ[02,[i71 LFFFLPFPLO2

[98~~7 [iCLGLK 0. 121

F91 KAFRFIQCL JIO.01'21

FT SLA G TLSV 19:91?

110.ii LLKVRP LQH [9CO8II[ IL. LLGILLRI 10.-08-1195_1 FIQC LLLGL E=0081

H371 -iFYY 9k9LF-1 F FLPEFPLW E0.06[14T 1I.TFNFLFFF- 0.006

FA- KI FESFTKRKKK Fq9.P9717JffLFFFLPfJL006

1I.FQ9GIM-QM- ][.079J

105 I1jSRf !9 II9PLQ G K

Ji31iFQ~l F. OI9 41

jq:1 LRITFNFF 0.004

M2 LF-x

87 LKK KAFR FO.T93,

47] VAQGLELL 0=.002

_76-1 SCDCERGYF 19921

00

00

1[ Table XIV-V9-HLA-Al 1OI-_L.9mers-191P4D12BI

Each peptide is a portion ofSEQ ID NO: 19; each start

position Is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide Is the start position

____plus eight.

j~arti Subsequence Iscorel

Lf1 67 vAGTLSVHHJ[000FCL 727SVHHCACEJ[002j

L 63 ]SASL AGTLJp0

F7i]RFIQCLLLG 1102]___]__1LLRITFN- .002.9~

I PLFF ic..

L 33 YFYFYFFLE 0.001 1

F48]j AQaGLELLGJl[5.00188j __]KLKKAFRF FO9691

116 j NFFLF ffLP joOjII_5JLELLG-SSN.0011

I8 ]SFTKRK L 0.011I] FL LR1TFNFFL 110.0011

L~p~ i RPLHQ~v .0aoo1 128 J{ QAA q E.~0o II iii fLFT PFJO.R011

RRELAGIL[07.0012

T0jijqPHQGVNSq 10.001'L QM PWEGT 0.9211

=1i EIQGVNStCECIKp901]LF i ALLRT jol1

421_] MESHYVAQA 110.9011

7 SHVQG.0001

F1il LLEGL LKVRP iFO.ooolL F TSHHA 10.90

49 QGLE LLGs 0.000!F127 Jj LFM~qMWEjg DOO~L SS E.IsA~ I.709

Table XIV-V9-HLa-A1 10-1*9mers-191P4D12B

Each peptide Is a portion ofSEQ ID NO: 19; each start

position is specified, the lengthof peptide Is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight. FStar 7d S ubse qu e nce] soe

F[7h1LsN'HLKA F 60.666FT]IRKK LKKA7IOO

Table XlV-V1 0.Al101-9mers-191.P4Dl26

Each peptide Is a portion ofSEQ ID NO: 21; each startI

position Is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

pius eight. Startj Subsequence I Score'

II9_J GTSDVVTVV 11 00 0

I 6LGELGTSDvvjIF.00312FIT ROAEGJN.001.

JF Ei GTjDVVTVj[000=5L EGSDV L9

T ELGTSDV [ooo

=71711 GRCPAGELG3[a=0O

[7111 AGLGTSD 000

Table XIV-V1-AI1O-9mers.]191 P40128

Each peptide is a portion ofSEQ ID NO: 23; each start

position is specified, the lengthof peptide is 9 amino acids,

and te end position for eachpeptide is the start position

plus eight. I_Subsequencel[Taores

F7 ]f RV VP.PLPSIO.2

j7~ _RVMPSL0.006

JD7 71 MVIPLPSN I 0002

Table XlV.V1l.A1101-9mers-]

Each peptide is a portion ofSEQ ID NO: 23; each start

position is specified. the lengthof peptide is 9 amino acids,

,and the end position for eachpeptide is the start position

plus eight.

t _FARLRLRv m vjo. 6o6;7ILLR~VM4~ 0.000 I

Table XlVMVM2Al101-9mers-191NPD1213Each peptide is a portion ofSEQ ID NO: 25; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight.

I PI jjoC Y_ 0 01]~F I FL~~C SY S ogoo[77VMSEEPEGC T00

7~ZLPECYT .0001

[711 EEG 0.000j1

f Table XlV-V1 3-Al 101 -9mers-191P4D128 r

Each peptide is a portion ofSEQ ID NO: 27; each start

position is specified, the lengthof peptide Is 9 amino acids,

and the end position for eachpeptide is the start position

_pius eight. J[rt Subsequence Score

I..1_j[EQ T yLAI T LJ9YTVDVLAD j[ 004]

[Mi[ PYVL: 9D. I E.02!.

00

00

Table XIV-Vi4-AI 101-9mers-1!95-41Bt

Each pepide Is a portion ofSEQ ID NO: 29; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachIpeptide is the start position

plus eight.Start JISubsequence (Score!I

F- SALA GTL Lo:0021

[fl~sNPPSAj 0..01AS VA IF.00

A- ~PrAS SL 1 0.0017i7] A 1 SLL 199

[T][ASLV GT~0.0001SSNP ASI 1.000!,

~7~JjPASASVAqIO00

LTable XV-VI..HLA.A1IO1 1.

Each peptide is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

plus nine.Start~ F usqec Ico rel

401 F y-ooj~.5 0-1

364 LVVVLMSRR1l1.2001

f #L HIREGAMVLK1080§YVMSEEPEGRJ[O.BO0

I T IAQ LALLK Joo0I 4 1LRAEGHP!DSLK 10.76001

L .I5WLsRyiHRRI Fq6016

PT] 'VLDPQEDSGK Fq10.400;I ~0JL~~r~N O. 0300

~354i GVIA LLFLJI0.2701I LOj.( RLHSHHTDR P0.240

I LLLL A§FTGR IF..120

ITable XV-V1-HLA-A1 101-1j Omers-191P4D12BjEach peptide is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

plus nine.

Rl-12 ILKrqsY!wT.] 10.00IR~j 48 [YEEGT JF270.0

KGTTSRSFK I0.090I

P1112811 L- RVTPG FOl.0.9P

![lj Q19 QDGYCJ0.060

[352j WVqALF 1 0.040j

F 301_VVPVWLMS R 000

lF?5P]LLyylQyIT 10.0361T q~

iL~~Asv I0.030i

F1 1-111 GrmnGRGHI .0Ef2J[ gLQnLHI (1.024.1

QVfl GQVA A R 100207

lF2-i GRVEQPPPPRH 10.0241

[Table XV-V1-HLA-A1 101-1 Omers-1 91 P4DI 28

Each peptide is a portion ofSEQ ID NO: 3; each star

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

plus nine.

LStartl__Subsequence jscore

1479.11 tED Q DE GEIT.0

_tL TSHR 10.0181

[F58JITELLSPGSGR 0.-018

14 [QDAKLPCFYR 11.018

LT9Jl qIqAMN-FY] 0. 012]

[Eljz. 1. QMNFJlO.0121

G1_LTLAACT _91 21

18 -kI YLHV~spA 0.012i

L284 Ij RLDGPI-P§GY]051'I 1 [RYHRIRKAQq 0I.012J25 DLFIRCPAGL]Fj!OJ

lj TCWSHPGL =0.10I

[2-'f[_nuLHYLF 0.010!

F L5EL41cLL"17P.i0.98.

FI !l..ALEEGqGLTL ff-08D257l [NLWHIGREGA =0.008

(315 jC YSNE FSSRjq06

NI88][LHvSPAYE GR I F-6-66j-

I 156f GPALE =GQGIJ(0.006358 IO. 0LF 0l96i

I. P1.l1. IYINGRGftlV j.006

I 79JI._ LHSKY9 i1295

I 493LWAKTGNGlFj[.006]FkAziI L CLLW 0.006

d II RVEPPPPRj0063 62] 0.LW V 0M0L06

12941 =VDO.006bos161FLLLL L16.6AS56.1~

00

I 00

ITable XV-V1-HLA-A1 101-10mers-191P4D12B I

Each peptide Is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide Is 10 amino acids,and the end position for eachpeptide Is the start position

plus nine.

Kt Subs-ybequence I Scorel

1312- 1LYCHVS N!EF EWE-06FI 69 I RYAGEGAQ 9 006

L29. _LRVDGDT 0.JIO006:

1223 1 CSPLqpf-- 10. 006

[I7MGPAWLL10,05.1

GO.RTLRA KPTGN 0.0051IL!!HSFLAEA I 10004]

F426] §LKDNSSCS 10.0041

IILVPPPSLN IL..004!,

~_Table XV-V2-HLA-Aii11.l0mers-191P4D12B

Each peptide is a portion ofSEQ ID NO: 5; each start

position Is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

plus nine.

~t t L sbs eq e ne I scReIE2 G1QD-AKLPCLTY E:6:81

[3 QDALPCLYR] 21.08

1i :61LLY-RG5 SGEQ P6149~DI1I.nKLYRGDs 99-11[i]LI CLYRGDSGE j0.001

DAKLPCLYRG L0.00~

AKLPCLYRGD 000

Each peptide is a portion ofSEQ ID NO: 15; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for each

peptide is the start positionplus nine,

SStart S1 ubsequepce-IS-core]

[711 SQSEEPEGRI 0012

;7F71 DPRSQSEEPE IaOOOJ

j:]7F7 HHTRSQSE P000

TI~able XV-V9-HLA-A11O1-I lmers-191P4D2Bj

*Each peptIde is a portion ofSEQ ID NO: 19; each start

position Is specified, the lengthof peptide Is 10 amino acids,and the end position for each

peptide Is the start positionplus nine.

i 82 Ij TK RKK KJ 2.000]

ELE1L E LLLGLLK .209PI. .Th.IF CACFE FTK jja60]0

L lRELLAGBR[l 18

I-El SFT_ KRIKKL 100][27 JjyVFIYFYj 0.090

DI8EE 9!JLf [LLK 00

ff~F Q0.q90L7UIiJ1L LLFNF 110.054]

IF7 ES qFFT7R Fo0.040]11102 _GLLKVRPLqH 0.036]

1121RITNFFLF 10.0243111 F[YfYfYLP 1L04J

787, C CFSTKRK]Oq

Table XV-V9-HLA-Al 101.lomers-191P4D12B

Each peptide Is a portion ofSEQ ID NO: 19; each start

position is specified, the lengthof peptide Is 10 amino acids,and the end position for eachpeptide is the start position

plus nine.

f Stat Subsequencej JScore

F66.11,LVAGTLSVHH F10.02ii -4.1LR ILqUL.FI2:

[91JJ~FRFRILL[.-O1

29IVFFIYFYFYF 1F001211 JL~LRTFNffL ]E.12

[45 I FYVAQAGLE I .012J

F23] TFF LPF-P LVV]lE. 0128

16 I NFLFFFLPFIK 19081F33 lfYfYfFLE!J02

12QGVNSCDCE06

-1 FY.Yil0251 FPiL VVTFF g.711006]

I 79CLLLGLKV lt.096L J L~FL 19.006

F L ILRT 10.004

19 l FFINF LFPFLI 0.004]5II 7 j TSVHHAC 0.0045

F92 ]AFRFIQCLL .00

38 Fii EM. !l'I[9.031

00

00

LTable XV-Vg-HLA-AI 101-I Omers-1 91 P4D1 2B

Each peptide is a portion ofSEQ ID NO: 19; each start

position is specified, the lengthof peptide is 10 amino acids.

Iand the end position for eachIpeptide Is the start position

plus nine. jFstart L~usqjecescoref

13 ii YFYFYFFLEA 10.0021

(81 KKLKKAFRF [.oo21

D71 RELLAILL] 01001,[AQAGLELLSIOO1

1_26 jPLVVFFIYFY .0011

I. 7JjMQMPWE .00101j

F-7( ASLVAGTLSV 0t.i90i

F1. ~ni~ KKARF90JI.1

(11911 ERGYFqGIF 1!~I

F1, FMQMAPWEG I O~OOO

[LSSNPPAS. M00F10011 LLGLLKVRPLI1K000

581 SIFNPPA!SASLVJI0.000I(103 1LLV-RPL-QHQ (.000

!F2 121FGYF "P K670O1

r F7 KRKKLKK b7O00F17 J. FFLFFFL5PF.00

Table XV-V9-HLA-AI 101-0mers-19P4DW2B

Each peptide is a portion ofSEQ ID NO: 19; each start

position is specified, the lengthof peptide Is 10 amino As,and the end position for each

peptide is the start positionplus nine.

Startl Sfubsequen~e coe 9

us f[N CtcERYF 0.000(63y SASLVAGTLS (0.0001

7-T] MRRL-LAGII.I0.000J7~T] VA GLCII.009J

7~]LAs~~GI._)[0.0001

Table XV-VIO0-HLA-A1 101

Each peptide is a portion ofSEQ ID NO: 21; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

plus nine.,_,

E[IE:TpyYTLyY' L 0:P.[~7[ELTSDVTV F01]

I7L9 LG7TL9LYVP7.p00

LVGRCPAGELGT ILO.oOO

11 Table XV-V11-HLA-A11O1-10mers±91P412B

Each peptide is a portion ofSEQ ID NO: 23; each start

position is specified, the lengthof peptide is '10 amino acids,and the end position for each[peptide is the start positionj_ plus nine...

art71 SubsequenceF-77 RRVVPPPL 110:901

AO: 7i1 KPLPLy i 110.0041

Ff7* LRLRVVP .I02oo3 7 ALVMVPL 11.001F]LVMVPPLPS 110.0001

ITable XV-V12-HLA-A1 101-IL__0mers-191P4D128__Each peptide is a portion ofSEQ ID NO: 25; each start

position is specified, the lengthof peptide is 10 amino acids,

Iand the end position for eachpeptide is the start position

.plus nine. fLs 7aq Susquence JScore

10 CSj YSEtLTTVR.0081

IDTM] GCSYSTLT 10.0001

3 MEEEGCSY ~ooo

=5i1 LEEPEGCSYST 0.9OI

ITable XV-V13-HLA-,AlIO1-1[ 0mers-191P4D12B

Each peptide is a portion ofSEQ ID NO: 27; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for each

peptide is the start positionplus nine.

IF7LTIDVLA DP 7CE 0.002WLQpy.l-AfO2

F]DgWJl9-

00

00

Table XV-V1 3-HLA-A1101-I Omers-191 P4D12B

Each peptide is a portion ofSEQ ID NO: 27; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for each

peptide is the start positionP -plus nine.

[S~taRtJE Sbs quence I s- rel-TVDVLADPQI ,021

7T] DVLA PO GI0.000!

[7 DSQVTVDVLA!j0.000j

~J 6 VDL ADPQ S K l 0 00

r FTabe XV-V14-HLA-A11OIL_1 Omers-1 91 P40128IEach peptide is a portion of

SEQ ID NO: 29; each startposition Is specified, the lengthof peptide Is 10 amino acids,1and the end position for each

peptide is the start positionplus nine. __j

ItrjSubsequence- !LSoeE.57 NPPASASLVA.04Li. il UAVGT SV 1P011fT ]SNPPASASV o_ o7W] A SLVAGTL 119.0001LFi7IiI.SASLVAGTL 0.000I

L771LGSSNPPASA 1.00L7.ss~~Jj~pp I

S7]GSNPPASAS .77W] PPASASA 10.000]

FT7 PAALAGT .R990]

le~ XVI-VI.HLA-p,4..gmers-

Each peptide Is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide is 9 amino acids,and the end position for eachpeptide is the start position

-plus eight.I

Star.t Subsequence I Score

1501 IYINGRGHL30.0

111241. EYECR VS fP0990

~Table XVI-V1-HLA-A24-9mers-'I 191P4D12B jEach peptide is a portion of1SEQ ID NO: 3; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight.

rt ,,tSubsequence Score,

7I 485 Q KEELTT Li .0

Iio5RNLDGSL 12.07001

15 8 JI_tKYGLHYSPA _I 00~[i121 _RLRVLVPPLjI .E6 9J10 _q P I F.6470I

i 53621 CLVVVV'/L 8 '.00

I~5i~Y~Y~ 1L.42001141 AWLLL [T7200]

:F5'2 WLGQDAKL 6.600382j MITQKY E E L L6. '600

_R7J AGE GAqEl .I[633611200lR AAISEFIL.16L1

:12221TCWHGL.o

I'53 F 6.0-00'l j IETQITELLII6.00.I i11ALHSKYjLII 60001I2 I VTSEFHIiOOO00

[1111 GpEAWLLLL 1L6.o.1251LAEASVLL60 LO

ff7 AALLFC LL i l_5.76I

12811LNTLGk 4.800.-l

1111 EAWLLLLL. .800-o135iVIALFCL 49-FYI A-4.800

I261 TGRCPAGEL f7 4.400EMWGPEAWLI4.000 I

'12941

L Table XVI-V1 -HLA-A24-9mers-191 P40128

Each peptide is a portion ofSEQ 10 NO: 3; each start

position is specified, the lengthof peptide is 9 amino acids,and Ile end position for eachpeptide is the start position

pj lus eight.

Star Subsequence Scre

11 35!'[.SFQRLRLI400[211 ARlLDRD LL4.000

1? 9! HGREAML.! I4._0017411 EGA QELL 114.000

S 4~l1L~A 000

'1 7jL9M H F 0~IA LL2 .00

L5 45) D KPCF I2.000b 2] YSTF ALS 1 014951 KP TGNGYIL?:T090jL QlI LTLRN~

IPIL TVRE 11.650-1l~iILVVVVLMI1.001

WLLGEi O 01

11571 EGGL ~0.8641

Y12I AYGV~t EI F.750J

111 IFPAGSFqAJ 07501[I7LEFH LVIDI

361LFCLLVVVV 110.600]

3931 T RE NSR 0.6001

00

00

Table XVI-V1 .HLA-A24-9mers-I191 P4D1 2B

Each peptide is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight.

Star Subsequence Score

2371[ HILHSFL] i0:6001

53 LFYRGDS GEQ P I-50L301EFSRSQV 1 050

F195][SFKH§RSAA If 0.:500

L2.!~I SRMNGq Lj[ O. Oj[297 I[.qDTG FP P l 48250]1YRGLEDQIN1L 0.480

[384 1-KYEEELTL 7 0.480'

F?2i 1. R GLEqDQNvLW [o0.-457?341 [KQVDLVS AS .42

L3?8 LKA QqMTCqK 1ii .39 6-E I L9CPAGELETIA3 q_014[Y-LPLPLIEtO.300

E3].RfITHLHVS !Fi 0.280I58 SGEqqVGqyA! I. .252_j

F16 [LP LPLN 02.216.]110~ 1 "'--LNAJ0~~

IFI-01 FOPLC j 216-

I3T1LqpPPSYNVT I I[VTWALqQPAJF 6-Ti

LableXVINM}LAA 24 9mers-

Each peptide Is a portion ofSEQ ID NO: 5; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachipeptide is the start position

'I plus eight.[starjasubsequenceI IcreF][iGQDAKLP-CL IF00

Table XVl-V2-HLA-A24-9mers-191P4D12B

Each peptide is a portion ofSEQ ID NO: 5; each start

position is specified, the lengthof peptide is 9 amino acids,and the end position for eachpeptide is the start position

.pus eight.

lFatI Subseq uence I.P9.F yRI)SqQ ~0.550;FT LPCLYRGDS r0.100I

77 QDAKLPCLY 02

D711 K L m

lTable XVI-W7-HLA-A24-9mers-191 P4D12B_

Each peptide is a portion ofSEQ ID NO: 15; each start

iposition Is specified, the lengthIof peptide is 9 amino acids,and the end position for eachIpeptide is the start position

_plus eight FStartj .Subsequence J co q

D ][TD §R II 0.00217_TtDPSQ002

LI] TDRSSE j0-

[Table XVI-V9-HLA-A24-9nmers-IK 191P4D12B.. J-

Each peptide Is a portion ofSEQ ID NO: 19; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide Is the start position

plus eight..,-ar; ubsequence IiScore I

32 IYFYFYFFLU203

i, TFYFYFFLEM j 3a0001

Table XVI-V9-HLA-A24-9mers-19P4Di2B-

Each peptide is a portion ofSEQ I D NO: 19; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

.pus eight.

[Start Isubsequence 11 coe

I LF FLPP 24.000I

Fi FLFFFLPF

[T7 J F FlY 8I1.002i

'I'd FNFFLFFI1 5.000

[*5J P AFRFClqq1! 9.609]

F5 I SNPPASASL 1 7.200j

IL 6,1 FYFFLEM[I6.00

(1q~i[GL~L 6.000]LS![ FNFLPFF 57601

63 7 SAF SLVAGTL II 5.600 I

9:61F IQLLGL 480

Fk] R2 RIFNFLF IA:0

F 711 F S t qjI 3.000OI LRITFNffJ 2.880

23- 3 LPFPLW-FF280

I. il LKKFF 1=.400

176~~i SODOE YFI 2.000

Ii23iLYFQ(LFMQ? ij-t260 I

WT FFELEM--L0-0

Pl. 1 L F VVJI 0.90II75I1HYVAFlE _1_0.750_

00

00

~Table XVI-V9-HLA-A24-9mers-IL -191P4D12B

Each peptide is a portion of 1SEQ ID NO: 19; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide Is the start position

plus eight._

Fi11LRITFNFFL (0.600]FFFLPFPLV]OVFFIFYF 1(f0.600

IFz. II w KKK( F O.60

1122 G QGFQ1051

4 P LWFFIYFQ q 0.360

F11 RFPQQGF 10TF7 FPLVFFI II 0.252

Ij 7 iLHAE F ILPSfl ot7

,L769LGTILSYHHCA 0.210O I

[T201 ERGYFQG(IFF .o

Y. FIQLLLG 0.10

LF..ILFLE:MESHYV 1[.10i

L6.iU AsLVAGTL F(01561

I CERGqi YFI 1[ 0.144K

F I i FQGIM2 0120i 9

M09 FTLQHQGVNSC L9 1!_0.1

111'5 1NSCDCERGY '_0.12

I 56 SSNPAS F .100P- gSSNPS Fq[67ThoI

Fj?1LMQAAPWEGT [I 9:Iq7

EfYJT[[ HGVN SC DC -0 0

[Table XVI-V9-HLA-A24-9mers-

Each pepffde Is a portion ofSEQ ID NO: 19; each start

position Is specified, the lengthof peptide is 9 amino acids,

and the end position for each

Lpeptide is the start positionplus eight.. -1

[i26 f[~FMMPWF .1700

[7ATLSVHHC j[05.iqpLLGSSNP l[.100t

9I 1 FMQAWE [I06:6'IFT[F8 ST jL~ g.

[~Y1 FFEMEH [0.507,[Tqfl]!KVRPL-qHQG ]L .7i

K "L [0F.0722

I 106 _QHqGy [L 018FL4o]J~tMESHYVA jj0=.18

I LLSSNPPLO081 43JI SH AQAq jf.01-7

ffTljfGVNSCCR_ .07

Table XVI-VI 0-H LA-A24-S 9mers-1 91P4D1 2BEach peptide is a portion ofSEQ ID NO: 21; each start

position Is specified, the lengthIof peptide is 9 amino acids,

and the end position for eachpeptide Is the start position

plus eight.

IStart[ Subsequence 'IScorel

l77[Grso w.W 0.1681AGELGS~y 0.1501

!FT-F7] oLTDV :1.10

FTable XV1-V1O(-HLA-A24- 19mrs11PD2B J

Each peptide is a portion ofSEQ ID NO: 21; each start

position Is specified, the lengthof peptide is 9 amino acids,

and the end position for each

Ppeptide is the start positionplus eight.

LS!9rt]I Subsequence ji®cre

F iL EG YI JK.ooI

PA-GELG IjL0100

F 7_ ZL~I~ pI Iqk:: GL OL03

Table XVI-V 1-H LA-A24-9mers-1 91 P4D12B

Each peptide is a portion ofSEQ ID NO: 23; each start

position Is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide Is the start position

____plus eight.

St art( Subsequence I r

Y MVP1L 8[.000V_]MVfPPSL 17.2001

F ][RLRLRRVM .OI

E23 ][.LRLRVMP Fi

r_1[LRVMVPPLP ~0502]E7 LRRMVPP I[.02j

Table XVI-VI 2-HLA-A24- 19mers-1 91P401 2B

Each peptide is a portion ofSEQ 10 NO: 25; each start

position Is specified, the lengthof peptide Is 9 amino acids,

and the end position for eachpeptide Is the start position

p lu s e i g h t t.=tartI Subsequenc Scre

F7IP=EGCSYST [..o501

111111~ VMEPG7§7LCSYSTL t~O.12O[77 0.1

00

00

Table XVI-V1 2-HLA-A24-9mers-191 P4DI2B

Each peptide is a portion ofSEQ ID NO: 25; each start

position Is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide Is the start position

plus eight.

1. Start Jlbsquen.~c relEL L2~TLT II0.1001K-7 SPEG SY S 0 J.018

[77IEEPGSY P.018

Table XVI-V1 3-HLA-A24-9mers-191P4D12B i

Each peptide Is a portion ofSEQ ID NO: 27; each start

position is specified, the lengthofpep ie is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight.

IStr jI Sursquce I §;oReF iL D i0...20;

Zli LADPQEDS IO,0i12i

71111 PQy~j[p 01

9mers-19 1 .01 2 1

Each peptide is a portion of1SEQ 10 NO: 29; each start

position is specified, the lengthof peptide Is 9 amino acids,

and the end position for eachpeptide Is the start position

L- plus eight W[Subse quence [Scjr&

F 3J[NPPSS [.0

7Ti FK PASAS7LV [q[0.!5]0F 7711 FTPAS-LVkG-T] Fq.120

FT] GSPPS 0.1001FPASASLVA I0.010

PASASLVAG0.001~

FTable XVll-V1-HLA-A24-10mers-191P4D12B

Each peptide Is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

plsnine.

1Ir:I Subsequencej corej

1[33]RYHRRKAQJ 60.000 1

[TL42jRSQPEESV9Lj--.i0

KI'GVLSP J000

ifl705jR iPLDG

F[6][EQPPPP P L FK4 0j

I31FjC-FPU'LLVL I 7.200k

!I1q8.jAL GQGYLL 17.'200

Iji j~GPwu~~IK7.00GVIAALLFGCL .9200.

k~IEEGRYST I=.000]

[-2F =ITWsHPGLLI

2311 LQQRITILJ5.

!F3] FYRGDSGEQ 1 so]

I ~I[F~SRGL1 .0011249EAWYLLLLL1[4.800123 41F LERENSIRRL1L4.800

1YNWTRLDGP J4I LO 4.800

12351 RITHILVSF 4.800

Table XVII-V1-HLA-A24-

Each peptide is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide Is 10 amino acids,and the end position for eachpeptide is the start position

plus nine.

Start Su. bsequence 1 Scorej

9MWGPEAWLL 14.8001'12961 DTLG FPPE1II4.800_ILi56I GPALEEGQGLU[4.800

TqKEEEL 14.40011132 ?I TPAG SFQARLIDL4O1

261. .ITHILHVS7F.I401[2211 y§ LTVV -GLI 14.000

128 [IIRVSTFPAGSFI1 4.000

L134 [GSFQTR~ 4.000

[501MYNRGH 4. 000F EM GP AL 4118L..L .000

3~3Fl!;[qEEELTh L9. 0[E5 1g PGPA1L FA9.-11611 F LLL LLAIF L60 I~

47 61EIQMH .0

[IE2 I WGVMLLF J 2.000[E2 .9h!DQNLWHI I 1.800jF?239J[QRTtH 1.800

I4JI.LEQTELLJ1 'A

F3LG- Q 1.26.2I3 9P ILTTLTRENS!J1 2=01

I?!71IHGLLQDR 1. 200

1124 ]YERV STFP 1105

473l- =QDGIQA LQ8IWj01[ Q ??!THs 10.900113 6 RL R Vl F- o 76

00

00

[Table XVII-V1 -HLA-A24-l0rners-191PD2

Each peptide Is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide Is the start position

plus nine.

Ltrt Subsquence Sore

P24 FIR -S Q-VTV Dv Q FT .80027 SYNWTRLDG

(11 RRVLPPYI1O .720!

I[6 0] FO LL YV-VVV'J.7001F( 51-j FVRIE-TqTE jI

62j GREGAIVLKC 0.0

SWHIGREGAM 00

_201 EFSDQ I0.600

§.27 PPSY vTrR 0.600

F !AEMWGPEAWI'1 L 0.600VOAGEGAQEI

I 34KQDLVSAV! 0.504JSfLWHIGREGA I

L7 LRAGS [LJ0480

P2]SRSMNGQOP 0.480

[3 QEDSGKQVD1L43 NH EL 1.0 '4001

L29 YRVDGTLFIO.360

LI 9j[ sL YS vsF [0.3081

[;97]RVEQPPPR 0.300

[11RSMNGQPLT~ 0.3001

I~ D 28 1R ELT(.300-1

(41 PESGLRA [L0..

(43j RA PGGy 0.240

11123]K GEYECR V7STF *0.240 1

Table XVII-VI -HLA-A24-i0mers-191PD12B j

Each peptide Is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

__pus ne.

I LVPPSLN F-.2-6j

[274 T 0.P N O216

[Table XVII-V2-HLA-A24-1 Omers-1 911P4D1 28

IEach peptide is a portion ofSEQ ID NO: 5; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

plus nine.-[tatSubsequene] cr

[T1 LGQDAKLPCL] 7.200

[i~I KPCLRGDS 0.3001[f DKLPCLYJ 0.120

FLYRGDSGtq1 0.011

[7]LPLYRGDSGI .1

[T-]FPCLRGDSE([ 0.002

IF QDAKL-PCLY F0507,

Table XVII-V7-HLA-A24-1

IEach peptide is a portion ofSEQ ID NO: 15; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for each

peptide is the start position

plus nine._

;F~7_QEEPEGR A120

R-8 SE1 PEGR IFo.03077T T R9~E!41

F Table XVII-W7-HLA-A24-II l0mers-1191P412B jEach peptide Is a portion ofSEQ ID NO: 15; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for each

peptide is the start positionplus nine.

l.1i~siHD~i~Q1[O0 II 1 HHTDPRSQsJ0.0101( T T DPR S Q S j 0r o1_ 3 [HHTDTPRSQSE IToqoolI17IL! -Q EPEG l[0.ooppjFTabeXVV 9 -HLA-A2 4 j

1 Omers-1 91 P40128Each peptide is a portion ofSEQ ID NO: 19; each start

position Is specified, the lengthof peptide Is 10 amino acids,and the end position for each

peptide Is the start positionplsnine.

(Start I Subsequence- Pjcj(

IL 451 HYVAQAGLEL 330.0

1 F Q LL 1720 -'jID T7LNF!FFFL j320

I .Fl~T~YL118.000

16]NFFFLFI1.2.o

FLqR!FQLLI 11.200

LT.-YIyfY-FYF 1110o.0001[j].-GYFQGIFMQ 8.400j

5 IUL- ],F.200

M12]RITFNFFLFFIK[T80011811 FLFFFLPFPLJ(M.01

ESFTKRKKKL 9WGL RN L4.400I

119 1 ILLRITFNFF ]4.000

00

00

Table XVII-V9-HLA-A24-1 Omers-1 91 P4DI 2B

Each peptide is a portion ofSEQ ID NO: 19; each start

position Is specified, the lengthof peptide is 10 amino acids,and the end position for each

peptide Is the start positionI- plus nine.

[startlE Su bsequ e nce J LScre IL4-61.nA~qA LL ]J[,4.9*99Uoj L_LLKVPL I .0001

I E-V IL T!Yy IF 3.600

I.2FLPP LW FF][ =.600

[3 fj YFYffyFLkEM

Gfl 2.400

1118 fDCRGqFqGI F2.160!

W[ LL~ILLI ~2.10 01[i3i jf rNfFLFFF1200

3 i_LP~fLWFTFI l~.680 1

I KAFRFI .601jLF1iI2 YFQG Fq 09001

Las. YFYFFLEMES][ 0.660j

FLi][MLLAGILI 0.76-.o

r [Y[LFFLMESHY [.76

[36 f FFFLMESHILO=.5001

86 jj KKLKFRF 1 P.[711 ][LRITFNFFfj~.36O1

[~~Z~iIF KKKA I I ff60 I

j1105 IKVRPLQHQGVIIO28L77lI vHHCACE~sff I02406

1 -19J CERGFQG-Lf F[ 20SNPS-V[A0

[j-TT][QCLLLGLLKV ifoIl5.j53j1 ELLGSS',NP-PA1FO.1j50

7Table XVII-V9-HLA-A24-I1 Omers-1 91 P401 2B__

Each peptide is a portion ofSEQ ID NO: 19; Eac tr

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

F647LSLV GTLSYI0.-15O IFLLFE:-EtYA 1.0..150]I 2TLFQApW. G. 114591ri:2 LPV]

L1. 6 y R~9 1FO150

681 J]ALEHaA 0-14I~qA 24O- I.f)Y94 7iC

.YflYY1I0.120_1

WI] LLGLRT -0.120:'

55 1LGSSNPPASAj 510gp 0[114 IIVNSCDCERGYI 0.-100 I

[9 ii GNP=PASj 0.100]

[E3A.YGTS~ 0.100]LJIL GTLSVHHC F0- o1-0 0

F127 IRIMQMw?)G]LO.0831

.i~i LE0Yqql_.050 1

1oi][ILLKVRPL4o992t]][RGYFQGIFMQ 1L2.q20 I

ii9jCLLLGLLKVR FO 018F7 I VAQAGLELLG .0-O187I. 12 IqqYSCDCERLQ2

51 .L~ELI-GSSN.?j[ 0.015 I

26IPLVVFFIYFY 10.015'

F able XVI I-V9-HLA-A24-L....I9mrs-191 P4D1 28

Each peptide is a portion ofSEQ ID NO: 19; each startposition is specified, the lengthof peptide is 10 amino acids,and the end position for each

peptide is the start positionplus nine.

Dad[subsequencej1 Score I

F211 II KVIRLgHJ[0.1[l JkV L~v~ AcF E I 1 15 j

Table XVII-V1O-HLA-A24-110mers-191ND P4B -j

Each peptide is a portion ofSEQ ID NO: 21; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

plus nine..

FSt][f Subeq uen ce cr

[10] GTSK3V11-00

[7IFG LGTSDWV 0.1591

L=91[K9TS D V VTV V0.1091q[LALF LGTSDVVT fl

7 2 PAGELGTSDJ 0.01

F7]lE PAELGTqpVj =0.012LIT]19..CPAGELGT 0.01217 Ifp- T CRCPA GELG 0.0 101

Table XVII-V1 1-HLA-A24-lomers-191P4D12B

Each peptide is a portion ofSEQ ID NO: 23; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

plus nine.

1 Startj Suseunc__ o

8 VMVPPLPSL

F7-7LT-LRMVPPLJ 777.FW IFQALLRVMII-o..0

00

00

Table XVIl-V1 1-HLA-A24"l0mers-191P4D12B__

Each peptide is a portion ofSEQ ID NO: 23; each start

position is specified, the lengthof pepide is 10 amino acids,and the end position for eachpeptide is the start position

plus nine.

L__iiSubsequence. te[7i7 LVM VPP LN .0.2161

7Y] QRLRLRMVII.1 20

[FT7 RLRVPPLLP]0.0181

FF77 ILRVM VPPLPS] P0.9517__7 ,ARLRL RVMVPI{0:0.021

Table XVII-V12-HLA-A24-l0mers-191P4D1.2B.

Each peptide Is a portion ofSEQ ID NO: 25; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for each

peptide is the start positionplus nine..

ILta.1 l.Subsequence core

1111 sYTLTfvR~j[0.50O

111]EEPECSYSTT 1

SEEEGSY L.o181

=0 oLqSTLTTVR !R.121[7F L EGCSYSTLTjI. I

L Table XVII-VI 3-HLA-A24-110mers-1 91MP41283

Each peptide is a portion ofSEQ ID NO: 27; each start

position Is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

plus rne

[I strtj[ Su bseuenc e

I Table XVII-V1 3-HLA-A24-

Each peptide is a portion ofSEQ ID NO: 27; each start

position is specified, the lengthof peptide is 10 amino adds,and the end position for eachpeptide Is the start position

pius nine.

7T

W9LMLVP7P 0015

7~7[TDVLPD0QE 1 q t1

L Table XVI I-V1I4-HLA-A24-lomers-191P4D12B

Each peptide is a portion ofSEQ ID NO: 29; each start

Iposition Is specified, the lengthof peptide Is 10 amino acids,and the end position for eachpeptide is the start position

plus nine.

[-strtJLSubequence lScore

EN SSNP ASAS L 0. IT

~FZ3- PASN ASAST F0_1

I7CfLTA_As G y CIL

I Table XVII I-V -HLA-B7-9mers-191P4D12B

Each peptide is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide Is the start position

_plus eight.

Subsequencoe Ij

292 GVRVDGDTL]20.0

HQPPPPRNPL 00

IL -PDSL IFO.p226 LT9q.PAGE i 60.000

LISIL RRV=LVPPL Pl 9.929.

[L17 [GPEWLLLL 124.0001

LD.lI VVGVIMLL 12.0001

LV\KILL 12.0001

TfL7 2 9AQL 112.000,F7i1]1 DALLHSKYGL [11.L001

1E6LMLLqA -112.000J

13 LGSFY RLlI.0

11] _EMWGPEAWL IL6 992iIi45jLP PLPsL]I 600045_0]LTvREIETq:TJ] .000i222 1 TCWVSPGL 5-67660

[25]1 D SoVrVD vL .001287]GPLPSVRVJ4.000

I F~ICLVL I4.000E[1 IEWL .0iL260]1I.HIGREGAML II kLP0i41 0] L:ESVGLLPc00 I

741 EFQ4AL.±0 0 07FJI T~qKYEE L4.000

203 F3_00_051i[F2.7]5 F2.SNW J000]1322 1_SRDSqVTVII 2.000

AALCL I1.800 I

00

00

Table XVIII-V1-HLA-B7-9mers-191P4D12B

Each peptide is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight.

[Strt ubsequence 1 Score,[3ft MSRYHRRKA 11 ':oo

1331[ PAGSFQARL F 1.200]493 ,.AKPTGNGI 1[1.200

L1I AWILLLLL .036 ]LPVVTL IIoi4-3L EIETQTELL I 1.200L'iI PALEEGQL 1 .200F 7 j A\SVVWGVI 121.001F?249II SVRGLEDQN 1.1.999.!T74lIHRRKAQQM F .OO200j

ii EGRSYSTLT IFT0001

345 LVSASVVVV 111.0001S 1.000

j[YQVAWARVDA if 6oIi1[_PPRNPLDGS 1 0.6001I8ALLFCLL-W ;0.6001.17. APSVTWDTE [0F.6C0

501 IYINGRGHL 10.600151 PSLNPGPAL IL.6001

]CFYRGDSJ1E5

I439i EPEGRSYST 10.6001LsA~sVVVVGV I[ 609J

W9 SWVGVIA J~ 050O

L GV LFC 40.500 IASFTGRCPA j[ L450

i L CPAGELET.S i0.400j7i1 STLTTVREI 11 P0.0

GDTLGFPPL 110.400,

jl.3 QaoRIHIL jf0.400263 REGAMLKCL /10.400 1[28j WRLDGPL I0.400 1

39J LTLTRENSI .1L9A00;t~J HFVENGTL 0.400~

REIETOTIEL j 0.400[T3 j( QKYEEELTL 1 0.400!

1Table XVIII-VI -HLA-B7-9mers-191P4D12 B

Each peptide is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide Is the start position

puseiht.

Pt7q 1§y sejuqnce )I Score]302 IFPPLTTEHS i0..0023j THILHVSFL IL0400250 I VRGLEDQNL .400

GEGAELA .001a ~WGPEWLL- II OA9O

3371 EDSGKQVDL 0.4001Iflj.ILPSRVGj[ 0.300LT:iI GSVLLRNAV o1ij AVQADEGEY 0.300

MNGPLTCV 0~~F

B137II~FQAR~LRLRVI.3001

F7 ]WARVDAGEGIIO.300342 [QVDLVSASV 10.300

4q2 IISPGSGRAEE F300IiY1[ IRSMNGQPLTI 0.3001

211 VPSRSMNGQ [0.200

17][ NGQPLTCW FO.2opiFO. VIW 11020-0T.1]1 ETSDVVTW 1.v00

iil PPLNPGPALEEG LO.3PQTable XVIII-V2-HLA-B7-9me

191P4D12BEach peptide is a portion ofSEQ ID NO: 5; each start

position Is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight.

LtartI ubsequence liScorel?1 GQDAKLPCL [11ooi0

IFDL yLPLYi j0.600j

AKLPCLYR /I:9iS

[F]Jf CLYRGDSGE ]70117jiL LRGDSGEQ 0.010i L.D KLPCLYRGD 9j

WF7411 KLPPCIYRG 1.0031

Table XVI I-V2-HLAB79mers-191 P4D1 2B

Each peptide is a portion ofSEQ ID NO: 5; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight.

[start Subsequence score=2L QDAKLPCLY IL.021

[abe XVIII-V7HLA-B7-9mers-191 P4D1 2B

Each peptide is a portion ofSEQ ID NO: 15; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight.

Startl ISubsequence Scre

[7111 PRSQSEEP j.000

I71SSEEPEGR /101O

II LHHjDPRSQS J0005K HTDRSQE e.0031

FLIL SHHTDPRSQJ 0.001F PRSQSEEPE g0.000

Table XVlIkIV9iLA-B7-9mersI19D12B

Each peptide is a portion ofSEQ ID NO: 19; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight.

[tailSubsequncetll re

I6 ILA~LLi .0.000I2 1i FRFI9Q4L 112.000

L4iI VAQAGLELJI 12.000

I. 2J NPPASASLVI1 4.000[qJ FICLLLGL 4.000[iL IQCLLLGL!][4.00015s FNFFLFFFL] 4.q

00

00

[TablIe XV I I I-9-LA-B77-9mers-K. 191P4D12B jEach peptide is a portion ofSEQ ID NO: 19; each start

position is specified, the lengthof peptide Is 9 amino acids,

and the end position for eachpepide is the start position

plus eight.

KSar Su-§bsequence score

'i01 L-GLLKVRPL4.0F5'81 SNPPASASL F400]11IfRGYF-QGIM1.00

FK-VRPLQ HqG I[O. 500:

F 9Z!IF qPLQHqGVN [0.400

L[i 77LFTPFF Fj 00j

KLKKAFI I0.400 jL 1 SHVOAGL FT_00

TT171sF TKRKKL ff4o0 1L-.J.FVFF Y 0P.40071

FT IL IYTF7YFFFL Lo.4j0]RELGL 7( .40

Wi ICRGYF QGI ii .400F71 FFE CL 040

I111LF NFLEo40

[M71 LAGILRI 0.3001

f1 SLTSVL .301

FT1I LRELAL 0.120

E8[2L LQNS L 0S.100]659 [G TL_ [E2.OA0O

EOI lV H4j 1.9lMQqo.

FI =F HCC E 10071

Table XVIII-V9-HLA-B7-9m~ers-I___P4W2B

Each peptide is a portion ofSEQ ID NO: 19; each start

position Is specified, the lengthof peptide Is 9 amino acids,

and the end position for eachpeptide Is the start position

plus eight.

ItE~rjI Subseqence score

[7 t-.AG ILLR I TF I 009 0F flQPAGLELL W, 66]

E F1 SLVAGTL 0.06

TPFEjALELLGSS FO0060

WLLYT ATLVH IA( 50F7fl I-11AF JR C I

L L THR [9030[2]FYLPFPLWF 1 0.030]

[7T]IIEY!I CF J S F030 I55 LSNPPASJ0.2

21 LffLPF PL V!0.2

E2 iL RITFNFfFLIO01I7WiL 1T F=NF i020Li SCDCERGY J

fl ITFNF] a020F 13i M j q_9F ITYF-F-YFF-7L0

[iP GLLRPLQ 1. 0.015.]

Ai1 GFQP IF-l .1L281FMQMPWEG 0.1

I[ __LFFF F 0.01

F!iq.oi LLLVRP 0.1

Iip!.I LLKVRPLQHj 0.0

TbeXIIi-V9-HLA-B7-9mers-1191P4D12B

Each peptide Is a portion ofSEQ ID NO: 19; each start

position Is specified, the lengthof peptide Is 9 amino acids,

and the end position for eachpeptide Is the start position

plus eight.Stat Subsqec I

83JLTKRKKKLKK 010 190O LKKAFRFIQC 0L01 i

[L2]Ki MESH LAQAL 0.01 1L±]LS nAGILLR- 10.010

K-L o-io 1 n

[*IIL1I LGPP 11 0.010]

E1J±LnS-cDCERG .oLFIl]. SODGERGYF 1 =0.009]

F?17]IP I-FMAPWE][0.004]

LTable XVII-11-A-7.__9mers-191P4D12B__

Each peptide Is a portion ofSEQ ID NO: 23; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachpeptide is the start position

plus eight.

[1 rJt [ubsequence SIeF RLRVMVPL 0.000

M]?AIRLRIRYI3000W-80EPPLP.?L 6.000

ELK =VVPP .450

DII RLLRRVVPYD T !L W ARLRLRVMV', FT90 1

LD] LRYVVPLPJ i0001_

00

00

Table XVIiI-VI 2-HLA-B7-9rners-191P02

Each peptide is a portion ofSEQ ID NO: 25; each start

position is specified, the lengthof peptide is 9 amino acids,and the end position for eachpeptide is the start position

plus eight.

S Su bs e-qu en ce ISEPEGCSY~Ti 0. 600

9Li CSYSTLTTV IL0.200[Fl-7-T TJ 0,100

17L_ _UE 0.1001

tE99Y§11 0.040

Table XVI 114V13-HILA-B37-I9mers-191P4D12B JEach peptide is a portion ofSEQ ID NO: 27; each start

position is specified, the length 1of peptide is 9 amino acids,and the end position for eachpeptide is the start position

plus eight

fstart] S u bsequence] -score.)[qVTVDVLA II 0100

7~7IVLA PQED I .5

EyI qV TLDVLA7CI 0050]

17710 LVAPESL030_I

111yVT V 0.010EWDL Fq igL-G q

TalXII I ypyk HLA-B7I I[Ta _9mers-191P4D128 _1

Each peptide is a portion of7SQ ID NO: 29; each start

position is specified, the lengthof peptide is 9 amino acids,

and the end position for eachIpeptide is the start position

plus eight.

I ar~j ubsequ nce]Screj

Fk J L VL 7. F 2000I

FT able XVIII-14-HLA-B37-9mers-1 91P401 2B

Each pep tide is a portion ofSEQ ID NO: 29; each start

position is specified, the lengthof peptide is 9 amino acids,and the end position for eachpeptide is the start position

plus eight.

SatSubsequence IIScore

rT][NPPASASL II4.000j]ASASLVAGT]I030

§2NAS FF/A 0:

1 I*ALVGTLS 6~0.6

ASASLVAG E.03_j

ITable XIX-VI-HLA-B7-1 Omers-I

Each peptide is a portion of1SEQ ID NO: each start

position Is specified, the lengthof peptide Is '10 amino acids,and the end position for each

peptide Is the start positionplus nine.

K1t![ usauencj Sc ore

1249] SVRGEDQI 0o

I DPRSQPE2SV060.00

IEPERST 24.O00035itVVVV GFMA.i 20.0003501 WVGV I 0WJ

FL[q1. GVIANjLFCL =4666600

1 .'I1 EAW YLLLLL L I1@:.9

I

IF79]LA~LLHSKYG9L]I. o000

Table _XIX-VI -HLA-B7-1 Omers-I191P4D12B

EIach 'peptid is a portion ofSEQ ID NO: 3; each start

position Is specified, the lengthof peptide is 10 amino acids,and the end position for each

peptide is the start positionplus nine.

F 99] EQPPPPRNPL_ L-00F1 3781- QARLRLRVLV 1 9.000

19 LY~NniL8.000PT?7]HPLQQ 1 i[00i

1_I~qG 1YL][.00025 FTRPn I 09

LTfIAMWGPEAWL 5. 4001

14021 ]RSQPEESVGL 'F4 4000]

F IL1. EP9Y 14.000

F 8 1 WGPEAWL LJL.095II 83lQiELTLi 4.000]

L7JL9~~Y~lI4.70001 E ITILV FL ±69i

91iSRVGT 4.0001

10 WGPEAWLLLL I 4.0001 2jqLIWsHPGL(L 4.000~SPSRSMNGQPLI.00

I280. Y T RLDP l40001M21 I LTCWVSHPGL 1 4.0001

IMALLFCLL l~IFQTQKYEE! _LJ 4.000

[T6]5 IT D 4TV

[i~fl ALEGQGLL60 COI~ F 1? AEAE _L360_0

[E7 )L\A9IIq 30001176I~PAPvTDT I2.oool

LQQHILv 1.200

SAVVGj[.200

11291]F IREGA MLKC F1.70001

00

00

Table _XIX-V1-H1L'-B7-1 Omers-]19PD1 2B

IEach peptide Is a portion ofSEQ ID NO: 3; each start

position is specified, the lengthof peptide Is 10 amino acids,and the end position for each

peptide Is the start positionplus nine.

Stat Suseue c o jSoe]397] SIRHHT [i00oo

61_I[QVGQVAWYI1.00441EGRSYSTLTT 100

189 jHVSPAYEGRV lL.. 2JL~2j[TOLLVVVWLM_11SY1.000]

:133 PLTTEHSG 9~.1P] 1~d QPY9Et:GLRF LO60 0

I IMLLCLLV ]0.600]358___ ALLFCLLVVV. 0.600

I4 75FVQNTRA 0~.500TVREIETQTE 10.500!

292 GVRDGDTG [0.500.

FT2[LASFTGRCPA I 9A 5 9REIETQTELL]L70400]

3241 RDSQVTVDVL 0o.40L7o: VOYAqGGAEL IL[O0IjJI APLSLG!_EMW 0.4 0 0

r? ILT GEGM T i 0.400.

F. LGEGAQELALL 0.400[Tj~jKPTGNGN 0.400J

F i1 LRAEGHPIDSL I0407 MWGPEAWLLL 10400

483 NH FVQQENGTL 1 0.40l l* rLLQDQRIWTH I

LRLRVLVPPL I .401

]4~jYSTLTTVREI .0.4001JF342, QVDLVSASVV LO.300

2SMNGQPLTCVj]q0.307P,T, D1 DGEGAQELA!Io0302141 RSMNGQPLTCl 0.300

IASVWVVGVIA 030 01I lDGSVLLRNAV ,1 0.300

Table XIX-VI-HLA-87-l0mers-191 P4DI 28

Each peptide is a portion ofSEQ ID NO: 3; each start

position Is specified, the lengthof peptide is 10 amino acids,and the end position for each

peptide is the start positionplus nine.

[Sart] 1. uj un e][Score

L1679 [ASqAEGSP ]Fo0.300][~fl[~PAEGRVEQ L:300

UL ff AE SPA P [0 2 0

FSRSQT LO.200i

Table XIX-2-H11A-B37-1 Omers-191 P4D128

Eh peptide is a portion ofSEQ ID NO: 5; each start

position is specified, the lengthof peptide is 10 amino acds,and the end position for eachpeptide is the start position

.plus nine.

[[cixi~q~qG][.200j

ET IL PLYRG L2 0.030D 10.039]

AKLLCLYRG I=.003]I[T]QDALPLR [2a002J

PAC LRSG 0.001

ITable -V47-H11A-B37-10mers!191 P4D1 28 I

Each peptide is a portion of]SEQ ID NO: 15; each start

position Is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

plusrfnin.'[start[SubsE FnjScorej

171[PRSQSE EEI200

~Tble XIX-W7-HLA-B7-10mers.191P4128J

Each peptide is a portion ofSEQ 1D NO: 15; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

plusnie

Fs-tartl fi ubsequence I[re]I

FA- SQSEPEGRS 0.030][fRQSEEPEGR fW1o

HSHTDRSQS.005]

5 TDI!PRSQSEPI 0.001

[[]PSSEEPEG. L7 P~9

Tble XIX-V9-HLA-B7-10 Orers-]191P4D128

Each peptide Is a portion of1SEQ ID NO: 19; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide Is the start position

plus nine.

IEtrtL sq uen ceJ =co]

46 IWA QAGlELQ 20.000I ii. AFRF i..9DLF MlkJ i.000

F6 jAS±SLAGTL j[ .O OO[105ERIKPLQHQGY 1000

L1 qPJWL~LLK~fI 4.000]

80K ESFTKRKKKL [00j

lAF5'_S[fQGLL 4.000

I. 9 ,NPPASASLVA [L0

L64T I[AkA~SJ 0. ITFFJ[ LAGVNSI 0. 400]

114~ L iiFF LFFF I] .400

00

00

Table XIX-V9-HLA-B7-1 Omers--19IP4D12B_ _J

Each peptide is a portion ofSEQ ID NO: 19; each start

position Is specified, the lengthof peptide Is 10 amino acids,and the end position for eachpeptide Is the start position

plus nine.[SrtjI Ln? Suseue c L~oreI

[_FPWFFIYFJIF0401_RHQCLLLGL ][000

1.TU[ [YVAqAGLEq LO40I[ KKFFIqQCl 0.4001I

I[~2VAGTSVHHIFO 300

IFI-.994 6LLLGLKV-J[ 0.200]8 1l SNPPASASLV F020

11281fMQAPWEGTIF .1501FL iLGSSNPPASA1 0.150j

'p 118]LqCERGYFQGI11F-.i20JI

IWFFIYYFYIL.100j IELLGSSPPA 1.100

11_12 ]V CACFES j 0100I -i1]T!R KKA Iol

2 jjLyLfF!YFI0.1:9PLU290jI EGYFQGFMJ 0 100

L11._AGILLRIT1F ]i 0.0901

[ilL AGB..LITFN 0.060]AGE-LLGSN 0.060

[T j1L%ELL§§[ FO.6-

AQAGLLLGJ0.040

56 GSNPSCDEGY 0P030

Li 77IACFESFTKRK 110.030

Table XIX-V-HLA-B7-lomersj191P4D12B Each peptide is a portion ofSEQ ID NO: 19; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for each

peptide is the start positionplus nine.

Sube unceScore

T9 ]I FLEM ESHY VA I 0.030 I]

F- I -LP0.LF 020

[iij 9ERGYfqqIW L2O I

F.jT5ILQqlIFM9AEW 0.0201rK7]Es-A4HI A0-Ln

GUIITFNF.] .1 2[Ifl21LTFNFLFF T .02.01

[11]LYTNCFLFFFJ( 0.020]LIFFLP FPL .07201

F~~~11_1 KLKFI 0.1jiOB VSOIL.0 0]

IW IQLLLLKVI 0.0157

L8U I LKK jlql90'5jF11[LLVPLQHQVS I 0.010

~iF-8-9 -1 l0.010

L065 L VATSH 0.010

L.i LLLLLVi0.010

FIo-91 I LQHQqVN.ScDI *o5oqi1-0Q1 GVN ScDC!L0.010oJ

IFLF .1L H YCE1If 0.010!

F. D26[9!!1QA V EI aoio I

[T E LFGF0~ 0010112 IFq!EMQ P~ 0.10

T~able XIX-V9-HLA-B7-1 Omers-191 F4D12B- j

Each peptide is a portion ofSEQ ID NO: 19; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

plus nine.

fft7ad I Subsequ-ec Scr~e

.7 jfCCFEST 010 IF 112JLQGVNSCDCE FOO-070

L _hI FLPFPLV 0,003]F12LRWIIq~ IFM MPW 0I-03 I40O I MEH.YYAQ ED 3

F i7 iCLSDERYF1FIaOo3

IFTable XIX-V1 0-HLA-7-]I1 0mers-191P4D128

Each peptide is a portion ofSEQ ID NO: 21; each start

Iposition is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

plus nine.[Start &!se quencel Scre

FLLT -SD 0.2001

E7]KTPAGLELG .100IGEL9TSPYIA 1

M RCLAGELGT [o

Table XIX-V1 1 -HLA-B7-L 0mes11~P1BEach peptide is a portion ofSEQ ID NO: 23; each start

position is specified, the lengthof peptide is 10 amino acids,

and the end position for eachpepti'de is the start position

plus nine.

F~aJ Subsequenc Score

LRVMVPLPSL90.00LiF-9]-2___0.99

00

00

Table XIX-V1 1 -HLA-B37-1 0mers-191P4D12B3

Each peptide is a portion ofSEQ ID NO: 23; each start

position is specified, the lengthof peptide Is 10 amino acids,and the end position for eachIpeptide is the start position

pls_--e

I start Subsequence IScorel

1_T1 FQ RVM 1.00

IELLPR vMPPL -1

K M-_-LRmvmvPPLP LO.io

D 71[MVPPL PSLN P 10.075

FflLLRVMVPPL]F [0.03

Tabl XI-VI2HLA.B7-I1 10mers-191P4D12B

Each peptide is a portion ofSEQ ID NO: 25; each start

position is specified, the lengthof peptide is 10 amino acids,

Iand the end position for eachpeptide is the start position

plus nine.

[start]1 Subsequence [Icorej

6_ EPGCSYSTLJ200

][CSVMS EPEG 1101 1..i ifGCSYSTLTT 0.200

[IJIVM§EEPEGCS F[0.030][fEEPGCSYST 10.010]

I.i7K. ILSySTLTTI J90.1.7LMSEPEGCSY Fo.oo6

SEEPEGCSYSII j

[Table XIX-V13-HLA-B7- I]0mers-191P4D12B

Each peptide is a portion ofSEQ ID NO: 27; each start

position Is specified, the lengthof peptide is 10 amino acids,and the end position for eachpeptide is the start position

plu nine.

IIS.~.tII Suseque c lcorel

jDVLADPQEDS 0.o150]

[T]I TVDVLADPQE 110.015j

Y VLAD DS .01

1 ijAjyDPQEDSG LO03

WI. VDVLADPQED R oJj-- 01

[Table XIX-VI 4-HLA-B7-l0mers-1 91 P4D12BJ

Each peptide is a portion ofSEQ ID NO: 29; each start

position is specified, the lengthof peptide is 10 amino acids,and the end position for each

p eptide is the start positionplus nine.

[LStart Subsquen [j cre

1[7 ASASLVAGTL 112d00SSN3 PPASASL '4.0 00

Ki-i [ESL VATLSV I0.600IF71]1 NPPA-SASLV 1LO-01!IT]IL9.SNPPASA FL1 501F~jI] -YAGTLS I0.060

Table XX-VI -HLA-B3501 -9mers-191P4D1 2B

Each peptide Is a portion of SEQID NO: 3; each start position Is

specified, the length of peptide Is9 amino acids, and the end

position for each peptide is thestart position plus eight.

iftftFu en -F r

I 78 AQQMVTqKYI1.00MM I RSAAVTSEF ][1o9-ooo

TbeXX-V1-HLA-B3501 -9mers-I191P4D12BJ

Each peptide Is a portion of SEQID NO: 3; each start position is

specified, the length of peptide is9 amino acids, and the end

position for each peptide is thestart position plus eight

su bsequei~ne] L ?7 KFT 81i7 P R Lg-.00-0L5iLRKPTGNGl oo

LA22IL~.~9ulYI 6000

L1j,]RLRVLVPPL L6.000I

71 J[DD EGA-EL I 6.I

[135 GSFQARLR L 5.0F0

4.00;

L287] GPPSV J 4.00L~il AQADGEY LO 3.026 IITGIRCPAGELI 3.000J

L2 I.A VTSEFHJ .0

1 I =QNLW I3.00029 I AE LES [L--00 0

13 EAL LLLLL 3.00pj356

D77 ILIMNHFJ 3.000]1=7 F~Jgs§PWsvrw LD=-566

FA-II VVV-VLM SRYIIZOOO IL75IILqPs-YNW]Lo00

li7 J1. 2.000. 1

Liiilj WGPEAWL 2 000L1.?F-PL-=H 91-~F 00K1

Ezz T' Fj Y qZR 0 zo

00

00

T able XX.Vl-HLA-B3501.9mers-1

Each peptide is a portion of SEQID NO: 3; each start position Is

specified, tihe length of peptide is9 amino acids, and the end

position for each peptide is thestart position plus eight._

StartI Subsequence Sco reLF44.]ItRSYSTLTTVI WOO0[-419-1EGHPDSL 15800 1

t6 il TD WL R1500

L3:1 J[qSR YHRRKAI 1.5001

F.L4iw~~ II E19 I foLIYIIL-LLLlLA F I1.0F P M F l 7o6 6

EjlF2. TQKYEEELJ]1.900]

=L6 2L Ep OK~

Li1~ LS j1.90F-L4-1LAwi:VID _[T1.o

~~LiF 1.ooo

'U38J D[SG Q VLj[F. 000C

L 2 iL IjHV 1. 0

531 EFLISSC~J FO.75

3 57 AALLF CLLV .11 0.6*00

LTable XX-V1 -HLA-B3501-9mers-1191P4D12B

Each peptide is a portion of SEQ1ID NO: 3; each start position is

specified, the length of peptide is9 amino acids, and the end

position for each peptide is thestart position plus eight

FL-tiI FSubsequence1 Scre

4 F J RIFEEG IO6039 IL SYKQ. IL0.600 I

Fi450]F PPVRNPLDGSQT- 0.600

F 72 T F0:600 1

GQPSN I0.500_19! [I ILQC 9.[I7 Kf.-r§i 1q07

=83 jj TQKEELT =L.520

I =.400~iF1~'

1 35 I E TVVL 0.400

Trable XXV2H A-3309mers-]

Each peptide is a portion of SEQID NO: 5; each start position is

specified, the length of peptide is9 amino acids, and the end

position for each peptide is thes__tartpositonplus eight.'

LPCLYRGS 2 .00

7F2GDA LPCL 0.3007O

jFF-KPCL 71 09

W I4 RC-LYRGG 0.01

Z-ZLJtCLRGj Loi

L able XX-W-HLA-B3501 -9mesI 91P4D12B

Each peptide is a portion of SEQID NO: 15; each start position isspecified, the length of peptide Is

9 amino acids, and the endposition for each peptide is the

start position plus eight.F t rPi S ubs eq u-en cejScr

Ii 7oDSQSEEPL=.6001FL771 _q9EEEI j .1 50 1Fi77KCLS~tGRI 0.030F7 71FrIffDPRSQS 0.0201

177 IH-I T PRSq IL7T 2

[Table XX-V9-HLA-83501 -9mers-1191 P4D12B

IEach peptide Is a portion of SEQID NO: 19; each start position isspecified, the length of peptide is

9 amino acids, and the endposition for each peptide is theI start position plus eight.

'7§tartliubseuen~i cr

I 0

Lj [iVP=CER=Gy1 20.000] 6-[TJITKAR=FIQCL 1I: .ooo][if jr[LYVHHCACF 5 .OO1OD7 1LII NPASASLV 4.00

UL11[ RGYFqa~fy ][4.00]F-F I[ _LTf NFFJ L.-=.000IfrLl LVAGL 3.000

1FiI KLKKAFRFI 2400OJIFFIYFYI 2.000

F [hITNF FL 1FlxY-KQ. GL 1O00O

F J FNFFFFL] FI.200--]

7j[ AGU=RITF [1L1.oOdPE~ILPFPL-NF ]I.00

L~i!.lLm~.IL Two0L 11 GLLqRPLjII.' -0 00j.~LI f1YXY± f 1I791 q

00

00

Table XX-V9-HL-A-B3501.gmers.IP4DI2B

Each peptide IS a portion of SEQ1I) NO: 19; each start. position isspecified, the length of peptide is

9 amino acids, and the endposition for each peptide is the

start position plus eight.I~J Suseqencej Score

I..-jI SNPPA SASL 1.00012!VVFFIYFY .000

ILLRITFNF 1 .000J13iJ ITFNFFLFF .19 I

96 ICLLLGLL F-1 6-6.85 1 RK tKKKAF f .600

E57]jj GFMQPW I=SA 0.500

I62t ASASLVAGT050

L6 4]...A.S-AGTLS! (561 GSSNPPASE 0. 0-

SQAGLELLGS 0450 Il

F LLAGLLRI 01]P 4 00L' MES:Hy.JL0.400J

2 Z AfRFIQCLL L 300L A1.j LLRIT 07.=300

DO MRRLAIJ 0.240

L P[ ASASLVAJ 0 .200

98 CLLLK 0.20034I FYFYFFLE E.O~OoiLVAGTL SijL 20=0

AGLELLGSSLl0[297 VFFIYFYFY L o oo-1191LCERGYFJI 0o

Lvi] TLSVHHCAc 0100

ll HQGVNSCDC .0FF IYFY F

11i. LRITFNFFL 010LGSSNPpA P A 0

32 IYFYFYFFL 00

I26! PLVVFFIYF 0.100

;FTT.b1~eXX-V9-HLAB3501-9rers-191 P4DI2B

Each -peptide Tis a portion of FSEQID NO: 19; each start position is

specified, the length of peptide is9 amino acids, and the end

posiion for each peptide Is the

,sar poito plus eight.[Sta Subse Serce

F1- TFNFFFLFF F 0 LIo I1447PSHAYVY H jG 0.00

109l TLSH CA~?9! [..100.

TT] FFLFFFLPF 0~j.io00

1[11I4] QGIFM~ 0100?74 Z41.t ACFESF1 ~o

7 HCACFEFff]F -090.[120J FEGYFQGF 0.100--

68! AGTLSVHHC o,0129 1MWEGTI .100j

100__fL] gL SHYV .090!

j[.84_IL KK-Li-KK 00-1105.! [TYRP9HC2 0.060

WIRRELLAGIL .060SjESFTKRKKK 0.05043ESHYVAQAG L. 050

If6 7lCACFESFTKI 0.045

[-C2 FTKRK'K-KLK 0.0p30

51 GLELLGSSN. 30~I 90j[ KKAFRFIQCJ[02L?.9.JLFLPFPLVJ0.2[Tl LEMESHYVA ~2_

I16 VRPLQHQGv L 0 2

1I114JVN-Lc cER~L01

I x 1 02[

EA JT72 =~HFj 01

18 FLFLFFFLPFP 1[0.010I 2 5_QGIFMQAAp II0.-010-1

TbeXX-V9-HLA-B3501.9mers.II Tbl 19IP4Di2BEach peptide is a portion of SEQI SD NO: 1; each start position is

specified, the lngt of peptide is9 amino acids, and the end

Position for each peptide is thestart position plus eight.

Ia r SubsequenceLco 197 ii CLLLGLLK 0.010J

'I1 2HKLU yRPLE1S 0010

ITable XXVOHL-30 19P4DI 2B

IDNO: 21; each start position is

speifid, helength of peptide Is9 amino acids, and the end

position for each peptide is thestart Positionjplus eight.

OStarti Subsequen~ce Score7FiCPAGELGTS

GTSDVVV L .400IsjfLGTSDVVA y]0.300j

RCPAELGT 0.200

57~ AGELGTSDV 6tLTSDW7I 0.020

WL~~~i~p j .ooJIGRCPAGELG0. 1

Table XX-V11-HIA-B33501.IF 9mers-191P4D128

FEach peptide is a portion of SEQID NO: 23; each start position Is

*specified, the length of peptide isamino acids, and the end

Position for each peptIde Is theStart Position DIus eloht-

00

00

Table XX-V1 1-HLA-B3501-9mers-191P4D12B j.

Each peptide is a portion of SEQID NO: 23; each start position isLspecified, the length of peptide is

9 amino acids, and the endposition for each peptide Is the

sart psition plus eight.,FI. jj[Sibsequeflcell ScreI

651 FLLRYVYVPPUF 0.001

Table XX-V12-HLA-B3501-9mers-191 P4D1 28LEach peptide is a portion of SEQ

ID NO: 25; each start position isspecified, the length of peptide is

9 amino acids, and the endposition for each peptide is the

start position plus eight-

L7CLTOmmd 11-0-i-

F~fl~.SEEPE CS 0.0

0.100

7T][EPEGCSYSI 0.020

LTable XX-V1 3-HLA-B3501-9mers-1 91 P4D12B

Each peptide is a portion of SEQID NO: 27; each start position isspecified, the length of peptide is

9 amino acids, and the endposition for each peptide is the

start position plus eight.

Liii SQVTVDVL 0100

'F Y8-L pPFR pSG [9.q jf7YIILIYDLADPQI 0.03-

91- qK F-.

I Table XX-V14-HLA-B3501-9rers-191P41281Each peptide is a portion of SEQID NO: 29; each start position Isspecified, the length of peptide Is

9 amino acids, and the endposition for each peptide is the

start position plus eight.IF Susequence i~~

4]~SV~T. F.000 I7T] SNASL-ASL I TP q

2 0.500

ElF SSPPASA Tgso_1 5 ]AASLVA L.201

PA-LA 1 03

Table XXI-V1-HLA-83501-I Omers-1 91 P401 2B

Each peptide is a portion of SEQ]ID NO: 3; each start position is

specified, the length of peptide is10 amino acids, and the end

position for each peptide is thestart position plus nine.

STart I Subsequence Score

F!9I[ R AKPTGNGIY 3.6.000

Table XXI-Vl-HLA-B3501-1omers-191P4D12BI

Each peptide is a portion of SEQID NO: 3; each start position is

specified, the length of peptide is10 amino acids, and the end

position for each peptide Is thestart position plus nine.

!a~iL eLun-ce 11[Fj3 L~I 3.000

201

[5L vvv SYJ 2.000F276 IPPPSYNWTIRL 2.000

I?]IRVSTFPAGS _F-ZOO1

FT,1_ ET-sDRvT-WL I 100E62] _LLVVVVLM][2.000LIN ]THLHVSF QWO

[144 RVLVPPLPSL 12.0.00[9J STLTFVREI.j[

10-q~ [WGPEAWLLL j 2.T009j

L§ iljAST.IL9PP U 9.7. RNPLDGSVLL Di2.000

24]j FLAEASVRGL .000

IIVRVDGDTL Lf.500.F192 jSSRSFKHSRSj 1.500[1 21_SRMNG PJ1.600I7 kI EMWGPEAWLL TT99

[j426 ILKDNSSCSV 1 1.200

141Ij QPEESVGLRA 120

1.1.03I[ PPRNPLDGSVJ 1.200

LjI..§Y VVVGVI L9.[Wfl[DQDEGIKQAMJ[1.200 I

IT1___LT !rHiHVSFL1 [1.000 1flj UTCSHPGL_1LI9q2i

[L??zFI jPGLLJul -OK0Fjz]II CPGELi 1F.000

VSASWW-VGV IL1999-LPY. 1[ DSGEQVGQVA 111.000FTI 94Jj RSFHSRS AAI jI7000 KM34! I..§SMNGQPLTC ILT.00

1581 qmi QMTQY- EE J[ i o

132 GPALGQ Lj 2i 0.0001

[4091 RSQPEESVGL j 15.000]L4O7LDltRSqPEESyjI12. 000 IFT] L i 10.00o0 I

F1 6]LjI HPGLLR 9!.000.J

'j 32 TRENSIRRL 1L.000

383 Q-K(EEaLTli 4500

F[2 PSVTWDTV. 4.000KFT5EGNGIYIN ',L4.00J

[T7Lf] LSEGQPPPSY~j L.0P..-:1_9 L LtKY9 7113.000

00

00

Table XXI-V1-HLA-B3501-LPmrs-l91P4D12BEach peptide is a portion of SEQID NO: 3; each start position is

specified, the length of peptide isamino acids, and the end

position for each peptide is thestart position plus nine.

[ar]l _Subsequence. Sore,

F375[ VIAALLFCLL F157000I 35-JL WGVqIAL 1_1.0,I 352 1_ WGVIAALLF D~:00.I

-L .VVIAL_ 1.T7p

1L~zi SNEfSSRD S- .1.000 .1[501GIYlNGRGHL]I 1.000

E,,L LLLLLASF iOq9J579 i qffPPRNPL 1 .1.000L 41ylWG1DAKL .'=00o

[Fi 1Ij AGSFQARLRL i'1.00GIKQAMNHFjEOO

'12i[FSSRDS Q\1V 1A.000lL1_ AVSEFHL-V- LO.900i

r 7]LWRYDAGEGA .00j

K-~QLVA..1 0.800 1

L~9ILSCTAES~j[ .750j1. iiDAGGQ I 0609j5[2331 V 0QIHLY[.60 _1

F1LP GQ91-Tl 0.600

L!561[ jAALLFCLLV j.09]

I 2 [HDsLKDNSS .60 L-O30911 HSGIYVCHV I[0.50 FO

28J[ AVRGLEDQN IF 0500]

1 74 !EGSAVTW I 0.500425 jjDSLKDNSSOS I .02013811 DSGKQV0DLVS d-O:0:1jlj 71 JI EGQPPPSYNW0.500[T7 GAEMWGPEA i0.0

Table XXI..VI -HLA-B3501 l0mers-191 402

Each peptide Is a portion of SEQID NO: 3; each start position Is

specified, the length of peptide Is10 amino acids, and the end

position for each peptide is thestart position plus nine. J

Start, Subequnce i 339i52!9Y ]'FA0.45 0

j INPLDGSYL~LR P.RKAQQM 91TQKY0.400.]

452][_REIETQT1ELL ]f 0.400389 D 1LTLTR ENSI

Table XXI-V2-HLA-B3501-1j1iners-i 91P401 2B

Each peptide Is a portion of SEQID NO: 5; each start position is

specified, the length of peptide is10 amino acids, and the end

position for each peptide Is the__start position plus nine.Strt Sbsequence T] LGDAKLPC L F52000-]

711 LPLYGDSG1 020]

]I DAKL-PGLYREj[ 0.090

7]CLYRGDSGEQ I 0. 0151

711111 CLYRS jI01

10.00-11

Table XXI-W7-HLA-B3501 -Ilomers:91P4D12Bj

Each peptide is a portion of SEQID NO: 15; each start position is

specified, the length of peptide is10 amino acids, and the end

position for each peptide Is thestart position plus nine.

[arj ~~sqecjscore

FEPRQSEPEL q-i.WLJ. EEPEGRS 1I0.200][11-]_RSQSEEPE9R]ff. 0J

HSHTDRSQ[ 75]

[Table XXI--HLA-3501-K I mers-191P4012B

Each peptide is a portion of SEQID NO: 15; each start position isspecified, the length of peptide is

10 amino acids, and the endposition for each peptide is the

start position plus nine.[stiart ISubsequence jco9e]4i HTDPRSQsE il 0.003

[7ITDPRSQSEEP I0.001L171711 PRQSEEPE9_JI aooOJ

Table XXI-V9-HLA-83501-

L 0mers-191P34D12B Each peptide is a portion of SEQID NO: 19; each start position isspecified, the length of peptide is

10 amino acids, and the endposition for each peptide is the

start position plus nine.

I~ .r lrE eI!~p

[.7i SNPPASASL J' 5.000

I L~9 .T-'LI .6?L NI!AQT..L 5.000

I IPLIRPLQHQGVNS I 4.000

[UIaLGILLITF- 000Li LITFNFFLJ .oooJ

[2Ki I[2_ I

[LU_[Y§CD .000105LK LQQ 1.2000

L~iL.AYA5-0 -0 1.

M Ij. fLffFLPFPL j[.000[1p 1 _L !KVPL LL99P J

[1171LRITFN..l 1. T000]I ~~JI.2 TT9b- -1 0

00

00

Table XXI-V9-HLA-B3501-10mers-191P4D1Bj

Each peptide is a portion of SEQID NO: 19; each start position isspecified, the length of peptide is

amino acids, and the endposition for each peptide is the

.start position pus. nine. _jIS~ttI .Subequece ScreJ

L~i.FIYFYFYF 0~

27 3 LVVLFFIYFYF 100

LPFLVVFF [1.000

I 86 KKLKKFRF .600-,

L125L~GFMQMWJI0.5001

[T LLGLR 0.400.JII1[:19]. CERGYFOGIF 0.300'

S.ASLVAGTLK][ 0.300

F~i _AFRFlqClL IL I49 1qAGLELLGSS I -Too0

l I ERGYFqGIF MJ .200

F58 S- Np-PPAsAsLVJ L[F2i[TO ,I KKAFFQCL]E.200 j[33] IYTIXLfM1I .200

F506 AGLELLGs SNJI 0200f

F26 [P.LVVfflYFYJ_0.200

[T7 FjFLMEtl-IY F___2.9[~ji.._RfIqCLLLGL COO.20

lAB jAQGLELLGS 1 0.150

[21J[FLPFPVVF 1.1001

Lf019 _Iff!YFYFYFF F- 910-0-

F §Y JI f SVHCE .100,I LGSSNPPS _q.10f169 TLSVHHCAC F0.1001

451 HVAQALELJ 0.1001

16 jFNFFLFFFLPF o io

I 2 NFFPEG 0j 0

AGTLSqj VHHCA I 9t92J

I Tabe XX-V9-LA-B33501 loes191P4D128J

Each peptide is a portion of SEQID NO: 19; each start position isspecified, the length of peptide is

10 amino acids, and the endposition for each peptide is the

start position plus nine.

W AGI qlLLRITFN ~I .1 LLGSSNPPAS] _0.100J

VHH cCFE 6O.166J

UL2] FFIYFYFYF JI .PJOO IWLA LLRIT1L010

E87] .iI 0.080LJ:81f IY !SYiL 0.0601

WI KKKRFIQIL.6=2 I_ RELLAGILL 0.060

E L1 SVHHqCF_ [q05osj

F~TF\~QAGELL]I .030

Ifl ASASLVAJI 0.030]IFT6Lq~FESFTK J aO-30 I

II~fl~rKR~KLK I0. -03-0_LKKFRFIQC ILQ~

ILEFEMESHYAQA IL09Pi139D _yLEA SHYVAiLj 0.30

[111RYFqGIFMVQJ 020

E4 21FPLVVFHI 020

D_9 IJLLFFFLPFPLVI .?9JFFLPFPLW][9020J? O

113 LqvnYsPqEGL:9[.1I 11ii H9vysUll.916 .1

_jl]ffFFLFFFLP 10 oo

T9 LLLq9LKVRPJi[.9q19.LVAGTLS§VH- [0.0 1

[FLL4KvrPQ o

Efi LL L g[ GI[ QAPEII

I l979jL tK I(.00.

Table XXI-9-H11A-B33501-10mers-191P4D12Bj

Each peptide is a portion of SEQID NO: 19; each start position isspecified, the length of peptide Is-

10 amino acids, and the endposition for each peptide is the

-start position plus nine.

.102 [_GLLKVRPQH1 0.0101

Table XXIMV 0-HLA-B3501 -1lomers-191P4D12B

Each peptide Is a portion of SEQ1ID NO: 21; each start position Istspecified, the length of peptide is

amino acids, and the endposition for each peptide is the

start position plus nine.

1[itg_ Susequen c c~.$17 1OJ[GSDVMTVL IL 2.000

RCAGE L L Sry 0L.300 1

i _il o .SD[ 0.200fl]IGETSIDV V IL.20 1

IK-EGTP 0.10-60IT1L 2I.19oe[7]TGRPGEG 0.030

IFLTRPAGE_ LGT .9 11 LEE U Y Li 0.010 I

FTable XXI-Vi1-HLA-B3501-1 Omers-1 91 P4D1 2B

Each peptide Is a portion of SEQID NO: 23; each start position isspecified, the length of peptide is

10 amino acids, and the endposition for each peptide is the

sta rt p o siio n plus nine [Start L-Sbsequ ence IS.ore .1

L ]9RLRLF Y~YV_1.800_J=9 FlLVIV PPLPSLNFT0.10I

75 ]LRRV VPL 0.06

LtIIVPPLPSLNP.IL=.010.M LRY- IL2 IWAR LLRM PI 901

00

00

Table XXI-V1 2-HLA-B3501 1~ 0mers-191P4D12B

SEach peptide is a portion of SEQID NO: 25; each start position isspecified, the length of peptide isl

amino acids, and the endposition for each peptide is the

start position plus nine.

Start Subsequen c L e'

L]L ECYSLI_60002 [tVMSEEPEGC§SILO.200

[TiSVMEEPGCI 50 JE f[ ICZ[GSYST LnT I~ 0.100

K771PE-GS L 0.001

[T TTTR E 0.001

[Table XXIMV3-LA-B33501-lmers-191F4D12B

Each peptide is agprtion of SEQID NO; 27; each str osition isspecified, the length of peptide is

10 amino acids, and the end1position for each peptide is theL-start position plus. nine.

[Sart LSubsequence j Sco re

FEI DSQ VT V RVL: II 0.500[TQEy ?Fi9EDS 0.100

f YI~~Di~oi[ .020:*

'[211 QTrDVLAD]32 F0.015

[T7VDVLAPQEJKII0 2

~IT able XXI-V4-HLA-B3501-L. 10mers-191IP4D12B

Each peptide is a portion of SEQ1ID NO: 29; each start position is

spcfethe length of peptide is10 amino acids, and the end

position for each peptlde Is thestart position plus nine, j

[St a- Subsequ ence 1. SceI~ASALVAGL 5.000.F .0

1G- AS IIGTS 0- .00MW AGSII. 0J

Li7ISNPA-yI 0.200.

LIIIIJP PSASL VAGI 0_.020 j

Tables XXII XLIX:

00

00

TableXXII-V1-HLA-Al-19mers-191P4D12B

Each peptide is a portionof SEQ ID NO: 3; each

start position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.Pos 123456789 score437SEEPEGRSY

1107 PDGSVLR 21305 LTTEHSGIY 21

3 TTEHSGIYV 21159 LEEGQGLTL 20

52 GLEDQNLWH 2HIDPRSPE

SYGLHVSPAY 1262 GREGAMLKC 19

SPEESVGLRA 196 VqENGThRA

494 AKPTGNGIY 191I GPEAWLLLL

ELALLHSKY 12 SEGQPPPSY 1

VLDPQEDSG 1YEEELTLTR 1TSDVVTWL 7AQELALLHS 17

1 DTEVKGTTS 1SVSHPGLLQD 1

LSEGQPPPSF RVDGDTLGF 17

38KQQMTQKY 1

f SGEQVGQVA 1

SALEEGQGLT 1

7 SDSQVVD 1SWVVLMSRY 1

SQIELLSPGS 1

1QDAKLPCFY 146 MSEEPEGRS Li~

TableXXII-V2-HLA-Al- 1I 9mers-191P4D12 1

Each peptide is a portionof SEQ ID NO: 5; each

start position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.[Pos 123456789 score

QDAKLPCLY I17GQDAKLPCL E 0

TableXXII-V7-HLA-Al-9mers-191P4D12

Each peptide is a portionof SEQ ID NO: 15; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.IPosi 123456789 score

3~ HIDPRSqSE 20

TableXXII-V9-HLA-A1 9mers-191P4D12

Each peptide is a portionof SEQ ID NO: 19; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.[os 123456789 scorel

25 FPLWFFIY 212 VFFIYFYFY 2

11 NSCDCE 191FFLEMEHY 16

1 ITFNFFLFF it11 LWFFIYFY 1

11 SCDCERGYF 1

211FFLPFPLW 1FLEMESHYV i 1Z

1 GLELLGSS N 111 CERGYQG 1

4 ELLAGILLR 1SSNPPASAS 11

SSLVAGTSV 119 FRFIQCLLL 1

9mers-191P4D12B

Each peptide is a portionof SEQ ID NO: 21; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.s 123456789 score

SAGELGTSDV 13SGTSDVVIhV 1

RCPAGELGT BGRCPAGELGZ

TableXX I-V1 1 -H LA-Al 9mers-1 91P4D1 2B

00 Each peptide Is a portionof SEQ ID NO: 23; each

start position is specified,CK1 the length of peptide is 9

amino acids, and the endposition for each peptideis the start position plus

eight.

FP;~ 1234j 5 6789 Fscorel

TabeXXIIMM2-LA-A1

cK1 Each peptide is a portionof SEQ ID NO: 25; each

ri start position is specified,00 the length of peptide is 9

amino acids, and the endc~-K1position for each peptide

is the start position pluseight,

Pos112456789

TableXXII,-V1-3-HL-A7I-9mers-191P4D12B

Each peptide is a portionof SEQ ID NO: 27; eachstart position is specified,the length of peptidle is 9amino acids, and the endposition for each peptideis the start position plus

eight.[Posj 12346789 re~~[7I]LADPQEDSG IDIJTVDVLADPQ]

EJVTVDVLADP 9JIEAQVTVDVLAD 1 7

511PPASASLVA 7

D~S~PSS

[FGSNP] S

1

00

00

TableXXIl-V1-HLA-A0201-9mers-191 P4D1 28Each peptide is a portionof SEQ ID NO: 3; each

start position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight

123456789score53 EIETQIELL 16

IYINGGHL 16

[I GPEAWLLLL 2 PEAWLLLLL 15

LLASGR[ 15E GELETDW IDSGEQMGQV 1

SEGAQEAl.L 15

j FQARLRLRV 1510 RLRLRVLVP j

MNGQPLTCV 15NGQPLTCW 1

0 LLQDQRITH 1hLHVSFLAEA 15

270 CLSEGPPP 15PLTTEHSGIHSGIYVCHV 1

VLDPQgDSG 153 RAKPTGNGI 1

TableXXIll-V2-HLA-A0201-9mers-

191P4D128

Each peptide is a portionof SEQ ID NO: 5; each

start position is specified,the length of peptide is 9amino acids, and the endposition for each peptideIs the start position plus

eight.[os 123456789 scorel

1 GQDAKLPCL 17-CLYRGDSGEL3

KLPCLYRGD 134 AKLPCLYRG 1

TableXXIII-V7-HLA-A0201-9mers-

191P4D12B

Each peptide is a portionof SEQ ID NO: 15; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.Pos 123456789 score

3 HTDPRSQSE 8

F8 SQSEEePEGRlI1 SHHTDPRSQ 4FJRSQSEEPEG 3J

TableXXIII-V9-HLA-A0201-9mers-

191P4D12BEach peptide is a portionof SEQ ID NO: 19; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.Pos 123456789 score

98 CLLLGLLKV 315 LLAGILLRI 296SLVAGILSV 29

95 FIQCLLLGL 2639 FLEMESHYV] 2146 AQAGLEL 2147 VAQAGLELL] F2191 KAFRF!QCL 2199 LLLGLLKVR 20

101 LGLLKVRPL 191jjMRRELGI 18

58 SNPPASASL 1863 SASLVAGTL 1888 KLKKAFRFI 1818 FLFFFLPFP 1721 FFLPFLW 1722 FLPFPWF 174 LLGSSNPPA 1

96IQCLLLGLL 17SELLAGILLR 169 ILLRIIFNF 6

F-44 SHYVAQAGL 162 ASASLAGT 166 LAGILRIT 158 GILLRITFN

TableXXIl-V9-HLA-A0201-9mers-

191P4012BEach peptide is a portionof SEQ ID NO: 19; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.Pos 123456789 score

11 LRITFNFFL j100 LLGLLKVRP

A0201-9mers-191P4D12B

Each peptide is a portionof SEQ ID NO: 21; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.Pos 123456789 re

SGTSDVVTW 201

F--3[8 LGTSDVVTV 19

[5 AGELGTSDV [6 GELGTSDW

ELGTSDVVT 13SCPAGELGTSI

TableXXIII-V11-HLA-A0201-9mers-

191P4D12BEach peptide Is a portionof SEQ ID NO: 23; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.Pos 123456789 score8 VMVPPL.PSL 295~ RLRVMVPPL 2 ARLRLRVMV 173 RLRLRVMVP 14

TableXXIII-V1 2-HLA-A0201-9mers-191P4D12B

00

00

TabeXXI Il-Vi 3-H LA-A0201 -9mers-

191 P401 28Each peptide is a portionof SEQ ID NO: 27; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.

Pos 12468 Fscore

7 QTeXIIVV-LA

A0201 -9mers-191 P4D12B

Each peptide is a portionof SEQ ID NO: 29; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.

FPos 124679score

F- ASASLVAGT 16FL1] GSSNPPASAF 10F-4 NPPASASLV

PASAS LVAG

TableXXIV-V1 -H LA-A0203-9mers-

191 P401283

N-lolResuitsFound.[TabieXXIV-V2-HLA-A0203-9mers-

191 P4D12B

-NoResultsFound._[TabieXXIV-W-HLA-A0203-9mers-

[191lP401 28

NoResultsEound. [TableXXV-V9-HLA-A0203-9mers-

1911P401283

[P os 12345789 sore]

NoResultsFound.[TableXXIV-V1 0-HLA-[A0203-9mers-S 191P4D12B]I

TabIeXXIV-V1 1-H A-F A0203-9mers-191P4D12B

E os 124679score]IFNoResultsFound.

TableXXIV-VI 2-H LA-A0203-9mers-

191 P4D128

99124567coreNo~suis~ond.

TabeXXIV-VI 3-H LA-A0203-9mers-

191 P40128

Po134679scoreNResultsFound.

TableXXIV-V14-HLA-1A0203-9mers-

191 P40128

TableXXIV-V4-HLA-FA02 03-9mers-

NoResults ound

TableXXV-V1 -HLA-A03-19mers-191 P401 28

Each peptide is a portionof SEQ ID NO: 3; each

start position Is specified,the length of peptidle is 9amino acids, and the endposition for each peptideis the start position plus

eight

14 0RRRLP 2

180 VTWOEVK

451 TWG DAK 2

24] DDLF 2

F2-1 LLLAF 2

459 DLSP9G

13621 CLFV\V 19M Fj415 EQN1 [1]

00

00

TabIeXXV-V1 -HLA-A03-9mers-191P40128

Each peptide is a portionof SEQ ID NO: 3; each

start position Is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.s 123456789

I9GLEDQNLW-II 19g QVDLVSASV 1

Isw l SWGA[191366LMSRY

137RKAQQMTQ]19FVENTLR][ 19ELETSDVT 1 8

QVAWARVD 18I1QELALLHSK 18

RVSTFPAGS 1829HLVPSRSMN 18SHIGREGAML LJ1

lI1RLDGPLPSG 13TLGFPPLTT 7i

SGIYVOHVSN J[DLVSASW IIGVIMALLFC I i1

j~JLLFOLLVV Lj1365 J 8417 GLRAEGHPD 118

4TVREIETQT 1J491TLRAKPTGN 1

F-2][ZI PLLGMW 17![6LLLLLLLAS [7F-16

191 LLLASFTG 17

158 ALEEGCLTI 1717641 GLLMSCT 773511 WMGIAA 171368 W LMSRYI 97!

WLLLLLLLA 1681 ASKYGLH 16

1971 KHS AAVT 16224 WHLLQ 16

TableXXV-V1 -HLA-A03-9mers-191P4D12B

Each peptide is a portionof SEQ ID NO: 3; each

start position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight123456789 o

D ISLGAEMWGP 13431VLGQDAKLP LE 491KLPCFYRGD 13F SKYGLHVSP 13

F 124 EYECRVST F 13LVL139 ALLVV 123AVTSEFHLV 13210 LVPSRSMNG 1236 ITHILHVSF 13

27NLWHIGREG [j1120CLSEGPP( 13

3041PLTTEHSGI3ssDSQMTV 13

391DVLDPQE3 D DPQEDS 13

LDPQEDSGK 13151WWVG!!M 13

371LMSRYHRRK 13

SRSYSTLTTV 113I4GIKQAMNHF IIi1

TableXXV-V2-HLA-A03-9mers-191P4D12B

Each peptide is a portionof SEQ ID NO: 5; each

start position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.[s123456789

SKLPCLYRGD II[11QDAKLPCLY j 1~

TableXXV-V-HLA-A3-19mers-1 91P4D12B 1

00

00

TableXXV-V9-HLA.A03.gmers-191P4D312B3

Each pepUde Is a portionof SEQ ID NO: 19; eachstart position is specified,the length of peptide Is 9amino acids, and the endposition for each peptideis the start position plus

eight.Pos 123456789 sor

FIGIL-LRITIN [14

26 -PLvvFFIYF IF14

F28WFYFF 1F53 ELLGSSNPP f 14F72SHCCE 1

F76CCEFK 1

88 LKAFI 14

[11 3VSDCR 1

[126GEQAP 4F21] FP F1 131[861KKKKFf J

38 FFEEH 12

EFKKK 123 LFWF 11571SPASS 1

F63SASL 7GTL 1TLSHHAC 11FQLLL 1

107 PLQHGVN 11,[TableXXV-VI 3-HLA-A03

[9mers-1 91 P4DI 2BEach peptide Is a portionof SEQ ID NO: 27; each

start position is specified,the length of pepuide is 9amino acids, and the endposl~on for each peptideis the start position plus

I eight.[pos 2468

76 DVADE

I~ VLADPQ 1VLDQEDS 121

00

00

TableXXV-V1 4-HLA-A03-mers-191 P4D1 28

Each peptide is a portionof SEQ ID NO: 29; eachstart position Is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.os 123456789 score

F -2SSNPPASAS 118 SASLVAGTL 11

3 SNPPASASLZ 99 ASLVAGTLSZ 9Z

F NPPASASLVZ 8PPASASLVAZ 8

I GSSNPPASALZ 76 PASASLVAGZ 7

I ASASLVAGTZ 7

TableXXVI-V1-HLA-A26-9mers-191P4DI12B

Each peptide is a portionof SEQ ID NO: 3; each

start position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.

PosI 123456789 score42 WLGQDAKL 19

L84184 DTEVKGTTS 19E3294 RVDGDTLGF 19331 DVLDPQEDS 19337 EDSGKQVDL 19

54 GVIAALLFC 19365VVVLMSR 191 EMWGPEAWL 18

60EQVGQVAWA 1871 DAGEGAQEL 18

145 VLVPPLPSL 182361 ITHILHVSF 18237 THILHVSFL 18313 YVCHVSNEF 1844918191 TTVRElETQ 1(18

VTVLGQD 17

13281VTVDVLDPQ 173551 VIAALLFCL 17411 TWLGQDAK 1

57 DSGEQVGQV 16

11301 STFPAGSFQ. 16

=1

298 DTLGFPPLT 1613271 QVTVDVLDP 163491 SVVVVGVIA 1616 MTQKYEEEL 16[450 TVREIETQT 161413 EESVGLRAEI 1414 ESVGLRAEG 15

14731 DQDEGIKQA12 PEAWLLLLL 14

[14 AWLLLLLLL 14[17 LLLLLLASF 14

VVLGQDA 4F16ol EEGQGLTLA 142601 HIGREGAML 14

345J LVSASVVVV 14367 WVLMSRYH 14

TableXXVI-V1-HLA-A26- 19mers-191P4D12B

Each peptide is a portionof SEQ ID NO: 3; each

start position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.

[Pos 123456789 sore387 EEELTLTRE 14

(437 SEEPEGRSY j 141452 REIETQTEL 14

1472 EDQDEGIKQ 14476 EGIKQAMNH 14484 HFVQENGTL 14485 FVQENGTLR 17

F1 GPEAWLLLL 1345 GQDAKLPCF 13

109 DGSVLLRNA 13135 GSFQARLRL 13142 RLRVLVPPL 13146 LVPPLPSLN 13161 EGQGLTLAA 13222 TCWSHPGL 13249 SVRGLEDQN 13320 EFSSRDSQV 13329 TVDVLDPQE 13344 DLVSASVW 13353 VGVIAALLF 13393 TRENSIRRL 13421 EGHPDSLKD 13438 EEPEGRSYS 13446 STLTTVREI 13

459 ELLSPGSGR 13o501 IYINGRGHL 1 13

TableXXVI-V2-HLA-A26-9mers191P4D128

Each peptide is a portionof SEQ ID NO: 5; each

start position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.Pos 123456789

I GQDAKLPCL 12 QDAKLPCLY 11

00

00

TableXXVI-V2-HLA-A26.9mers-1 911P40I13

Each peptide is a portionof SEQ ID NO: 5; each

start position Is specified,the length of peptide is 9amino acids, and the endposition for each peptidleIs the start position plus

eight.

[PoI 123456789lIcr

J 0A-KLPCLYR F

TableXXVI-W-HLA-A26-9mers-191P4D12B

Each peptide is a portionof SEQ ID NO: 15; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.

Pos] 1l24567891 [sr

TableXXVI-V9-HLA-A26-9mers-191P4012B3

Each peptide Is a portionof SEQ ID NO: 19; eachstart position Is specified,the length of peptide Is59amino acids, and the endposition for each peptideIs the start position plus

eight.

IP-o s 12 34 5-6 78 996iQCLLLGLL j14j 4 TFNFFLFFF lFi1-151 FNFFLFFFL 1

F26 PLVVFFIYF][I)F381 FFLEMESHY 13j931 FRFIQCLLL 1

101LGLLKVRPL]1105IKVRPI QHQGI 13

TableXXVI-V9-HLA-A26-9mers-1 91P4D1 2B

Each peptide Is a portionof SEQ ID NO: 19; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideIs the start position plus

eight.[Pos 123456789F27 LVFIFY 228 WFFiYFYF F2413 ITFNFFLF 246 YVAQAGLEL 2

120 ERGYFQGIFF 1923 LPFPLWVFF F18

FIQCGL1ESFTKRKKKF16

F91 KAFRFIQCL ]F16

[ELLAG LLR f157 AGILLRITF 115]66LAGTLSVH

12 RITFNFFLF 1429 VFFIYFYFY 14

TableXXVI-V1 3-H L--A26-9mers-191 P4D1 28Each peptidle is a portionof SEQ 10 NO: 27; eachstart position Is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.

DI~ DVLAQD 1DVTVD-VLAD7

I~ TVDVLADPQ 12~

[TabIeXXVI-V1 4-HLA-]A26-9mers-1 91P40128]Each peptide is a portionof SEQ ID NO: 29: each

start position isspecified, the length of

peptide Is 9 amino acids,and the end position foreach peptide is the start

position plus eight.Pos 123456789 fsc-~

D SASLVAGTh 1L:1 ASASLVAGD PAASVA F-

I

00

00

Each peptide is a portionof SEQ ID NO: 3; each

start position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.Pos 123456789 score

F0 Q PPPPRNPL13 GPEAWLLL 231 PPSYNWTRL I

1106 NPLDGSVLL122287 GPLPSGVRV 2

KPTGNGIYI4I1 LPSLNPGPA 1

EPEGRSYST 11 MPLSLGAEM 1818~ EMWGPEAWL [T

QPPPSYNWT 1LPSGVRVDG 1

33 EDSGKQVDL 1RLRVLVPPL j

151 PSLNPGPAL 16[2 TGRCPAGEL 1

TSDVVTWL 1GEGAQELAL 115

3 PPRNPLDGS l

132 FPAGSFQAR 1145 VLVPPLPSL 1471 VPPLPSLNP f159 LEEGQGLTL 15

SAWLLLLLL 1SPAPSVTWDAPSVTWDTE

21311SRSMNGQPL351 WVGVIAAL 14

362 CLLWVWL12 PEAWLLLL 1

1 EAWLLLLLL 1CPAGELETS 1

42 WLGQDAKL 174 EGAQELALL 13ISPAYEGRVE][ 131

1 RNPLDGSVL] 131GSFQARLRL 131

1 QARLRLRVL 1161 EGQGLTLAA[ 11

TableXXVII-V2-HLA-B0702-9mers-191P4D12B

Each peptide is a portionof SEQ ID NO: 5; each

start position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight

Po 123456789

L1GQDAKLPCL 13

6 LPCLYRGDSII 11

TableXXVII-V7-HLA-B0702-9mers-191P4D12B

Each peptide is a portionof SEQ ID NO: 15; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.

Pos 123456789 oreD PRSQSEEP 1j

TableXXVII-V9-HLA-B0702-9mers-191P4DI2BEach peptide is a portionof SEQ ID NO: 19; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eightPos 123456789

LPFPLVVFF 2160PPASASLVA 9 NPPASASLV 17

SYVAQAGLEL 14AFRFIQCLL 14RELLAGILL 12

[is FNFFLFFFL 12

22 FLPFPLWF 12

[3 YFYFYFFL 6 GSSNPPASA 7i/5 SNPPASASL 2

SASLVAGTL 1

FRFIQCLL

00

00

TableXXVII-V9-HLA-B0702-9mers-1 91 P4D1 2BEach peptide is a portionof SEQ ID NO: 19; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideIs the start position plus

I eight.7Pos 1l23456789 -icor

1FI QCL LLG7L T 12

1 017 FGRP 12

72 RRLAI 11

13FITFNFFLFF 1

FFPPV 1111

47VQGEL 1

81 SFKKKL 1911 KAR DQL 196 ICLGL 1

1179 EEEFQI1[129 QAP EGT 1

1 FLP0L11

[42MSYAA 1

TableXXVll-V1 0-H LA-B0702-9mers-

191 P40128Each peptide is a portionof SEQ ID NO: 21; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideIs the start position plus

eight.

[posI 2468[1F CAE3]S 1

[ELGSVTL2D j 'TA'TV 1

TableXXVII-V1 1-HLA-1130702-9mers-

191 P4D12BEach peptide Is a portionof SEQ ID NO: 23; eachstart position Is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.,

IEos 123456789] score]1

[TabIeXXVII-V1 2-H LA-B0702-9mers-

191 P4012BEach peptide is a portionof SEQ ID NO: 25; eachstart position is specified,the length of peptide Is 9amino acids, and the endposition for each peptideis the start position plus

eight.H I 123456789soeDI EPEGCSYST 19~

STableXXVII-V13-H LA-1B0702-9mers-

191 P40128

Each peptide is a portionof SEQ ID NO: 27; eachstart position is specified,the length of peptide Is 9amino acids, and the endposition for each peptideis the start position plus

eight.

Pos 123-4567891 scr

D] SQ V V DVLA EF EA1QVTVDD F-4,D1VLADPQEDs 12]

TabIeXXVII-V14-HLA-180702-9mers-191P4D12B

Each peptide Is a portionof SEQ ID NO: 29; each

start position is specified,the length of peptide Is 9amino acd s, and the endposition for each peptideis the start position plus

eight.

[P PA

[TableXXVIII-Vl-HLA-B08-9mers-1 91P40128

Each peptide Is a portionof SEQ ID NO: 3; each

start position Is specified,the length of peptide Is 9amino acids, and the endposition for each peptideis the start position plus

eight.

Pos 123456789

337 EDSGKQVDLF 23

4791TLAPG4777GKANF 2493 RAGG

362 CLVVV 19

00

00

Table)(XVIII-VI-HLA-B08-9mers-1 91RPDI 2B

Each peptide is a portionof SEQ ID NO: 3; each

start position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

Pos F 1234-56789 scor

F1T1 G PE AWLLLL0 17EALLLL 17

2 T GR CP AGELQ 17

F7 1] ALPF 1

LE AGEAQE 17

124 EERSF 1145VVPPL 1

[2 PPS7-7] 17

78~1 QD9RPL7hF1 PALE G G 16

247 FAV LE 16

265 AUCS 16267 MLCLEG

356 EALCL374 YHRKQM 6i439EEG YS[ I[453 ITTEL]

I 7DALCYR[1AA5OGf

[Fol PPR6L 15231 LQQTI 15

245LESVG 152 60 HIREM 15355 E9ALFL 1

1369 VLSYHRt1410O 15ESGLE~

113 LRAQ D 14

202 AAVT E 14

1411 AEHPDL 14h

TabeXXViIl-V2-HLA-808-9mers-1 91 P4DI 2B

lEach peptide is a portion]I

of SEQ ID NO: 5; eachstart position is specified,the length of peptide Is 9amino acids, and the endposition for each peptideis the start position plus

I_ eight

Epos 123456789 IscorelF- G QDAKLPCHO F211

STableXXVIlI-W*-HLA-1B308-9mers-1 911P4DI28 JEach peptide is a portionof SEQ ID NO: 15; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.

rTableXXV I I -V9-LA- 1BOB-9mers-191P4D12BjEach peptide Is a portionof SEQ ID NO: 19; eachstart position Is specified,the length of peptide is 9amino acids, and the endposition for each peptideIs the start posito pu

eight.Id

11031LLKVR-PLQH JF*821FTKKL

88 KLKFRILiLLLVRL 9

F8 11SKRKL jKRKKKK4]I~

[86 DKAKAR12i110 LLITNF

63 AVAGTL [1 J

91_ KAFRFIQCL ~5

TableXXVIII-V9-HLA-B08-9mers-1 91 P4D12B]Each peptide Is a portionof SEQ ID NO: 19; eachstart position is specified,the length of peptide Is 9amino acids, and the endposition for each peptideis the start position plus

eight._123456789 Isor

F95 FIQCLLLGLl

F2MRELAG 14

26 PVFIF 1

80E SF KR K 13

E A ILI 12

F58 ISNPPASASL Zi 1

TabIeXXVlII-V1 0-H LA-B08-9mers-1 91 P4DI 28Each peptide is a portionof SEQ ID NO: 21; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eigh

B08-9mers-191P4D12B

Each peptide is a portionof SEQ ID NO: 23; eachstart position is specified,the length of peptide is 9aino acids, and the end

position for each peptideis the start position plus

eight.

[Pos 12345678RLVVP [24

[D RLLRVMV

00

00O0

TableXXVIII-V1 1-HLA-B08-9mers-191 P4012B

Each peptide is a portionof SEQ ID NO: 23; eachstart position is specified,the length of peptide is 9amino adcids, and the endposition for each peptideis the start position plus

eight.

[PosI 123456789 score]1 []QARLRLRVM 191

D VMVPPLPSLI 11

TableXXVIII-V12-HLA-808-9mers-191P4D12B

Each peptide is a portionof SEQ ID NO: 25; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.

Pos 123456789 score6 PEGCSYSTL 10

EPEGSYSTI 814 EEPEGCSYS D

TableXXVIII-V1 3-HLA-0B8-9mers-191P412B8

Each peptide is a portionof SEQ ID NO: 27; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight

Pos 123456789 Iscore7 VLADPQEDSi 78 LADPQEDSG 4

SSQVTVDVLA 3

2 QVTVDVLAD 3

TableXXVIII-V14-HLA-B08-9mers-1 91P4012B

Each peptide is a portionof SEQ ID NO: 29; each

start position isspecified, the length of

peptide is 9 amino acids,and the end position foreach peptide is the start

position plus eight.

123456789 eSASLVAGTLI 17

[SNPPASASL 12

TableXXIX-V1-HLA-B1510-9mers-191P4D12B

Each peptide is a portionof SEQ ID NO: 3; each

start position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight

Pos 123456789 score237 THILHVSFL 22

208 FHLVPSRSM 20259 WHIGREGAM 18374 YHRRKAQQM 17393 TRENSIRRL 17I 36 TSDVVTVVL 1611362 CLLWVWL II 1135 GSFQARLRL] 151

1308 EHSGIYVCH 151337 EDSGKQVDL 15100 QPPPPRNPL] 141106 NPLDGSVLL 14]

1138 QARLRLRVLI 14145 VLVPPLPSL 14245 LAEASVRGL 141277 PPSYNWTRL 14325 DSQVTVDVL[ 14

1501 IYINGRGHL 14I 8 EMWGPEAWL][ 13

26 TGRCPAGEL] 13

71 DAGEGAQEL[ 131

S74 EGAQELALL[ 1311142 RLRVLVPPL ][T1311511 PSLNPGPALI 13

1159 LEEGQGLTL 13197 KHSRSAAVT][ 131222TCWSHPGL][ 131292 GVRVDGDTL 13297 GDTLGFPPL [13351 VWVGVIAAL 13i356 IAALLFLL 13

1403 SHHTDPRSQ 131404 HHTDPRSQPI 131

14101 SQPEESVGL 1

TableXXIX-V1-HLA-B1510-9mers-191P4D12B

Each peptide is a portionof SEQ ID NO: 3; each

start position is specified,the length of peptide is 9amino adcids, and the endposition for each peptideis the start position plus

eight.Pos 123456789 score

[419 RAEGHPDSL] 13[9 MWGPEAWLL 11 GPEAWLLLL

[73 GEGAQELALII1[821 LHSKYGLHV[88 LHVSPAYEG J[ 121los RNPLDGSVL [121[133 PAGSFQARL 121

[2131 SRSMNGQPLJ[ 1211382 MTQKYEEEL 12384 QKYEEELTL F 2]

14221 GHPDSLKDN 121452 REIETQTEL 12453 EIETQTELL 12484 HFVQENGTL 12

10 WGPEAWLLL 1112 PEAWLLLLL 1113 EAWLLLL 1142 WLGQDAKL 110 ALLHSKYGL 11

1157 PALEEGQGL j 1I1223 CWSHPGLL ii1226 SHPGLLQDQII ii[24J LHVSFLAEA (I1315 CHVSNEFSS Ii1352 WGVIAALL j[ III355 VIMLLFCL Fi0

1401 LHSHHTDPR ii1440 PEGRSYSTLj[11

[4831 NHFVQENGTII I

1232 QDQRITHIL 101

1236 ITHILHVSF 1250 VRGLEDQNLI 1011260 HIGREGAMLj

00

00

TableXXIX-V1-HLA- IB31510-9mers-1 91P41 281Each peptide Is a portionof SEQ ID NO: 3; each

start position is specified,the length of peptide Is 9amino acids, and the endposition for each peptideis the start position plus

eight.

263 REGAMLK-CL 10281 NTL L 13631]LVVVM 14] QDG1QA 0ITableXXIX-V2-HLA-

B1510-9mers-191 P4012B 1

Each peptide is a portion'of SEQ I0 NO: 5; each

start position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.

[TableXXIX-W-HLA-83151 0-9mers-191P4D12B

Each peptide is a portionof SEQ ID NO: 15; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideIs the start position plus

eight

Po-sl F123456789- (cr

TableXXI-9HA8151 0-9mers-

191 P4D1 28Each peptide is a portionof SEQ ID NO: 19; eachstart position is specified,the length of Peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight

Posi 123456789 scr

F74 H A F 16F46 YVAQ GLEL 14F11 LGLLKVRPL 13j32l IYFYFYFFLI[ 1258 SNPPASASL 12

F631 FSASLVAGT-L] 12

96 Q-CLLLG-LL 12

F- RRLLGI 1119 EEFPFL 1

F9j FL F 7LF 11F 21 L-I LVF LiiEq

F-1 KARFQC 1[ 0

U1 TNFFL1

TableXXiX-V1 0-1-LA-B1510-9mers-

191 P4D128Each peptide is a portionof SEQ ID NO: 21; eachstart position is specified,the length of peptide is 9amnino acids, and the endposition for each peptideis the start position plus

eightPos 123456789scrF-9 GTSDV-VTVV 6

EL SVVE GSW11

F-8 L4SVTVf~

ElRCAELEN PGEGS i~

AGLGSDV 1TabeXXIX-V1 1-H LA-

8151 0-9mers-191P4D1I28

Each peptide is a portionof SEQ ID NO: 23; eachstart position is specified,the length of peptide Is 9amino acids, and the endposition for each peptideIs the start position plus

eight.Pos 1234 5 6789 Fso-~

D MPLS 14]jj1 LVMPL 1

TableXXIX-V1 2-HLA-81510-9mers-

191 P40128Each peptide is a portionof SEQ ID NO: 25; each

start position isspecified, the length of

peptide is 9 amino acids,and the end position foreach peptide is the start

position plus eight.

TableXXIX-VI 3-H LA-6151 0-9mers-

191 P40128Each peptide is a portionof SEQ ID NO: 27; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.

IposI 124567-897D IQVTVDVLA0 3D VLADPQED)S

LA~ SQTVVL jj VDVLADPQ E

TableXXIX-V1 4-HLA-6151 0-9mers-191P4D128

Each peptide is a portionof SEQ ID NO: 29; each

00

00

start position isspecified, the length of

peptide is 9 amino acids,and the end position foreach pep de is the start

position plus eight.

[Pos 123456789 Iscore[3 SNPPASASL -71]

[SASLVAGTLI]

TabieXXX-V1 -HLA-B2705-Smers-19114D12B

Each peptide is a portionof SEQ ID NO: 3; each

start position is specified,the length of peptide Is 9amino acids, and the end

position for each peptide isthe start position plus

eight.

Pos 123456789 score

393 TRENSIRRL 26

250VRGLEDNL 1251452REIETQTEL 22

135 GSFQARLRL 21213 SRSMNGQPL 20[77j RKAQQMTQK j19

42WLGQDAKL 189RVEQPPPPR 13

2621 GREGAMLKC Th1351] VVGVIAAL 111I376 1RRAQQMTQ1I 181j3991 RRLHSHHTD 11 11[g1 E2AWLLLLLLL IIi

17 LLLLASF 17]11051 RNPLDGSVL 11111421 RLRVLVPPL ]I17

201RSMAVTSEF2061 SEFHLVPSR] 171~

1294 RVDGDTLGF 11 1712971 GDTLGFPPL 11 17141911 RAEGHPDSL 1 1714981 GNGIYINGR I~iF41 TWLGQDAK 16

S451 GQDAKLPCF 16IF8 ALLHSKYGL 1

96GRVEQPPPP

106] NPLDGSVLL 111451 VLVPPLPSL 16I

RITHILHV16

TabieXXX-V1 -HLA-B2705-9mers-191P4D12B

Each peptide Is a portionof SEQ ID NO: 3; each

start position is specified,the length of peptide is 9amino acids, and the end

position for each peptide isthe start position plus

eight.

[Pos 123456789 [scorel[243 SFLAEASVRII 1[ 6

261 IGREGAMLK 196[293 VRVDGDTLG L16

301GFPPLTTEH [jjN337 EDSGKQVDL LJ

384 QKYEEELTLD

4761 EGIKAMNH [31477 GIKQAMNHF 71E HFVQENGTL ]I flii GPEAWLLLL 13

0LLLASFTGR 1[61 QVQAWA 31I7111 DAGEGAQEL IIis7 EGAQELALL 75 GAQELALLH 15

7 QELALLHSK 151 PLDGSVLLR 1-51 8PAGSFQARL 15

19 5ARLRLRVLV F 7141 LRLRVLVPP 15

1 KGTRSFI 15189 GTSSRSFK 1 151

227HPGLLQDQRi 15)

271THILHVSFL I123REGAMLKCL][ 151281TRLDGPLPSI f 71

1(31 LDPQEDSGK][ 7j1[365 VVVVLMSR][ 15j3921 LTRENSIRR4661 GRAEEEEDQ[ 15

[4921 LRAKPTGNG~J 15[j A IYINGRGHL ]ERIJ EMhrWGPEAWLL FI

11 EAWLLLLLL LZ1

TabIeXXX-V1 -HLA-B2705-9mers-191 P4D1 2B

Each peptide is a portionof SEQ ID NO: 3; each

start position is specified,the length of peptide Is 9amino acids, and the end

position for each peptide isthe start position plus

eight.[Pos 123456789 [sce

27 GRCPAGELE[ 14j71GEGAQELAL

1041 PRNPLDGSV t 14[11411 LRNAVQADE [141201 ADEGEYECR 1 4

[13LRVLVPPLP[ 14[151 PSLNPGPAL[ 14157PALEEGQGL 14

[15 LEEGQGLTL[ 141861 EVKGTTSSR

11 SRSFKHSRS LiI199 SRSAAVTSE23 ITHILHVSF

127PPSYNWTRL .I1286 DGPLPSGVR 11292 IGVRVDGDTL J[ 14113131 YVCHVSNEF[14132311 SRDSQVTVD 143681 WLMSRYHR[14

F451 HRRKAQQET1378 KAQQMTQKY j[14

YEEELTLTR

[408 PRSQPEESV 1[410SQPEESVGL 711!

48 LRAEGHPDS 1440AEGHPDSLK 1

[4441 SYSTLTTVR 1114~1459) ELLSPGSGRI 141

lE1 MPLSLGAEM I13S121 PEAWLLLLL 11131S261 TGRCPAGEL 13~36 s(TsDVVL [1 131

S781 ELALLH SKY 1113]S861 YGLHVSPAY 13110 QPPPPRNPL Li112 EYECRVSTF L112 VSTFPAGSF 13

00

00

TabieXXX-V-HLA-B27059mers-191P4D12B

Each peptide is a portionof SEQ ID NO: 3; each

start position is specified,the length of peptide is 9amino acids, and the endposition for each peptide is

the start position pluseight.

F- 123456789 113 FPAGSFQAR(( 13

1138 QARLRLRVL 13202 AAVTSEFHL

208 FHLVPSRSM 13

129QPLTCWSH 113T WSHPGL 13

23 LQDQRII 13SGLEDQNLWH 1

SEGQPPPSY] 13PPPSYNWTR 1

P1T1 HVSNEFSSR 13WGVIAALL 13

I VGVIAALLF 133 IMLLFCLL (13

F WWLMSRY 1 38MTQKYEEEL

(391 TLTREN SIR i 3[~JRENSIRRLH ]I9

F44I0 sHHIT 131111 QPEESVGLR 13

481KDNSSOSVM [ThPEGRSYSTL][1

FVQENGTLR[ 13[JQENGTLRAK [71

[101 WGPEAWLLL 1247DAKLPCFYR

LYRGDGQ 126ARVOAGEGA 12

127 CRVSTFPAG 14 AGSFQARLR 1

192 SSRSFKHSR 122 PGQDQRI245LAEASVRGL 121

255DQNLWHiGR[259 WHIGREGAM 1Ej

HIGREGAML i

TabieXXX-V1-HLA-B2705-9mers-1191P4D12B

Each peptide is a portionof SEQ ID NO: 3; each

start position is specified,the length of peptide is 9amino acids, and the endposition for each peptide is

the start position pluseight

[os 123456789 score]281 NWTRLDGPL 1

308 EHSGIYVCH Ii3-25 DSQVVDVL fj1J55 VIMLLFCL 1

F33LLVWVLM 7iSVLMSRYHRR Li1

370LMSRYHRRK[32SRYHRRKAQ[ i

(396 NSIRRLHSH I435VMSEEPEGR

14511 VREIETQTE EI1471 EEDQDEGIK 2

474 QDEGIKQAM 7RAKPTGNGI 1

491AKPTGNGIY

TabieXXX-V2-HLA-B2705-9mers-191P4D12B

Each peptide is a portionof SEQ ID NO: 5; each

start position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.

Ps123456789 soe1 GQDAKLPCLtIISDAKLPCLYR Li1F-11 16

[~JAKPCYRG E8

TableXXX-V7-HLA-B2705-9mers-191P4D12B

Each peptide Is a portionof SEQ ID NO: 15; eachstart position Is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position pius

eight.

[PoF 123456789 s

D PRSQSEEPE 1

L SQSEEPEGR 12

RSSEEPEG

TabieXXX-V9-HLA-B2705-9mers-191P4D12B

Each peptide is a portionof SEQ ID NO: 19; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position pius

eight.

Pos 123456789 sco

2 RRELLAGIL 27

S931 FRFICLLLI 241S1 1I LRITFNFFL 2120ERFGF2[I MRRELLAGI 2

77ACFESFTKR 287KKLKKAFRF 2

RELLAGILL 18SELLAGILLR 18SKRKKKLKKA 18

8RKKKLKKAF 18

91 KAFRFIQCL 18

LIi AGILLRITF 17Z23 LPFPLWVFF II1783TKRKKKLKK] 17199LLLGLLKVR 1 171

[I ILLRITFNF 1 161[0ESFTKRKKK] ]j666KKKLKKAFR][ j.6l[11ITFNFFLFF jI

SHYVAQAGL 81 SFTKRKKKL 15197 QCLLLGLLK

101 LGLLVRPLI IGVNSCDCERI 151

121 RGYFQGFM

00

00

TableXXX-V9-HLA-82705-9mers-

191 P4D1 28Each peptide is a portionof SEQ ID NO: 19; eachstart position Is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.1Pos1 123456789 Iscore

F12 RlTFN FFL-F 141 5 F NF FL FF F-L 1

F 1 91 L FF FLP FPL 14F22 FLFPLF 1428 F FI-lY FY 1432 IYFYFY-FFLI 14

F37 YFFLEMES 1446 YVQGLL1

F58 S NPPA-SASL 14EF63 SALAT 1492AFR FI QCHLL 1 49-61 IQC LL LGL DF1 4

I71 LLGILR 13[1-71 FFF F FL P F 1327 LWFIF 17[31LFIYFYfYF 13j FFYFFLEM 13F47VAQAGLELL 166LVGTLVH 1376E9 EST 13,

F79 FESTKKK 13

F9 5 FiQCLF 13]122GYQGFM 1

[TableXXX-V1 1-HLA-82705-9mers-191 P4D12B

Each peptide is a portionof SEQ ID NO: 23; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.

[os 1 23-456789 IsEl5 RLRVMVP-PLI 16

EFVM-VPPLP-SL 1

DLIRRVMP 14E9 LMPL7P 13LE QALLV 11DLRLRVMV

TabIeXXX-V1 2-HLA-1B2705-9mers-

191 P4D12BEach peptide is a portionof SEQ ID NO: 25; eachstart position is specified,the length of peptide Is 9amino acids, and the endposition for each peptidleis the start position plus

eight.

os 124578 score:D EG6 YTL 1::SEEPEGCSY1

281 GCSYSTLTT] ZI6:91 =S6T~

TableXXX-VI 3-HIA-B2705-9mers-

191 P40128Each peptide is a portionof SEQ ID NO: 27; eachstart position Is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.[gs 1l23456 78 9-1jjEAPFQEDSGK 16

TableXXX-V14-HLA-B32705-9mers-

191 P40128Each peptide is a portionof SEQ ID NO: 29; eachstart position is specified,the length of peptidle is 9amino acids, and the endposition for each peptideis the start position plus

eight.[Posij 123456789 Esog

D~ SALVGT 14

D GSSN PPASAE:

(TaIeXXXI-V1-HLA-B32709-9mers-1 911P40128IEach peptide is a portionof SEQ ID NO: 3; each

start position is specified,the length of peptide is 9amino acids, and the endposition for each peptidleis the start position plus

eight.Po0s 1234567891scr

139 ARRLRVL 22

250 1VRGLEDQNL I1 211F39TRENSIRRL[212SRSMNGQPL

2341 QRITHILHV

104 PRNPLDGSV 19408] PRSQPEESV 18135 GSFQARLRLF 17142 RLRVLVPPL 16287 =GPLPSGVRV F16399 RRLHSHHFD 1

00

00

TableXXXI-VI-HLA-B2709-9mers-191P4DI2B1Each peptide is a portionof SEQ ID NO: 3; each

start position is specified,the length of peptide is 9amino acids, and the endposition for each pepbdeis the start position plus

eight

s 123456789se9 GRVEQPPPP 1

F RNPLDGSVL i1f~jGDTLGFPPL 1 5

RSYSTLTV I4 REIETQTEL 1

11 GPEAWLLL 1[jjAWLLLLLLL1ZIGRCPAGELE[ 14f GEGAQELAL [4j ALLHSKYGL FT1'22GREGAMLKC 14'23REGAMLKCL [14

1GVRVGDTL 14292 RVDGDTLGF 14

lICLLVVVVL It4lZ1RRKAQQMTQI i1 RAEGH1POSL11J

SGRSYSTLTT I 4GELETSDW lii

[LETSDVTV ]l13[i NPLDGSVLL11 CRVSTFPAG .i

941 LRLRVLVPP h(1 VLVPPLPSL 1il1f53 PSLNPGPAL [13

1 TRLDGPLPS If13324 1RDSQVTVDV [Th

I3QKYEEELTL 1T46GRAEEEEDQ 13

SRAKPTGNGI [J*1fJMWGPEAWLL( i21

w VVLGQAKLII21[lGQDAKLPCF 1126ARVDAGEGAI[12

Ii1i1 GSVLLRNAV 1121 PAGSFQARL EZ214 LRVLVPPLP [12

TableXXXI-HLA-B2709-9mers-1 91 P40128

Each peptide is a portionof SEQ ID NO: 3; each

start position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.[PosI 123456789 i17 PALEEGQGLI[ 121

1 AEGSPAPSV 12200 RSAAVTSEF

20 AVTSEFHL F12 TCWSHPGL]22CSHPGLL 2237THILHVSFL

fJSRDSQVTVD[WGVIAALL 712 ALLFCLLV 1

358ALLFCLLVV 121361 FCLLFVVV 1

372SRYHRRKAQ 1

D501 IYINGRGHL 11IIIN MPLSLGAEM E l

1WGPEAWLLL 11

12 PEAWLLLLL 1

13 EAWLLLLLL 112TGRCPAGEL 11T36TSDVVTVVL 1

711 DAGEGAQEL 1]]10 QPPPPRNPL [j1115 LEEGQGLTL If1i18 KGTTSSRSF] iii

191SRSFKHSRS [jj19SRSAAVTSE jj123AVTSEFHLV 11

28PGLLQDQRI 11231QDQRITHIL 1jj

25LAEASVRGL II1M27PPSYNWTRL j-121NWTRLDGPLI 111123VRVDGDTLG II1i

SDSQVTVDVL l1l37EDSGKQ VOL 11 l

VDLVSASW] illSDLVSASWV IIIvi

TableXXXI-V1-HLA-82709-9mers-1 91 P40128

Each peptide is a portionof SEQ ID NO: 3; each

start position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.Pos2456789 o

348 ASWVVGVI 11

351 WVGVIAAI. 11SVGVIMALLF ill

35 IAALLFCLL 1 j359LLFCLLV 11

1LLW VLM

38IRRLHSHHT ILAI4101 SQPEESVGL li1i1181 LRAEGHPDS 11 I

148KDNSSCSVM IIl STLTTVREI lil47GIKQAMNHF 114 HFVQENGTL IJIP42LRAKPTGNG 1145KPTGNGIYI 11

17 LLLLASF

I57 1DSGEQVGQVI 7 EGAQLALLI 101

14 LRNAVQADE

1129VSTFPAGSF L41I131FQARLRLRV] 10138QARLRLRVL] 11[81FHLVPSRSM F

ITHILHVSF 1

42 VSFLAEASV 1

26 -IGREGAML [45EFSSRDSQV 1l

SLVSASVVW 1U11 SAS D§GV j1371 VIAALLFCL Ii Th6

30LFLLW V J QYHRRKAQQM

135 RRKAQQMT ~iMTQKYEEEL

30LTLTRENSI 40PEGRSYSTL

00

TableXXXI-V1 -HLA-B2709-9mers-1 91 P4D1 28Each peptide is a portionof SEQ ID NO: 3; each

start position Is specified,the length of peptide Is 9amino acids, and the endposition for each peptideIs the start position plus

eight7Pos F 1234-56-789-[4511 VREI1ETQTE l453EIETQTELLI 10

TableXXXl-V2-HLA-B2709-9mers-191P4D12B

Each peptide is a portionof SEQ ID NO: 5; each

start position Is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eightPosl 13579

(TableXXXI-V7-HLA-B2709-9mers-

191P4012BEach peptide is a portionof SEQ ID NO: 15; eachstart position is specified,the length of peptide Is 9amino acids, and the endposition for each peptideis the start position plus

eight.

FE 6PRSQsE E 10~

TableXXXI-V9-HLA-82709-9mers-1911P4D1283

Each peptide is a portionof SEQ 10 NO: 19; eachstart position is specified,the length of peptide is 9aino acids, and the end

position for each peptideis the start position plus

eight.

IPos 124578 ore

TabIeXXXI-V9-H-LA-B2709-9mers-19 lP4D12B

Each peptide Is a portionof SEQ ID NO: 19; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.

FPo 1-23-456789 sor

DIRRELLAGIL ,rF93 FRFIQCLLLI23

01MRRELLAGII1106 VPQQV1

[871KKLKKAFRF L91 KAFRFIQCLI 14

[1211RGYFQGIFMj 1-4

E1 RITFNFFLF 13

232PPVF

[jjFNFFLFFFL1] hLFF1FP [2

84 RKKLKA 12

TableXXXI-V1O-HLA-B2709-9mers-

191 P4D12BEach peptide is a portionof SEQ ID NO: 21; eachstart position is specified,the length of peptide Is 9amino acids, and the endposition for each peptideis the start position plus

eighL

Posl 1123456 789 (cr

1 GRPAGLG146 GELGTsDW~ 1-i38 LGSDT 1 3

TableXXXI-VIO-HLA-B2709-9mers-19IP4019R

Each peptide Is a portionof SEQ ID NO: 21; eachstart position Is specified,the length of peptide Is 9amino acids, and the endposition for each peptideis the start position plus

eight.

[Pos 123456789DGT-SDVVTVVr2

DAGELGTsDV E:j

TableXXXI-VII1-HLA-832709-9mers-

191 P401 28Each peptide is a portionof SEQ ID NO: 23; eachstart position is specified,the length of peptide is 9

Lamino acids, and the end

is the start position pluseight.

F12] RRRM 22

114] RL V V P 163F-8] VVP 13

!I1 MVP E9L1,DRVVPPD 1ITableXXXI-V12-HLA-

B32709-9mers-191P4D128

Each peptide is a portioniof SEQ ID NO: 25; each

start position isspecified, the length of

peptide is 9amino acids,and the end position foreach peptide is the start

position plus eight.

[Pos 123456789

EqCSYSTLTTV F11

TableXXXI-V1 3-lILA-1B2709-9mers-191P4012B J

00

00

Each peptide is a portionof SEQ ID NO: 27; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.Pos 123456789 score

2 QVTVDVLAD 4

VDVLADPQE

6 DVLADPQED 31l] SQVTVDVLA 2

F-3J VTVDVLADP 1

4 TVDVLADPQj 18 LADPQEDSGI 19 SIjADPQEDSGKJ 1

TableXXXI-V1 4-HLA-B2709-9mers-191P4D12B

Each peptide is a portionof SEQ ID NO: 29; each

start position isspecified, the length of

peptide is 9 amino acids,and the end position foreach peptide is the start

position plus eightPos 123456789 score

3I SNPPASASL 18 SASLVAGTL ii4 NPPASASL D9TableXXXIl-V1-HLA-

B4402-9mers-191P4Dl2B

Each peptide is a portionof SEQ ID NO: 3; each

start position is specified,the length of peptide is 9amino acids, and the end

position for each peptide isthe start position plus

eight.

Pos 123456789 score7 AEMWGPEAW 27

4371 SEEPEGRSYI 2512 PEAWLLLLL Il2359 GEQVGQVAW[ 2373 GEGAQELAL 23159 LEEGQGLTL 23263 REGAMLKCL 23

452 REIETQTEL 23

ITableXXXII-V1-HLA-4402-9mers-191P4D12BEach peptide is a portionof SEQ ID NO: 3; each

start position is specified,the length of peptide is 9amino acids, and the end

position for each peptide isthe start position plus

eight.Pos 123456789 score

272 SEGQPPPSY 22

440 PEGRSYSTL 22

g LEDQNLWHI 21470 EEEDQDEGI 2114 AWLLLLLLL 18

413 EESVGLRAE 17

13 EAWLLLLLL 16

100 QPPPPRNPL 16351 VVVGVIAAL 16388 EELTLTREN 16

9 MWGPEAWLL 15106 NPLDGSVLL 15124 EYECRVSTF 15138 QARLRLRVL 15237 THILHVSFL 5i246 AEASVRGLE 15

337 EDSGKQVDL 15

393 TRENSIRRL 15453 EIETQTELL 5487 QENGTLRAK 15494 AKPTGNGIY 15

1501 IYINGRGHL 1536 TSDVVTVVL 14

74 EGAQELALL 14]78 ELALLHSKY 480 ALLHSKYGL 1498 VEQPPPPRN 14

135 GSFQARLRL 14

145 VLVPPLPSL 14151 PSLNPGPAL 141

160 EEGQGLTLA 14173 AEGSPAPSV 14202 AAVTSEFHL 14

232 QDQRITHIL 14274 GQPPPSYNW 14294 RVDGDTLGF 14

TableXXXII-V1-HLA-B4402-9mers-1 91 P4D1 2B

Each peptide is a portionof SEQ ID NO: 3; each

start position is specified,the length of peptide is 9amino acids, and the endposition for each peptide is

the start position pluseight.

Pos 123456789

307 TEHSGIYVC [14

319 NEFSSRDSQ 14362 CLLVWVVVL 1387 EEELTLTRE 1394 RENSIRRLH 14

420 AEGHPDSLK 1438 EEPEGRSYS 14

PLSLGAEMW 13

8EMWGPEAWL 1310 WGPEAWLLL 13

11 GPEAWLLLL 1317 LLLLLLASF 13

LETSDVVTV 1342 WLGQDAKL 1377 QELALLHSK 1386 YGLHVSPAY 13

105 RNPLDGSVL 13117 AVQADEGEY 1375 GSPAPSVTW 13

188 KGTTSSRSF 13213 SRSMNGQPL 13231 LQDQRITHI 13251 RGLEDQNLW 13348 ASWVVGVI 1335 WGVIAALL 13

353 VGVIAALLF 13356 IAALLFCLL 13378KAQQMTQKY 13

38 YEEELTLTR 13

410 SQPEESVGL 13446 STLTVREl 13458 TELLSPGSG 13468AEEEEDQDE 13471 EEDQDEGIK 13

TableXXXII-V2-HLA-B4402-9mers-191P4D12B

00

Each peptide is a portionof SEQ ID NO: 5; each

start position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.pos] F 2-345678-9

1 GQ DA KLP CL1 Li?2 Q DA K-LPC LY 12]4F PCLYRG L

FTTab -eXXXII-V9- HLA-FB4402-9mers-

191P4D12BEach peptide Is a portionof SEQ ID NO: 19; eachstart position is specified,the length of peplide is 9amino acids, and the endposition for each peptidleis the start position plus

eight.

Pos 1 123456789 scoeF J I LL R ITFNF 14j4MI FLRIT FN FFLD1 221 FPFLW 14J

RKKKL-KK-AF 1f93 FIQL 1 141 01 L G L LK-VRPL 14~

F 15 FNFFLFFFL 13F17 FFLFFFLPF 1

19 LFFLFP 1271 LWVFFIYFY 1328 FFIFYF 13291 VFFIYFYFY 13

FFIYFYFYF F1-3

F79FEFTRK 1387 KLKAFR 13

961 IQCLLLGLL 1311 NSCDCERG-YF13

11-6 SCCEGY 13

126 GIMQAAP 132

2FPLWFFIY 1

F47VAQAGLELL 1

5FICLLLG 12

[14 TFNFFLFFF r71124F PFPLVVFFII 1iiL31 FIYFYFYFF F1138 LMESHY 11E44 ISHYVAGL Dlj

TableXXXI I-V9-H LA-B34402-9mers-191P4D12B

Each peptidle is a portionIof SEQ ID NO: 19; eachstart position is specified,the length of pepticde Is 9amino acids, and the endposition for each peptideis the start position plus

eight.Pos 123456789 scr

461 Y VAQAGLEL D =1l774 HHACEF 11

88 KLKAR I

TableXXXII-V9-HLA-B34402-9mers-

191 P4D12BEach peptidle is a portionof SEQ ID NO: 19; eachstart position is specified,the length of peptidle is 9amino acids, and the endposition for each peptidleIs the start position plus

eight.

FPo sI 2468

12 ELA IL 2F GILRTF2

11-9 CEG F 20F23 LFLF

F91 KAR F 17]F13IFFLF 1

F5-8]PASS 15F63 FLV1T 15I 811 FKKK s

92j AFRFqc-L-L L-:15j

TabIeXXXII-V1 1.HLA-B34402-Smers-191P4D12B

Each peptide Is a portionof SEQ ID NO: 23; eachstart position is specified,the length of peptide Is 9aino acIds, and the end

position for each peptideis the start position plus

eight.Pos 123456789 sore

LD] MvPPLP~sLNF-

TableXXXII-V1 2-H LA-B4402-9mers-191P4Dl2B-

00

00

Each peptide is a portionof SEQ ID NO: 25; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.

Posi 123456789 Iscore

73 SEEPEGCSY 2476 PEGCSYSTL

:[EEPEGCSYS 13

Each peptide is a portionof SEQ ID NO: 3; each

start position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.[pos( 123456789 [score

71] DAGEGAQEL 2245 LAEASVRGL][-23

1287 GPLPSGVRV [23i34ZI SASVVVGV Lz 2l[493 RKPTGNGI

KPTGNGIYI

106 NPLDGSVLL

QA2LRLRVL L 357 MLLFCLLV 1911571 PALEEGQGLI jj1S11I GPEAWLLLL I i9F13 EAWLLLLLL F 1912021VTSEFH L

228 PGLLQDQRI(3561 IAALLFCLL Lf1

110 QPPPPRNPL 181

(27NGQPLTCW[ 18(27PPSYNWTRLI Lip'II1DPQEDSGKQ I 8

345 LVSASV 18

419 RAEGHPDSL 1

ETSDVVTW F179PAYEGRVEQ IZ Z7

13 PAGSFQARL fjffASVVWGVI4RSYSTLTrV46STLTTVREI

10 WGPEAWLLL

3GELETSDWI 6

[121 DEEYCV i[21911 QPLTCWS1-I]16

129LPSGVRVDG][i6(135DSQVTVDVL][16[1VDLVSASW][161 DLVSASVW] 1639ILLCLWV J76T

TableXXXIIII-V1-LA-B5101-9mers-191P4D1

Each peptide is a portionof SEQ ID NO: 3; each

start position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.

[PosI 123456789 scre]

36 0 LFCLLWW 13621 CLLVWL 61(3901 LTLTRENSI D 16

LETSDVTV (65 VAWARVDAG[ 151F79 LALHSKYG 1 151[148 PPLPSLNPG

12311 LQDQRITHI] 1511276 1PPPSYNWTR][ i5338 DSGKQVDLV[

13581 ALLFCLLW 151lI1QKYEEELTh f's

(407 DPRSQPEES][ 1411 IQPEESVGLR1[ 22LASFTGRCP

26TGRCPAGEL j 29 PAGELETS31 AGEETSDV4

47 DAKLPCFYR 14

75~ GAQELALLH 1 141

[2LHSKYGLHV j( 141

1721 TAEGSPAPS 1

11761 SPAPSVTWDI 14253LEDQNLWHI

286 DGPLPSGVR 1((FPPLTTEHS FT4jPPLTTEHSG [7iMPLSLGAEM 133PAGELETSD 1113/3TSDVVTL 13

5LPCFYRGDSi 131f31 EGAQELALLI 131

9VSPAYEGRV1 131302 PPPRNPLDG 13

[1471_VPPLPSLNP L1

TableXXXII-V14-HLA-84402-9mers-191P4D12B

Each peptide Is a portionof SEQ ID NO: 29; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eightIsi123456789scrSSNPPASASL 15

LI 81SASLVAGTL 15

,E21 SNPPASASI Li7

-TableXXXIIII-V-HLA-LB5101-9mers-1 91P4D1 2B

00

00

TableXXXIlII-V1 -H LA-85101 -9mers-1 91 P4D1 28

of SEQ ID NO: 3; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position pius

eight.[Pos[123456789 sor1501 LPSLNPGPA -1-3'177 PAPSVTWD-T]13178APVTT 13211 VPSRSMNGQ 1275 QPPPSYNWT13j300 LgFPPLTTE [13322 SRDSQvTV 1

37 KQM TQKY 14 78 1KQ A MN HF V 13r42 WLGQDAKL 12

~YRGDSGEQvI 12F86 YGHVP 12101] PPPPRNPLD 12109 DGSVLRNA] 12119 QADEG EYEC 12154 NPGPALEEG 121i59 LEEGQGLTL F12167 LAASCTAEG 12

[168 AASCTAEGS 12234 QRITHILHV F122-65 ALK C LS E 12309 HSGIYVCHV 12I339 SGKQVDLVS 1246-7AEEEQD12480 _QAMNH FVQE 121

,F 1LGAEMWGP 1158 SGEQVGQVA 1

F67 WARVD AGEG 11103 PP RNPLLDGS 1116 NAVQADEGE 11137 FQ ARLRLR 1139 ARLRLRVLVF11201 SAAVTSEFH 11216 MNGQPLTCV F11247l FEASVRGLED 1 1111

1 TableXXXIlIII-V1 -HLA-B5101-9mers-191 P4DI2BjEach peptide is a portionof SEQ ID NO: 3; each

start position is specified,the length of peptide Is 9amino adds, and the endposition for each peptideis the start position pius

eight9os 123456789 score285 LDGPLPSGV 11296 DGDGpp 1304 PLTTE HSGI 13-06 TTEHSGIYV- 11310 SGIYVC HVS 1324 RS VV335PQDSKQ 1

35 1 W GIAL3931 TRENSIRRL I1427 LDSCV1

470 EEEQDEGi11502 YINGRHV 1

TableXXXIIII-W7-HLA-85101 -9mers-191P4D12B

Each peptide is a portionof SEQ ID NO: 15; eachstart position Is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position pius

eight.Pos3456789

f ableXXXIII-V9-HLA 85101-9ers-191P4D128

Each peptide Is. a portionof SEQ ID NO: 19; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.Pos1E 123456789 score

59 NPPASASLV

6SASLVAGTL E2101l LGLLKVRPL47 VA(aGlL

9KAFRFIQCLI JLLAGILLRI E

21 FFPFPW iA23A LPFPLWVflEF25 FPLWFFIY 16

24PFPLF VFIF10-O7 RPLQHQGVN jj~

fIVRRELLAGI j:LA-GNLLRIT j

60 PPSALVA fiji461 PASASLVAG 14j67 VAGTLSVHHEE98 CLLLGLLK 7

LI1CERGYFQGIfl 139QAGLELLGS F126CACFESFTK 12~

20O FFFLPFPLVE:f50O AGLELLGSS fnj]

121 RGYFQGIFM

Tab~eXXXIIII-W7-HIA-B5101-9mers-

191 P4D12BEach peptide is a portionof SEQ ID NO: 15; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.P34679 ce

00

00

TableXXXIIII-V1O-HLA-851 O1-9mers-191P4D12B

Each peptide is a portionof SEQ ID NO; 21; eachstart position Is specified,the length of peptide is 9amino acids, and the endposition for each peptideis the start position plus

eight.

[PLGTsDVVT 21J-678fGTDVV 217

79LGSD 1EFPAELTS 1

1IAGL3]D 1F1JPAE TSL9

TableXXXIIII-V1 3-H LA-85101 -9mers-

191 P40128Each peptide is a portionof SEQ ID NO: 27; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideIs the start position plus

eightPos 123456789 scr::]IADDS-G

ADQE ~j

213 VTVDL=5

TableXXXIV-V1-HLA-Al l0mers-191P4D128

Each peptlde is a portion ofSEQ ID NO: 3; each startposition is specified, thelength of peptide is

amino acids, and the endposition for each peptide isthe start position plus nine.Pos]1234567890 ~ER

36 KS D-VVT VL G][771 QELALLHSKY[ I7

3061 TTEHSGlYVC[ 17!377 RKEQ2KY411]QESGR 74 f DAPGSY 7

304 PTESI 632 VDQDGK[1365VVLSR]385KYELLT L__.4571 ILSGS 6

85 LH PAI S[116NVAEE T[251 TEFLVSR

LTableXXXI V.V2-H LA-Al-]l0mers-191P4D12Bj

Each peptide is a portionof SEQ ID NO: 5; each

start position is specified,the length of peptide is amino acids, and the endposition for each peptide isthe start position plus nine.

[P0s 123456789l[IJ GQDAKLPCRYL

[TableXXXI V-W-H LA-Al l0mers-191P4D12B

Each peptide is a portionof SEQ ID NO: 15; eachstart position is specified,the length of peptide is amino acids, and the end

position for each peptide isthe start position plus nine.[Posl 1234567890 I~eR[~DPRQE

TableXXXIIII-VI 2-HLA-851 01-9mers-191P4D128

Each peptide Isea portionof SEQ ID NO: 25; eachstart position is specified,the length of peptide is 9amino acids, and the endposition for each peptideIs the start position plus

I eightPos [123456789scr

F~ CSSLT 17

F EPEGSYST=1PE GCSST .8

TableXXIV-V1 -HLA-A1 -1l0mers-191P4D12B

Each peptide is a portion ofSEQ ID NO: 3; each startposition Is specified, thelength of peptide is 10

amino acids, and the endposition for each peptide isthe start position plus nine.

F1RS] 124680 sc-ore271 LZEGQPPPSY -3

45GDAKLPCFYLZ405 HDPRS QPEE F-2493 RKPTGNGIY [-20158 kLEEGQGLTL i

11GPEAW LLLLL F-172 1AGE GAQELAL [j8

E10 PLDGSVLLRN F-1

I3iE!ETQTELLS L1Z8

00

00

TableXXXIV-V9-H 'AAl l0mers-191P4D18

Each peptide is a portion ofSEQ ID NO: 19; each start

position is specified, thelength of peptide Is 10

amino acids, and the endposition for each peptide Isthe start position plus nine.Pos 1234567890 scorr281 W FFIYFYFY [F17924 1PFPLW\FFIY1. 8

RE2 A ILL] 1[37_1YFFLEMESHY][ 77[_26 PLV F -YF 1114 1\VNSCDCERGY 16~6-82 FTKRKKKLKKj 15

F391 FLEMESHjYVA IF13116]jSCDCERGYFQ 1118DCRYGI1

331 YFYFYFFLEM I 11[41 EMEHYAQ 1]

551F 1z SNP1SS

I9F RFIQLLL 102

96 FIQC LLLGK [j

TabIeXX(XIV-V1 0-H LA-A1-10mers-191p04D12B

Each peptide is a portionof SEQ ID NO: 21; eachstart position is specified,the length of peptide is 10ami no acids, and the end

position for each peptde Ithe start position plus nine.P-osli 12345 67890 lscorel

Each peptide is a portionof SEQ ID NO: 23; eachstart position Is specified,the length of peptide is

aino acids, and the endposition for each peptideIs the start position pius

nine.fEos 1234567890 scre

F-1 61 MPEP I=i

TabIeX)(XIV-V1 2-H LA-Al l0mers-191 P401 28

Each peptide is a portion ofSEQ ID NO: 25; each startposition Is specified, thelength of peptide is 10

amino acids, and the endposition for each peptide Isthe start position pus nine.

E9os 124680score[D MSEEIPEGS 19f

TableXXXIV-V1 3-H LA-Al-It 0mers-191P34D128Each peptide is a portionof SEQ ID NO: 27; eachstart position Is specified,the length of peptide is 10amino acids, and the end

position for each peptide isthe start position plus nine,

IEos 1123567890 scorefD LADPQEDSGK [74]D1 TXVDVLADPQE F10DNSV=TVDV=LAD

21VVDVLADPIQ 7

rTabIeXIV-V1 4-H LA-Al-j10mers-191P4D12B

Each peptide is a portionof SEQ ID NO: 29; eachstart position Is specified,the length of peptide is 10amino acids, and the endposition for each peptideis the start position pius

nine.Po1346790sc r

SLVGTLV 1

[DNASAS-LVA1121

[TableXX(XV-V1 -HLA-A0201-10mers-191 P4D1 2BEach peptide is a portion ofSEQ ID NO: 3; each startposition Is specified, thelength of peptide is

amino acids, and the endposition for each peptide isthe start position plus nine.

E~ol 1234567890 244 IFLAEASVRGL 3-58 IALLFCLLVVV [2913591 _LLFCLLVVVV][ 29215 SMNGQPLTCV 27158 IALEEGQGLTLI 26

F30] LLQDQRIT-HI F3-44 DLVSASVWVV 1125133]1 ELETSDVVTV239 ILHVSFLAEA 24

426 SLK N T 1C 24

1B LLHSKYGLHv][ 23NJ~ RVLVPPLPSL Li f252 GLEDQNLWHI][ z

12841 RLDGP LPSGV if23!357 AALLFCLLW 112316g LLLLLLLASF 1122350 WVGVM I_362CLVVVVLM Dj22!392 LTRENSIRL f]22l3Ij GVMLLFCL7 ij3551 VIAA4LFCLL j[ 21179J LALLHSjKYGL F1 27

1236 THL'IF F3476 VSASWWGV F50oof GIYINGRGHL 2!1411 LRLRVLVPPL 1912351 WVGAALL -jj9~

1356 ILFCLLV JI 1ii!9f36 FCLLYVL7h3811 QMTQKYEEE-L 19Th

147 GIKQAMNH7FV F1Th![1 EMWGP AWLL 11815 WLLLL A 1

10s-19=T1428f

00

00

STableXXXV-V1-HLA-A0201 -1 Omers-1 91 P4131 2BEach peptide is a portion ofSEQ ID NO: 3; each startposition Is specified, thelength of peptide Is 10

amino acids, and the endposition for each peptide isthe start position plus nine.

[Pos 1234567890 ts.cor[1-71 LLLLL.LASFT [iI-1-8

[i121 VLLRNA6VQ FT181152 SLNPGPALEE [181[121 TAEGSPIAPSV [[181201 [SAAVTSEFLJ[I-221 LTCWVSHPGL]I 181[2-4J9SVRGLEDQNL F -78j

F ]SASVVVW:GVl F 8[36 0_ LF C LL WV F1814181 LAGP J1811 WGPEA FLL-17111 LEAWLLLLLLL F 171 25 FTGRCPAGEL][-1-71

GDSG EVGQV[ F1 7]VDAGE GAQEL] 17

S73 GEGAQELALL Jr 177Fj-3 FPAGSfQARL J[ 71137 FQARLRLRVL]-7

1202 MTEFHLVJ1 177~2411 HVSFLAEASV]IIIP305 LTTEHSGYV ILPI

F3631 LLWVVV'LMS ILII713891I. ELTLTflENSI ]lZ 118 LLLLLASFTG 16 A~F61 QVGQVAWARVI 161l

[89 IHVSPAYEGRV II[1381 QARLRLRVLVj Il-1401 RLRLRVLVPPI 16

11641 GLTLMSCTA J1r.iil-11-66 TLAASCTAEG ]161[257 NLWHIGREG j[ 1611259 IWHIGR EGAML l[ 16[341 KQVDLVSASV jF- i1370 1LMSRYHRRKA IiI1441 GRSYSLTTV IF 176

7 J AEMWGPEAWL[ ]5iZii GPEAWLLLL ]Ej

TabieXXXV-V1 -HLA-A001 -lomers-1911P4DI2B

Each peptide Is a portion ofSEQ ID NO: 3; each startposition is specified, thelength of peptide is 10

amino acids, and the endposition for each peptide Isthe start position plus nine.

[Pos 1234567890 1s-r[191 LLLLASFTGR 1

[34] LETSDYWVTVV LA1721 AGEGA ELAL71181 vTwDTEVKGT E2291 GLLQDqRITH j:j262 GREGAML-KCLF17299 TLGFPELTTE JD321 FSSRDSQVTV] 75343 VDVAV I 15

1349SVWVGVIAA] 15~-~397 SIRRL-HSHHT] 175

[409 RSQPEESVGL I(1511445 YSTLTTVREIr71447 TLTTV(REIET 1 7h460LLSPGSGRAE flF1-55011 IYINGRGH7LVF 7

F-12] PEAWL LLLL.r 74LLLASFTGRCELJ5

f[J LLASFTGRCP] 74jETSDVVWL] 14

F80 ALLHSKYGLH F14[871 GLHVSBAYEG 7i i[i-07] PLDGSVLLRN I[14[iii1]1 SVLLR NAVQA][ 141113 LLRNAVQADE]L4FI1501 LPSLNPGPAL] 14~1156 IGPALEEGQG-L][ 141

118APSVTWOTEV][14195 SFKHSRSAAV][ 14f233 QRITHLHV ][jr1j~ SGVRVDGDTL [T1412981 DTLGFEPLTTJ 173-11 GIYVCHVSE]D323 SRDSQVTVDV 14324RDSQVIVDVL 71

13321VLDPQESGK] F1411342QVLVAS JD142 EIE TTELL II 141

TableXXXV-V1-HLA-[A0201-l0mers-1 91P4D)12B3Each peptide is a portion ofSEQ ID NO: 3; each startposition is specified, thelength of peptide is

amino acids, and the endposition for each peptide isthe start position plus nine,

[P0s 1234567890 e

[47j LRAKPTGNG11I 4I

TableXXXV-V2-HLA-1A0201-l0mers-

191P4D12BjEach peptide is a portion ofSEQ 10 NO: 5; each startposition is specified, thelength of peptide is

amino acids, and the endposition for each peptide isthe start position plus ninel

[10 LYRGDSGEQ4II14CLYRG6DS GEQ D

,D1~ KLPCLYRG-DS-F 711

TabieXXXV-W-HLA-A0201-1 Omers-

191P4D128Each peptide is a portionof SEQ ID NO: 15; eachstart position is specified,the length of peptide is amino acids, and the end

position for each peptide isthe start position pus nine.[PosI_1245780 R~

TableXXXV-V9-HLA-[A0201-l Omers-1 91 P4D1 281Each peptide is a portion ofSEQ ID NO: 19; each startposition is specified, thelength of peptide is

amino acids, and the endposition for each peptide isthe start position plus nine.j

[PosI 124567890 e[1001 LLLVRLF -2]E J LLAGILLRIT JA~

00

E

0

0

O

(O

O0

TableXXXV-V9-HLA-A0201-10mers-191P4D12B

Each peptide is a portion ofSEQ ID NO: 19; each start

position is specified, thelength of peptide is

amino acids, and the endposition for each peptide isthe start position plus nine.

Posl 1234567890 Iscor

A0201-10mers-191P4D12B

Each peptide is a portionof SEQ ID NO: 21; eachstart position is specified,the length of peptide is amino acids, and the end

position for each peptide isthe start position plus nine.Pos 1234567890 so

8]ELGTSDVVTV

GTSDWTVWL 18-ILGTSDVVTrVV

IPAGELGTSDV 13

TableXXXV-V12-HLA-A0201-10mers-

191P4D12B

Each peptide is a portion ofSEQ ID NO: 25; each startposition is specified, the

STableXXXVI-V1-HLA-A0203-10mers-191P4D12B

Each peptide is a portion ofSEQ ID NO: 3; each startposition is specified, thelength of peptide is

amino adds, and the endposition for each peptide isthe start position plus nine.

00

00

IPOSI1 1234579 score1160 IEEGQGLTLA[ 19

[-R4 RSHSRS F1 9349 SVWVGVIAA 19F59 1GEQvGQW F18

12391 IjLHVS 7pEA 18..J.1671 EGQGLTLAAS [ThIj19511 SKHSRSMAV F 177350 IWVWGVIMAL 11171

LGAEMWGPEA1j 1-0111 AW1L.LLI-LA j]iof-221 LASFIGROPA I 921391 'VTVVLGQDAJF 10

I 571 DSGEQV GQVA F .1I 63 GVAWARV0Al 10!

F67 WAV6RVDA GEGAf10711 DAGEGAELA]j. 10

F-84] SKYGLHVSPA] I 101-0811 LDGSVRN Fi 10F1111 SVLLRN8VQA] F10F125 YECRVS TFPA]. 10FL301 STFPAGSFQAJ 110JF49]1 PLPSLNPGPA]. 10RLs9] LEEGQGLTLI 10FW641 GLTLAA SCTAJ 7f161F1691 ASCTAEgSPA.1 ][i0F11931 SRSFKHSRSA riol2-371 TH-IiH-vSFA 170

F257 NLWHIGREGA ][iIq339 SGKQ VODLVSA 170

[3-J8]ASVWVGVIA][ 103701 LMSRYHRRKA][ ]iO

F4-] QfPEESVGLRA[ -101ELLSPG SGRA] ][10

4721 EDQOEGIKQAj I1- 01[4851 FYIQENGIRA ]j70

G AEMWGJPEA F91

F-2]ASFTGRCPAG JF2lVTVVLGDAK I[ 21

F58 SGEQvG.QvA~ 219QVAWVAGE

681 ARvDAGEGAi 9F7-2] AGEGAQELAL 91J

KYGLHVSPAY 119

TableXXXVI-VI-HLA-1A0203-1 Omers.1 91 P4DI 2BEach peptide is a portion ofSEQ ID NO: 3; each startposition Is specified, thelength of peptide Is 10

amino acids, and the endposition for each peptide isthe start position plus nine,,

[PosI1 1234567890 j[score]1109 DGSVLLRNAV 112 V LLRNLV6QAD ][79176 E~jRVSTFPAGLi131 jTFPAGSFQAR 9I~

[1501 LPSLNPgPAL LI^ 11651 LTLAASCTAE]FEI1170 SCTAEGSPAP [I-12381 H!LH-VSFLAE [21240 LHVSFL.EAS FE~q125 LWHIGREGA-M [27340 GpKQvDLSA~s][91-g371MSRYHRRKA L79412 PEESVGLRAEF 714-60 LLSPGSGR-AEIF79473 DQDEGIQM 1486 VQENGTRA ]7 9

TableXXXVI-V2-HLA-A0203-1 Omers-

191 P4012BEach pepbde is a portionof SEQ ID NO: 5; each

start position Is specified,the length of peptide Is 10amino acids, and the endposition for each peptideis the start position plus

nine.PoIs 13579 cr

1101E DiTL

FEach peptide is a portion ofSEQ ID NO: 19; each start

position Is specified, thele ngth of peptide is

amino acids, and the endposition for each peptide isthe start position plus nine.Po 1234567890123 YFGFA 19

41l EMS-VQ 18

124 F I1~M 17

59 NPAASV 681ATSHC 831 TKKKKK 0

12 YQIMAL~40LEEHVQ19

MEHYAG[9!5=4 LLSNPA [9

=5 GSNPAA 60l PPSSLA Z69GTSHCC[

84 KRKKLKA

TableXXXVI-V1il-HLA-A0203-1 Omers-

191 P40128

Pos 1235679NoResultsFound. -11

TableXXXVI-VI 2-H LA-A0203-1 Omers-

191P4D12B[PosI 124679 Fscoi

TableXXXVI-V1 3-HLA-1

191P4D12B JEach peptde is a portionof SEQ ID NO: 27; eachstart position is specified,the length of peptide is

TbeXX-V9-HLA-1A0203-lOmers-I

19=,=j 4D~12B=~J

00

00

TabIeXXXVI.V1 4-H LA-A0203-1 Omers-

191 P41I2BEach pepfide is a portionof SEQ ID NO: 29; each

start position is specified,the length of peptide is 10amino acids, and the endposition for each peptide isthe start position plus nine.

rPo0s 12356790 e

G S SNPPASAPPASASLV

E]SNPAAS

TableXXXVII-VI HLA-A03-lomers-191 P4D 12B

Each peptide is a portion ofSEQ ID NO: 3; each startposition Is specified, thelength of peptide Is

amino acids, and the end

position for each peptide isthe start position plus nine.Pos 13457890 ]]score152 LSL NPGPALEE] 203 AVTSEFHLVP 284 RLDGPLPSGV]1_20345 LVSASVVVG

3521 wGVMLLFf21369 VLMSRYHRR1~ 201

17 LLLLLLASFT 1191135 VYVIWRY 191

4 1-9 R HP LK T19F19 ILLLASFTGR 118

117AVADEEY][181

1442] PLSL 1

[3591 LLFCLLVV F 18]400 RLHSHHTDPR [18450 TVREIETQTE 1181

WLLLLLLLAS 1718 [LLLLLAS FTG F1742 VVLGQDAKLP 1

Bj~ LLNAVADE iZ145 VLVPLPSLN J-7

jjgKGTSSRSFK F 7j17KHSRSMAVTS 171

F24 RVDGDTLGFPF 173PLTTEHSGIY F 77

376 LVVVVVLMSRI 17391 TLTRENSIRR 17443 RSYSLTTVIR F17460 LLSPGSGRAE Il1f[ QEALHS 16g LLHSKY GLHV -16

11 VLLRNAVQAD 16F1-23 GEYERVSTFF 17[C6jLV PPPSLN P 1 61E SUAEg

00

00

TabIeXXXVII-V2-HLA-A03-l0mers-1 91P4D12

Each peptide is a portion ofSEQ ID NO: 5; each startposition is specified, thelength of peptide is 10

amino acids, and the endposition for each peptide isthe start position plus nine.

P0s 12345678907 [scoree

CLYRGGEQI 181SKLECL~GDS 11

LYRGEQVII1CZ QDAKLP~LYR( 1j GQDAKLPLY 91

PPCRGD 81

TableXXXVII-WI-HLAA03-.i0mers-191P4D12B I

Each peptide Is a portion ofSEQ ID NO: 15; each startposition is specified, thelength of peptide is 10

amino acids, and the endposition for each peptide isthe start position plus nine.

1234567890score

[HTDPRSQSEEL16

TabIeXXXVII-V9-HLA-A03-10mers-191P4D12

Each peptide Is a portion ofSEQ ID NO: 19; each start

position is specified, thelength of peptide is 10

amino acids, and the endposition for each peptide isthe start position plus nine.

Ps 123567890 [scoreSSLVAGTLSVH 24

102 GLLKVRPLQH 23

E2ILLRIN FF 216LVAGTVHH [21

98 CLGLKR 21121 RITFNFFLFF

96 I61L]GLLK LII105 KVRPLHQGV Li

FL2FP21 FF 1

!I LL!GLLKVRP 18

TabieXXXVII-V9-HLA.A0310mers-191P4D12B

Each peptide is a portion ofSEQ ID NO: 19; each start

position is specified, thelength of peptide is

amino acids, and the endposition for each peptide isthe start position plus nine.

Po 1234567890 score

L ELLAGIRI [i21 FFLPFPLW F 17

[8 FTIRKKKKII 726 PL FFIY

2 WFFIYFYFY 2816I GIIRJIFNF I

7 HCACFFTK[151

88 KLKA IQ IE9[I RELLAGIR ]7I~-16 TFFL I 14

F-27! LWFFIYFYF 1439! LEMESVA 1

50AGLELLGSSN 14

51 GLELLGSSNP1453ELLGSSNPPA

77 ACFESKRK 14LLAGILLRIT 1

17RPLQH0VNS 1331 FIYFYFFL 1

LLGSSNPPAS 12[2ASASLAGTL] 128RKKKLKKAFR) 71

86 KKKLKKAFRF 12F18 12126 GIFMQMPWE] 12

1 FLFFFLPFP L 1114!YVAQAGLELL ii7SVHHCACFES[Jj7FESFTKRKKK F71

811 SFTKRKKKLK Li1100 LLGLLVRPL [i1l103 LLKVRPLQHQ 11

125I 11

0 r9 1ableP±2122JIj 3-10mE- 9P41 BI

00

00

Each peptide is a portionof SEQ ID NO: 21; eachstart position is specified,the length of peptide is 10amino acids, and the endposition for each peptide isthe start position plus nine.F os 12 3456 7890f s=co re78] E LG-T SD V VT V1F-_

[]JRPAGLGT 11

F4CPAG-ELGT-SD1119

TabIeXXXVII-VI11-HLA-AO311mers-191 P412B3Each peptide Is a portionof SEQ (D NO: 23; eachstart position is specified,the length of peptide is 10amino acd s, and the end

position for each peptide Isthe start position plus nine.rPos 1245780 R~[D RLR LR VM VPP,[g RLRVVPPL 18

-8 RVM=VPPLPSL EN]M -PLPSLNP F16

[-A3]LRLRVMV 131,

of SEQ ID NO: 27; eachstart position is specified,the length of peptide is 10amino acids, and the end

position for each peptide Is[the start position plus nine.PosJ 1234567890 sejD LADPQEDs3KF 16

)j3]QVTVDVLADP 15E jDVaD ES 1DI~VL-ADPQEDSG LI:ADOWV~LADPQE 131

fTableXXXVII-V 4.H LA-A03-1 Omers-1 91 P4DI 2BEach peptide is a portionof SEQ ID NO: 29; eachstart position is specified,the length of peptide is amino acids, and the end

Iposition for each peptide isthe start position pius nine.I

[Posl 1234567890 iscore

D SSLATF-4NPA1 ALV 1

10 A S V GT3]L

[IDJSSPPSAL[I~1NPPAASL 8GSNPPA6]

TableXXXVIII-V1 -HLA-A26-1l0mers-191P4D12B

Each peptide is a portion ofSEQ ID NO: 3; each startposition is specified, thelength of peptide is 10

amino acids, and the endposition for each peptide isthe start position plus nine.

Eo1234567890score):38]1 DVVTVVLGQDI27r51 ETSOVD W 27KJ WWVGVIAAL 1) 2-71

GVIAALLFCL 26JVVWVLM-SRYI 251

j ]J[TWVLGQDAKLj 2[ 4:131EAWLLLLLLL ]F-231

IfableXXXVIII-V1 -HILA-A26-I Omers-1 911P401 2B3

Each peptidle Is a portion ofSEQ ID NO: 3; each startposition Is specified, thelength of peptide is

amino acids, and the endposition for each peptide isthe start position plus nine.

[gos 1234567890 ]Fc~r144 RVLVPPLPSL -23455 ETQTELLSP-G]Eg~351 WVVGVALL]Eg~[792 LTRENSIR7RL. 22RM EGKQMHF 2211861 EVKGTTSSRS 121)

369 ITIL FL il21

128 RVSTFPAGSF1 331 DVLD)PQEDSG

F439 EPEGRSYSTL[ JD9 91 EQPPRP I 9

24-91 SVRGLEDQNL F191

EN EMWGPEAWLL) 18)129811 DTLGFPPL7TT [18~J-2 FTGRCPAGEL Liz)223 OWSPGLLQ 17

11231 GEYECVSTF[16

224 WTSHPGL 16

2-96 TLG FPP 161472 EDQDGI KQ-A 16

10 WGPEAWLLLL F33 ELETSDVVTVJF F60EQVGQAWA

~jQVA WAR VDAG

116 NAVQADEGEyr 1l30 STFPAGSFQA

1EGQGLTL s 129)SGVRVDGDTL 1

294 1RVDGDTLGFP][

327 QVVDVLDPQ( ThE95 421 EGHDSKDN

00

00

Tab~eXXXVIII-VI -HLA-A26-1 Omers-1 91P40128

Each peptide Is a portion ofSEQ ID NO: 3; each startposition is specified, thelength of peptide is 10

amino acids, and the endposition for each peptide isthe start position plus nine.

[Pos 1 1234567890 1 sco-re4531 EIETQTELLS JI 1-5]2041 VTSEFHLVPS 1[ 141222 TCWSHPGLL II 1412351 RITHILHVSF 174

F24 1FLAEASVRGL I 141247 IEASVRGLED)Q] 142-59 1WHIGREGAML IF14293 VRVDGDTLGF] 143081 EHSGIYVCHV .1-4[328] VTDVLDPQE JF -1 I337] EDSGKQ VOL 14

13451 LVSASVVVVG III Th413-66 IWVVLMSRYH [1413-67 VVVLMSRYHR 14

141 ESVGLRAEGH[ TF4(14291DNSSCSVMSEjF 14(4-36 IMSEEPEGRSY f71444811 LTTVREIETQ IF141F44-] TTVREIETQT IF17450 TVREIETQTE 1l 4452 REIETQTELL JF14.4831 NHFVQENGTLI. 14

[-1-11 GPEAWLLLLLIF 7121 PEAWLLLLLL J[1l-3

[16LLLLLLLASF jIF713F4-01 VRVVLGQ9DAK]Fi131

1131riS581 ALEEGQGLTL It Thi31-8011 SVTWDTEVK Fi1311-11 VTWDTEVKGTII 131203 AVTSEFHLVP F132-331 0QRITHILHV 1F13

DQNLWHGR 1313-05 LTTEHSGIY Fj173

TTEHSGIYVC 17F4381 EEPEGRSYSTJJ 131441] EGRSYSTLTT F131

1471 EEQEGK L3

TableXXXVIII-V1 -HLA-A26-1I0mers-191P4D12B3

Each peptide is a portion ofSEQ ID NO: 3; eac; trposition is specified, thelength of peptide is 10

amino acids, and the endposition for each peptide isthe start position plus nine,Pos 11234567890 ]s-core

485 FVQENGTLRAIF 3500 GIYINGRGHL J13

TableXXXVIII-V2-HLA-A26-10mers-191MP412B

Each peptide is a portionof SEQ ID NO: 5; each

start position is specified,the length of peptide is amino acids, and the end

position for each peptide islthe start position plus nine.1

[P05 12456890Iscore

TableXXXVIII VW-HLA- 1A26-l0mers-191 P40128BEach peptide is a portionof SEQ ID NO: 15; eachstart position is specified,the length of peptide is 10amino acids, and the end

position for each peptide isthe start position plus nine.

[Po 124680score][D HTDPRSQ-SEE o

jTab~eXXXVIII-V9-HLA-A26-I Omers-1 91P401283

Each peptide is a portion ofSEQ ID NO: 19; each start

position is specified, thelength of peptide is

amino acids, and the endposition for each peptide isthe start position plus nine.

1234567890 score(13 ITFNFFLFFF lFi24

28 LWFFIYFYFY Lz24[80 ESFTKRKKKL 123

215

(TableXXVIII-V9-HLA-A26-jliners-I 91P4D128

Each peptide is a portion ofSEQ ID NO: 19; each start

position is specified, thelength of peptide is

amino acids, and the endposition for each peptide isthe start position plus nine.

[Pos 1234567890 []FsoeF271 LWVFFIYFYF 1D

46j YVAQAGLELL 221

S9 FQLLL 17

4E EHYAQ( 16]

121 FRITFNFFLFF] [14

45 HYAA LE

19FLFPW 13

LI~I ILLRTFNF 12

F11 LRTNFF 12

11 11FLPP

F 22 1 FLFLF f l

29!FYYY I121

00

00

Efa-ch peptide is a portionof SEQ ID NO: 21; eachstart position is specified,the length of peptide is 10amino acids, and the endposition for each peptideis the start position plus

nine.jFos 123-456789-0 score]

GT-SD V-VTVVL Q IELGTSDVVT-V 15]

TableXXXVIII-V1 1-HLA-A26-I0mers-1 91 P4121Each peptide is a portionof SEQ ID NO: 23; eachstart position is specified,the length of peptide is 10amino acids, and the endposition for each peptideis the start position plus

nine.

RVMVPLPS 23

TableXXXVIII-V1 2-H L1A-1A26-1 Omers-191 P4D12B

Each peptide is a portion ofSEQ ID NO: 25; each startposition is specified, thelength of peptide Is 10

amino acids, and the endposition for each peptide Isthe tart osition plus nine.

[PosI 1234567890 reEPEGCSYSTLF20

[j3 1MSEEPEGCSY 14

8 EPGCSYST1-1 E SYSTLTT 13N

TabIeXXXVIII-V1 3-HLA-A26-1 Omers-19I1 413Each peptide Is a portionof SEQ ID NO: 3; each

start position is specified,the length of peptide is 10amino acids, and the end

position for each peptide Isthe start position plus nine.Pos 1234567890scr

7 DVLADPQEDS 18'

3I~ QVTVDVLADP [1

STVOVLADPQELIZF-2 SQVTVDVLAD F- lD I DSQ VTVD VIA

TableXXXVIII-V14-HLA-A26-l0mers-191P4D1B

Each peptide is a portionof SEQ ID NO: 29; eachstart position is specified,the length of peptide Is 10amino acids, and the endposition for each peptideis the start position plus

nine.EPos 1234567890o- (score][FSNPAAS3m

Each peptide is a portion ofSEQ ID NO: 3; each startposition is specified, thelength of peptide is 10

amino acids, and the endposition for each peptide Isthe start position plus nine.

[PoRs 12345679 score]132 FAGSFQARL 24

[150 LPSLNPGPAL j4[ii GPEAWLLLLL Iii[439] EPEGRSYSTL 23156 GPALEEGQGL IEE2~1I78 APSVTWDTEV [21!l276 PPP-YN-wTrRL 21176 SPAPSVTWDTI. 19103 PPRNPLDGSV L18407 DPRSQPEESVI 18411 QPEESVGLRAIE1835 ETSDVVTWL 1772 AGEGAQELAL 117

AGSFARLRL F17227 HPGLLQDQRI 1

3PPLTTEHSGI 16

DPQEDSGKQV 16289 LPSGVRVDGD 15H34 DSQVTDV -75

1 TabeXXXIX-V1 -HLA-8B0702-1 Omers-1 91 P4012Each peptide Is a portion ofSEQ ID NO: 3; each startposition is specified, thelength of peptide Is

amino acids, and the endposition for each peptide Isthe start position plus nine.

[Pos 1234567890 ~E1F-71 AEMWGPEAWLI 14D MPEAWLLL 14

[99_EQPPPPRNPL] 1114FI 581 ALEEGQGLTL 14249 SVRGLE QNLI_296 DGDTLG-F-PP-L fi136 1 FCLLVVVV )1409 RSQP-EESVGL] 14!D EMWGPEAW-LL 13M121 PEAWLLLLL E13E13 EAWLILLLLL J[13j

70 VOAGEGAQEL][13j[23j GEGAQELALL 13[11 PPPPRNPLDG 13

11061 NPLDGSVL-R] 13141 LRLRVLVPPL [:1j212 PSRSMNGQPL]1 13236 I _THILHVSFL 1 1329 H gREGAL 1277l PPSYNWTRLD 13j287 GPPSVRD9 131336 QEDSGKQVDL][ Th

1351j VVVGVIAALL ][1j355 VIAALLFCLL ][13j495 KPTGNGlYINI[13~

10!1 WGPEAWLLLL Eg~1-00 QPPPPRN PLO 12104 PRNLDGSVL IF12137 FQARLRLRVL 12~j144 RVLVPPLPSL I121

114881 PPLSL-NPG-P]II1215 NPGPALEEGQ jiD160 EEGQGLTLAA j12E [VPSRSM NGQP 12

(231 LITIL 2

00

00

TableXXXIX-V1 -HLA-80702-I Omers-191PD12Each peptide is a portion ofSEQ ID NO: 3; each startposition is specified, thelength of peptide is 10

amino acids, and the endposition for each peptide Isthe start position plus nine,

[Posl 1234567890 ]ER~1244 [LEAVGLI ].1211262 IGREGAMLKCL] 7213081 EHSGIYVCHV ][12]1337jEDSGKQ VOLV 12[1~13-50 WVVGVIAAL][2383 [QKYEEELTL][ 121

i3921 LTRENSIRRL][ 12,14-41 EGRSYSTLTT][ 12145211 REIETQTELL 11 12

FTGRCPAGEL][F 171F 411 TVVLGQDAKL] [i1i

F5-61 GDSGEQVGQVF1 Lii138 QARLRLRVLV 11ll

2011~ sAAvTSEFHL 2-191 QPLTCWVSHP.F- ]I2211 LTCWVSHPGLJ. 112575QPPPSYNWTR F1112-80 YNWTRLDGPLF Liii354 GVIAALLFCL J[F-Ti357 AALLFCLLWV IF 17113581 ALLFCLLVV\I IF j1ji14181 LRAEGHPDSL j- 1i11423 HPDSLKDNSS [j i14-51 VREIETQTEL l111r1462 SPGSGRAEEE] 1I v11500 GIYINGRGHLD

TableXXXIX-V2-HLA-B0702-1 Omers-

191 P40128Each peptide is a portion ofSEQ ID NO: 5; each startposition is specified, thelength of peptide is 10amn acids, and the end

position for each peptide isthe start position plus nine.Pos1 1234567890 1score

L GQDAKLPCLj 11-

TableXXXIX-V2-HLA-80702-l0mers-

191 P4D128Each peptide is a portion ofSEQ ID NO: 5; each startposition is specified, thelength of peptide is 10

amino acids, and the endposition for each peptide isthe start position plus nine.

[Pos 1234567890 scre

I LPCLYRGDsGF [71]1LYRGDSGEQV 1010

TabeXXXIX-V7-HLA-830702-l0mers-

191 P4D1 28Each peptide Is a portionof SEQ ID NO: 15; eachstart position is specified,the length of peptide is 10amino acids, and the end

position for each peptide isthe start position plus nine.Iposi 135 789 scorel

TableXXXIX-V9-HLA-B0702-l0mers-

191 P4D1 2BEach peptide is a portion ofSEQ ID NO: 19; each startposition Is specified, thelength of peptide is

amino acids, and the endposition for each peptide isthe start position plus nine.

[Po 124679 score

F59 NPA2S0A723 LPPLFF25 FPV IY JZ92 AFFQ1L 6~fj

F94 RFQLLG 31100lLGLVPL] 3117RLQQVS] 3IZ MRE1AI 72~

1-4 T FF FFFL 72~I 43 ESHYVAQAGL F172F57SNPSS 2

[TableXXXIX-V9-HLA-B0702-1 Omers-

I 91P4D12BEach peptide is a portion ofSEQ ID NO: 19; each start

position is specified, thelength of peptIde is

amino acids, and the endposition for each peptide isthe start position plus ine[Po 1234567890 1 s~r

E@90 KKAFRFIQCL 1jDlDI RRELLAGILL 1[j11E12 RITIFNFLFF Il...iiE18 FF FLPFL] IiE[f 3111FFFL [46 F1QGLL] li

53 EL SPA[11!

19 PAALAG] I-JASLVAGTLSV] iijl

[E FKKK] ii[9 KfRFQLL]

[87 KKKARI F95 FQLLLL]..1

[ios~ F- KRLHV] 01

EA 20 FFL L]91

E33 YFYFYFFLEM][--9[41 EMESH 1AA]91Ess GSNPS]9I[70 TLVHAC]9F83 TKKK K]9F84 KK K F]9

[12 ERYFGIF][[123YFQGIFMQM][F9

TabIeXXXIX-V1O-HLA-B 0702-1 Omers-

191P4D128

00

00

Each peptide is a portionof SEQ ID NO: 21; eachstart position is specified,the length of peptide is 10amino acids, and the end

position for each peptide Isthe start position plus nine.,IPosl 1234567890 1scorel

GTSDVVTVVL 1F-4]CPAGELGTSD [1477GLTSV~1F7E8 TDVT l

TableXXXIX.V1 1-HLA-80702-1 Omers-

191P40128Each pepde is a portionof SEQ ID NO: 23; eachstart position is specified,the length of peptide is 10amino acids, and the end

ipositon for each peptide isthe start position plus nine.

JPos]13479 0 screl

L RL R VMVPPL F13-8 R VM VP-PL-P SL 13

F- QARLRLRVMV F11]

F lRL RLRVM F

TableXXXIX-VI 2-11-A.80702-1 Omers-

191 P4D12BEach peptide is a portionof SEQ ID NO: 25; eachstart position is specified,the length of peptide is 10amino acids, and the endposition for each peptideIs the start position plus

nine-- POs 1234567890

D EPEGCSYSTL 2

TableXXXIX-Vi 3-H LA-B0702-1 Omers-

191 P4012BEach peptide is a portionof SEQ ID NO: 27; eachstart osition is spcfied,

tihe length of peptide is 10amino acids, and the endposition for each peptideis the start position plus

nine.[posI 123-45-67890 score

DDSQVTVDVLA

D J QVVVLD Z

TableXXIV-V1 1-HLA-A0203-9mers-

191 P4D1 28

IFNoResultsFoun. j

TableXXIV-V1 2-H LA-A0203-9mers-

191P4D12B

Posl 1234678NoResultsFound.

rableXXIV-V13-HLA-A0203-9mers-

191 P4D12B

[Pos 12345678NoResultsFound.

TableXXIV-V14-HLA-A0203-9mers-

191 P40128IPos 4679score

[NoResults Found.

TableXLl-V1 -HLA-81510-1 Omers-

191 P401 28

NoResultsFound.

TableXLI-V2-HLA-831510OA0mers-

191 P4D12B[Es 1.245677890cr

NoResults =ound.

TableXLI-W7-HLA-

191 P4D128[PsI1234567890 IscoreNoResultsFound,

TableXL-V9-HLA.B15lO-l0mers-

191 P40128

7Pos 45780scoreNo ZesultsFoud

TableXLl-VI 0-H LA-

191 P40128

TableXXIV-V7-HLA-A0203-9mers-

191 P40128

PH 1g 23456789 score

TableXXIV-V9-HLIFA0203-9mers-

191P4D12BPos 123456789cr

NoesultsFound.

TableXXIV-V10H LA-AO203-9mers-

191 P4D1 28

Pos 123456789crNoeuts0n

00

00

TableXLI-V1 0-H LA-Bi 510-1 Omers-191P4DI2B

12456790 sc-r el[NoResultsFound.

TableXLI-V1 1-HLA-81510-j1iners-

191 P4DI2B

E 124680score

,[NoResultsFound.

TableXLI-V1 2-HLA-831510-1 Omers-

191 P4D128

jEs 124679icore

IFNoResultsFound.

TableXLI-VI 3-HLA-B15IO-l0mers-

191 P401 28

[P-osJ 124680icorel,t NoResultsFound.j

TableXLI-Vl4-HLA- I831510-j1iners- J

191P4D12B23456890 soore

,FNoResultsFound.

IITableXLII-V1-HLA- 1B 2705-1 Omers-

191P4012B

I[gI 124679scoreNoResultsFound.

TableXLII-V2-HLA-B2705-1 Oiners-

191 P4D12BPos 124680scoe

N oR es-ul-t s-Fou-nd.7

TableXLII-W-HLA-B2705-l0mers-

191 P4D1 28Po 1346790scre

TableXLI-V9.HL1A-B2705-l0mers-

191 P4DI128

Pot 135680 cr

TableXLII-V9-HLA-B2705-1 Omers-191P40128

I 7s12467890soreNoResultou.

TableXLII-VI 0-H LA-B2705-1 Omers-

191 P4012B

[Pos 124679icore],FNoResultsFound.j

TableX~LI-Vi 1-HLA-82705-1 Omers-

191 P4D1 287Pos 124679 coreIFNoResultsFound.[TableXLII-V1 2-H LA- iF 2705-10Oiers-S 191P4D12B13579 cr1

NoResultsFound.][TableXLII-VI 3-HLA1B2705-1 Omers-

191 P401 28

No~esultound.

TableXLII-V14-HLA-B2705-1 Omers-

191 P401 2BPos 124680score

NoResultsFound.

TableXLIII-V1 -HLA-B2709-1 Omers-

191P4D12BPos 123457890sco re

N[-oResultsFound.

TableXLlIl-V2-HLA-832709-1 Omers-

1911P401 28Pos 123-456789-0 score

FTableXLIll-W-HLA-B2709-l0iners-191 P4D1 28

PoN 235780score

TableXLIII-V7-HLA-B2709-1 Omers-

191P4D12B

[Pos score790FNoResultsFound.JTableXLIII-V9-HLA-

191 P401 28

NoResultsEound.j

TableXLll-V1 0-H LA-F82709-1 Omers-191 P401 28

NoResultsFound.

TableXLIII-V1 1-HLA-82709-1 Omers-

191 P4D1 281PsJ12345678901 jscor

NoResultsFound.

TableXLI-1 42-H11A-B 2709- 1 mers-

191P4D128Pos 12345 7890

Noeut ud j[TableXLIII-V1 3-H LA-FB2709-1 Omers-

1 o 9lP4Dl2B

TableXLIlI-V1 4-HLA-832709-1 Omers-191 P40128

Pos 234567890 Fsor]

FNoResultsFound.

[TableXLIV-V1 -HLA-84402-

Each peptide is a portion ofSEQ ID NO: 3; each startposition is specified, thelength of peptide is

amino acids, and the endposition for each peptide isthe start position plus nine.

TableXLIV-V1 -HLA-B4402- Ta bIe X L V- V1 HLA.8- B4 402 Tabi1eXLiV.VI-HLA-844(l0mers-1 91 P40128 l0mers-1 91 P40128 l0mers.1911P40128Each peptide is a portion of Each peptide is a portion of Each peptide Is a portion00 STEQ ID NO: 3; each start SEQ ID NO: 3; each start SEQ ID NO: 3; each staposition Is specified, the position is specified, the position Is specified, th(length of peptide Is 10 length of peptide is 10 length of peptide Is amino acids, and the end amino acids, and the end amino acids, and the enposition for each peptido is position for each peptide is position for each peptidethe start position plus nine, the start position plus nine, the start position plus ninPos 1234567890 score Pos 1234567890 scr os 1234567890452 REIETQTELL F25 259 WHGEGM~7 VDAGEGAQELKF-7 AEMWGPEWL24 262 GREGAMLKCL 794 E LALLHSKYGL12 PEAWLLLLLL 23 319 NEFSSRDSQV 1412 DEGEYEORVS E:

F_ 7 EAQLL 2354 GVIAALLFCL 1125 YECRVSTFPA E:7i77 QELALLHSKY 2 392 LTRESRRL] 14 E4 RVLVPPLPSL 1-23 GEYEORVSTF F22 [409 RSQPEESVGL 1F87 VKGTTSSRSFK

[336 QEDSGKQVDL 22 412 PES=VGL=RAE1422T SHGL l00 469 EEEE000EGI 20 41 EESVGLRAEG 14 20 LLQDQRITHI F199 EQPPPPRNp F 18 439 EPEGRSYSTL 1424IAAVG174 EGPPVT 8483 NHFVQENGTL 14249 SVRGLEDQNL E:ETSDvvTVVL 17 4941 AKPTGNGIyi 14 2-53 LEDQNLWHIG Er72 AGEGAQELAL 17 jDJ GAEMWGPEAW 113 27 1 LSEGQPPPSY E13 EAWLLLLLLL 16l1 GPEAWLLLLL 1322 EQPPy

134GSQGLL 16 E9 LLASF 13347 SASVVVVGVI E16 EEQGT02 6 GELETSDvvr 13 355 VIAALLFCLLEl476 EGIKQAMNHF 16 128RV STFPAGSF 1337RKAQQMTQY

81 EMGFA 1-5 141 LRLRVLVPPL 1 383 TQKEEELTL E1K-9I MWGPEAWLU.. 15 159 LEEGQGLTLA 1389 ELTLTRENSI 1j;98 VEQPPPN 15 199 SRSMVTSEF 13 394 RENSIRRLHS 11158 ALEEGQGLTL 15 231l LQDQRITHIL 13 440 PEGRSYSTLT 1r,173 AEGSPAPSVT I 15 250 VRGLEDQNLw 1 5 IETQTELLSp 1r.2773 EGQPPPSYNW 15 29 1 SGVRVDGDTL 145TELPGr 1[3-50 W GVIMAL 15 1293 VRVDGDTLGF F13361] FCLLVVVVVL 15 296 DGDTLGFPPL 1 TableXLIV-V2HLA-I38-7 EEELTLTREN 1 15 824RSVTDLF13 4402-l0mers-1388 EELTLTRENS 1535 VVVGVIAALL 13 191P4D126

peptide is a portion1420 AEGHPSLK0 15 [352 WGVIAALLF 13 of SEQ ID NO: 5; each437 SEEEGSys 15 438 EEPEGRSYST 13 start position is specified,R EDQE KQ]EN 468 EEEEQDE 13the length of peptide is 471 EE D Q D E G K 1 5 4 8EEEEDQ DEG 1 3 amino acids, and the end10o WGEW l1 7 EDDGK1 position for each peptide is158 SGEQVGQVAW 14 487 QENTLRAKP 13 the start position plus nine.KYGLHVSPAY 14 4-93 RAKPTGNG1Y 13 PR 123467890 score104 PRNPLDGSL 14 E MPLSLGAEMW 12 GQDAK LPCLY LII14 25 FTGRCPAGEL FI LGQDAKLPCL [I-]l7FQARLRLRVL 14 4 LETSDVVTVV 12 L~ AKLPCLYRGD

1L SLNP.PAL 14 4 TVLQDAKL 12206] 4LPR 14 LGQDAKLPCF 1f2l iTableXLlv. HLA2I I246 AEASVRGL ED 1A~ 45 0 G-QDAKLPCF 121 L2~-9Po3

00

00

Each peptide is a portion ofSEQ ID NO: 15; each startposition is specified, thelength of peptide is 10

amino acids, and the endposition for each peptide isthe start position plus nine.

Pos 1234567890 scorel2 SHHTDPRSQS4 HTDPRSQSEE[JHSHHTOPRSQ 22

STDPRSQSEEP 2I[9 SQSEEPEGRS 2

HHTDPRSQSE 1[7 PRSQSEEPEG [2[8 RSQSEEPEGR [2

TableXLIV-V9-HLA-4402.I 0mers-191P4D12B

Each peptide is a portion ofSEQ ID NO: 19; each start

position is specified, thelength of peptide Is 10

amino acids, and the endposition for each peptide isthe start position plus nine.

Pos 1234567890 score

11 CERGYFQGIF 21

8ESFTKRKKKL 18

RELLAGILLR 1721 FFLPFPLWF 1711 LRITFNFFLF 16

16 NFFLFFFLPF 1662 ASASLVAGTL 15

SFESFTKRKKK 15

[i KRKKKLKKAF I 15S91 KAFRFQCLL FIS92 AFRFIQCLLL

94 RFIQCLLLGL 192 ILLRITFNFF 13

13 ITFNFFLFFF 11423 LPFPLVVFFI 114

1301 FFIYFFYFF 1TLEMESHYVAQj[ 141

42 MESHYVAQAG][ 141

I 57 SSNPPASASL[ 141KKAFRFQCL II j4i

j125 QGIFMQAAPW 142 RRELLAGILL 134 ELLAGILLRI 13

TableXLIV-V9-HLA-B4402-10mers-191P4D128

Each peptide is a portion ofSEQ ID NO: 19; each start

position is specified, thelength of peptide Is 10

amino acids, and the endposition for each peptide isthe start position plus nine.

Pos 1234567890 scoreI LAGILLRITFl 138 GILLRITFNF I

118 FLFFFLPFPL 13

22 FLPFPLVVFF 1324 PFPLWFFIY 11131

S25 FPLWFFIYF 13126 PLVVFFYFY 11328 WFFYFYFY 13

I37 YFFLEMESHY 13S52 LELLGSSNPP 13

I 86 KKKLKKAFRFII 131100 LLGLLKVRPL J[131115 NSCDCERGYF[ 1312 RITFNFFLFF

29 VFFIYFYFYF E 1243 ESHYVAQAGL 12

I46! YVAQAGLELL 1287 KKLKKAFRFI 1295 FQCLLLGLL 12

11E VNSCDCERGYI 1211 MRRELLAGILL 11I

.14 TFNFFLFFFL 1145 HYVAQAGLEL 11]70 TLSVHHCACF 1173 VHHCACFESF 11

SAGILLRITFN 101 LLRITFNFFL 10

1 271 LWFFIYFYF 1031 FIYFYFYFFL 10

[18DCERGYFQGI][ 101

TableXLIV-V10 HLA-84402-1 Omers-

191P4D12B

Each peptide is a portionof SEQ ID NO: 21; eachstart position is specified,the length of peptide is amino acids, and the endposition for each peptide

is the start position plusnine.

1234567890 s

SGTSDVVTVL 1ID GELGTSDVWT 1

TableXLIV-V11-HLA-B4402-10Dmers-

191P4D128

Each peptide is a portionof SEQ ID NO: 23; eachstart position is specified,the length of peptide is amino acids, and the end

posion for each peptide isthe start position plus nine.

1234567890 scoeLRLRVMVPPL 1

8 RVMVPPLPSL 12[ARLRLRVMVP [2TableXLIV-V1 2-H LA-

84402-1 Omers-191P4D128

Each peptide is a portion oSEQ ID NO: 25; each startposition is specified, thelength of peptide is

amino acids, and the endposition for each peptide isthe start position plus nine.

1234567890 scor

SEEPEGCSYS 14EPEGCSYSTL 14EEPEGCSYST 3PEGCSYSTLT 11

L11MSEEPEGCSY TableXLIV-V1 3-HLA-

B4402-10mers-191P4D12B

Each peptide Is a portion ofSEQ ID NO: 27; each start

position is specified, thelength of peptide is

amino acids, and the endposition for each peptide isthe start position plus nine.Posi 1234567890 s

2 SQVTVDVLAD 610 ADPQEDSGKQ S1 LADPQEDSGK 4N DSQVTVDVLA

F-41 2~F51TVDVLADPQE 7

[D y0PE]~

[Is 112345678flO score1EI -MeltsFoundjl

00

00

TableXLV-V1 3H LA-83510 1-j1iners-

191 P4D12BPos 23457890score]

NoResujitsFound.

TableXLV-V14-HLA-85101-1 Omers-

191 P4D1 28

fNoResultsFound.TableXLV-V1-HA85101-l0mers

191 PD128F 1345789 score

LNoReusoud

TableXLV-V2-HLA-B5101-l0mers-

191 P4DI2B[Po s 12345678901 s

INoResultsFound-.

TableXLV-W-HLA-B51O01 -1Omers-

191 P4D1 28

NoRs-ultspound.

FTab-e XV-94LA-SB5101-l0mers-191 P41)1 28

P123457890or

NoResultsFound.

TableXLV-V1O-HLA-851 01-l0mers-

191 P40128FPos 34689E[R

INoResults Found.

TableXKLV-V1 1-H LA-851 01-l0mers-

191P4012B

L TableXLVI-Vl -HLA-DRB1 -0101-l5mers-191P412Each peptide is a portion of SEQ ID

NO: 3; each start position isspecified, the length of peptide is 15amino acids, and the end position

for each peptide Is the start positionplus fourteen.

Pos 12456789012345 [Fc~oe1279] SYNWTRLDGPLPSGV L...N140 RLL3LP2SL205 TSEFHLVPSRSMNGQ 3212991 TLGFPPLTTEHSGIY 32

3SDVVVLGQDAKLP F 371141VTVVLGQDAKPCYJ 31j

[3401 GKQVDLVSASWW 31349 SVVVVGVIAALFCL31]144 RVLVPPLPSLNPGPA 30g147 VPPLPSLNPGPALEE 30350] WWVGVMlLFCL 351 I PCFYRGDSGEQVGQV 212 PEA WLLLLLLLASFT 2

247 EASVRGLEDQNLWHI F27358ALLFCLLVVVVVLMS] 27371l MSRYHRRSQQMTQ-K 26

GAEMWGPEAWLLLLL 213 EAWL-LLLIIASFTG[2514] AWLLLLLLLASFTGR[25

LLLLLASFTGR F25]1

TableXLVI-V1-HLA-DRB1-01 01 l5mers-19 P D 2

Each peptide Is a portion of SEQ IDNO: 3; each start position is

specified, the length of peptide is amino acids, and the end position

for each peptide Is the start positionplus fourteen.

Eos 123456789012345

19j LLLLASFTGRCPAGE 10-2 PPPRNPLDGSVLLRN

1109! DGSVLLRNAVQADEG 1122 1193 SRSFKHSRsAAvTSE 239 ILHVSFLAEASVRGL J1 251255 DQNLWHIGREGAML

12651 GAMLKCLSEGQPpps j[ i310 [SGIYVCHVSNE~S 454 IETQTELL-PGSGRA] 2[ [64QVAWARVD-AGEGAQEJ[ 24J[76 AQLLLHSKY GLHV 1f 24[79 LALLHSKYGLHVSPA 1[12 ECRVSTFPAGSFQAR JF24[1-56 I GPALEEGQLAS iDi162 GQGLTLAASCTAE-GS ][24

181VWDTEVKGTTSSRS] 24210 LVPSRSMNGQLTV] 24j

tJSRSMNGQPLTws [241282 WTLDPLSGRD 4

1347 SASVVVVGVIAALLF U241353 VGVIAALLFCLvJjiI357 AALLFCLLVVLIIR LVVVVVLMSRYHRRK[24

395 ENSIRRLHSHHTDPR F-24442 GRSYSTL1 MEET 24

1LLLLLLLASFTGC 238RCPAGELETSDVTV 23

184 EKTSR FF(-I23228] PGLDQIHLH 9

123IQRITHILHVSFLAE 1 23J289 LPSGVRVDGDLGFP 23

3391 SGKQVDLVSASVVWV 23SVSASWVVGVIMLL 23

3FCLLVVVWLMS 23PIDSLKDNSSCVMSE 23

8 LTTV REIETQTELLS 2457 QTLSPGSGRAEEE j343 NHFVQENGTLRAKPTD23

00

00

TableXLVI-V1 -HLA-DRB1 -0101-1l5mers-191P4D12B

Each peptide Is a portion of SEQ IDNO: 3; each start position is

specified, the length of peptide Is 15amino acids, and the end position

for each peptide is the start positionplus fourteen.

[P o'sI 1234667-89012346- [score]LSLGAEMGPAL F72

1 551RGDSGEQVQAA F72F59 jGEQVGQVAAVA 7-12

[-1411 LRLRVLVPLPLN 72~12-041 VTSEFHLV PSRSMNG J[ 22[2501 VRGLEDQNLWHIGRE][221

12-68 ILKCLSEGQP-P-PSYNW][ 2[3111 GIYVCHVSN FSR [223271 QvTVDVLDPQ)EDSGK 1[[2-2]

[3601 LFCLLVVVVVLMSRY ][22[451_ VREIETQTESG ]22[2-18L GQPLTCWSPGL [211256_QNLWHIGREGAMK] F2127-7] PPSYNTRDPS]21F33[ELETSDVTVQD[20

IVAWARVAEAE] F20[1-23 GEYECRVFPGF20

NPGPALEEQ L ][2701321] FSRSVVVD [201429 DNSSCSVMEPG] F21482 MN H FV Q ENGTL RA KP] F2011490 GTLRAKPTGNGIYIN ][20

LASFTGRCPAGELET I[]19[391 vvVVLGQD)AKLPCF III 9[-38 QALL VPLPSIF191

QRITHILHVSFLAEA IF___2-42 VSFLAEA VRGLEDQ iF19[

14-121 PEESVGLRAGHDS F19][4151 SVGLRAEGHDLDU

71 AEMWGPEAWLLLLLL ]JF18[911 SPAYEGRVEQPPPPRj 178

[134J AGSFQARLRLRVLVP ]r18111651 LTLMSCESA 1181[26J rGMKCS1QP 8]Th2661 AMLKCLSEG3QPPPy1T8]

18 YNWTRLDGPLPSGVR F1 8368 1WVLMSRYR QM j[ 183871 EEELTLTRENIR F[ a81:11]1 GPEAWLLLLS DJz

Ta leXL VI-Vl .HLA-DRBl-01 01-I S5mers-1 91 P4DI 28

Each peptide is a portion of SEQ I0NO: 3; each start position is

specified, the length of peptide Is 15amino acids, and the end position

for each peptide is the start positionplus fourteen.

[Fos 11234567890124 soe67l WAR VDAGEGAQELAL ]j17

[681' ARDGGQEAL1171[78-3 HSKYGLHVSPAYEGR II 17[gI [RNAVQADEGEOR Jj17[125[YECRVSTFPAGFQA117135 GSFQARLRLR P E1117[1481 PP L PS LN PGPA LEEG ]..F1711501 LPSLNPGPALEEGQOEE171167 LAASCTAEG-SPAPSV l[-177120 SAAVTSEFEHLVPSRS [[171221] LTCWSHPGLQQ [17

122 VSHPGLLQDQII [[1712381 HILHVSFLAASR l[ 2h12-57 _NLWHIGREG L KCL j[17[25 LWHIGREGAMKL [11[2&I RLDGPLPSGVRVDGD][ i12911 SGVRVDGDTL-GFP-PL iF 1294RVDGDThGFPPLTTE ]I1303 PPLTTEHSGIYVCHVl 71330VDVLDPQEDSGKVJ Eii[33 VLDPQEDSGKV V] F1711342 QVDLVSASV GV 177[348 ASWGI LFC J[ 17

g3s GVAALLFCLLWW F-7356 ALLCLWW J9~1407DPRSQPEESVGLRAE][ 17

4321 SCSVMSEEPEGRSYS if1711458TELLS3GSGRAEEEE IF1-7[R DEGIKQAMNHFVQEN IF 17

TableXLVI-V2-HLA-DRB1.0i 01-l5mers-1 91 P4DI 28

Each peptide is a portion of SEQID NO: 5; each start position is

specified, the length of peptide is15 amino acids, and the end

position for each peptide is thestart position plus fourteen.

Pos *123456789012345 soeFI21 VTVVLGQDAKLPCLY 113 PCLYRGDSGEQVGQV1Z E21DAKLPCLYRGDGQ JDI~ VVTVVLGQDAKLPCL

Tab-1eXLVI-V7-HLA-DRB1- 010'1- 17l5mers-191P4D12B

Each peptide is a portion of SEQID NO: 15; each start position isspecified, the length of peptide is

15 amino acids, and the endposition for each peptide is the

-satposition plus fourteen.[Pos 123456789012345 sorDj IRRLHSHHTDPRSQ-S 14I HHTDPRSQSEEER[ I

F1 RSQSEEPEGRSYSTI[101DII SIRRLHSHHTOPRSQ [1[ii ]DPRSQSEEPEGRSYSI7F14 SQSEEPEGRY STLT 119[D RRLHSHHTDPSQEf2D I LHSHHTDPRSQSEE-P 18[q HTDPRSQSEEPEGRSLI[12 PRSQSEEPEGRSYST 11-8I[-4]RLHSHHTDPRSSE~L[ HSHHTDPRSQSEEPE L2-7

TableXLVI-V9-HLA-DRBI-0101-15mers-191P4D12B

Each peptide is a portion of SEQID NO: 19; each start position isspecified, the length of peptide is

15 amino acids, and the endposition for each peptide Is the

start position plus fourteen.123456789012345 scoeJ

[43 ESHYVAQAGLELLGS] IF--3[49 QAGLELLGSSNPPAS][32[36 FYFFLEMESHYVAQA][ 311[10-3] LLKVRPLQHQGVNSC[ 28~

F17 FFLFFFLPFPLWFF r[2790g KKAFRFIQCLLLGLL] F27]98[ CLLLGLLKVRPLQHQ [2618 FLFFFLPFPLWFFI 260 PPASASLVAGTLSVH 261 PASASLVAGTLSVHH- 2493 FRFIQCLLLGLLKVR 2L 97j QCLLLGLLKVRPLQH 2

00

00

TableXLVI-V9-HLA-DRB1 -01 01.-l5mers-191P4D1B

Each peptide is a portion of SEQID NO: 19; each start position is

specified, the length of peptide Isamino acids, and the end

position for each peptide is thestart position plus fourteen.

[Pos 1234567890124 1W] ER[61 LAGILLRITFNFFLF lIF72116 JNFFLFFFL-PFPLWVF IF72J

AGILLRI FNFLFF[22F521 LELLGSSNPPAS-ASL ]22

[1001 LLGLLKVRPLQHQGv] F22iGILLRITFNFFLFFF 1[211

L-2ZI LWFFIY-FYFYFFLE 21121 RITFNFFLFFFLI PPff0341 FYFYFFLEMES HYVA FI 20

S92 1FFQLLGLv 20f2]1 ELLAGILLFNFF 119f14 1TFNFFLFFFLPFPLV[[1l9!

11 FNFFLFFFLPFPWI[]F31 FIYFYFYFLEMESH J-gF33 YFYFYFFLEMESHYV][ 19

W4 YVAQAGLELLGSSNP] 19IFIQLLLKRPL 3[ 191LLRITFNFFLFFFLP ][18

19] LFFFLPFPLWFFIy F~F225]__FPLWFFIF FYF 181F 28 WFYYYFLM]

841 KRKKKLKKAFRFIQC ]F 18[120 ERGYFQGIFMQA~] iiI[j13 ITFNFFLFFFLPFPL [17

FFFLPFPLWVFFIyF 17I22! FLPFPLVVFFI YFF 129 VFFIYFYFYFFLEME 17

1371 YFFLEMESHYVQAG [17441 SHYVAQAGLELLGSS [794 RFIQCLLLGLL VRP[172] RRELLAGILLRF [1

21! FFLPFPLVVFFIYFY ri-1I39 FLEMESHYVAQAGLEF1641 EMESHYVAQAGLELL 1648 AQAGLELLGSSNPPA I 51! GLELLGSSNPP ss]Th541 LLGSSNPPASASLVA EE56 GSSNPPASASLVAGT j[1668IIV CC S J[ 161

TableXLVI-V9-HLA-DRBI-01 01-15mers-191P4D12B3

Each peptidle is a portion of SEQID NO: 19; each start position is

specified, the length of peptide Is15 amino acids, and the end

position for each peptide is thestart position plus fourteen.

Mjo 123456789012345 [sorTLVHAFSFTK E1

15 5]J KV RP LQH Q GVNSC DC 1 E16

TableXLVI-VI 0-HLA-DRB1-01 01l5mers-1 91P4D128

Each peptide is a portion of SEQID NO: 21; each start position isspecified, the length of peptide is

15 amino acids, and the endposition for each peptide Is the

start position plus fourteen.Flo-s1l 12345678901235I~~

Each peptide Is a portion of SEQID NO: 25; each start position isspecified, the length of peptide is

15 amino acids, and the endposition for each pepfide is the

start position plus fourteen.[Pos 123456789012345 seg[14! GCSYSTLTTREE I2412]IDNSSCSVMSEEPEGC [:I

12I CSVMSEE PEG CSYST [7-6[EFCSYSTL1TVREIETQ 1[]71

abIeXLVI-V13-HLA-DRB1..0101-115mers-191P4D12BJ

Each peptide is a portion of SEQID NO: 27; each start position isspecified, the length of peptidle is

15 amino acids, and the endposition for each peptidle is the

1 start position plus fourteen.l 123456789012345 scr

FSSRDSQVTVDVLAD [IDSQVTVDFA 1ED 7

14 ILAD)PQEDSGKQVDLvIF17[2]QVTVDVAPES 16

101 TVOVLADPQEDSGKQ Lji6i[SQVTVDVLADPQEDS

[2]SSRDSQVVDVLDP 141[12 DVLADPQEDSGKQVD [j

[TableXLVl-V14-HLA-DRB1 -01 'I--1

Each peptide is a portion of SEQID NO: 29; each start position Isspecified, the length of peptide is

15 amino acids, and the endposition for each peptidle is the

tart position plus fourteen.[PosI 123456789012345 score11i PPASASLVAGTLSVH D2] PASASLVAGTLSVH-H Eg~

L E LL G SSNp-pASA S-L 2 2[j GLELLGSSNPPASAS 16EN~2 LLGSSNPPASASLVA 16E2] GSSNPPASASLVAGT 16

2]AGLELLGSSNPPASAF1521LGSSNPPASASLVAG

i13 ASSLVAGTLSVHHO ELLG SNppAS ASLV 14

L:8] SSNPPASASLVAGTL 14

TabIeXLVI-V1 1-HLA-DRBI-0101..l5mers-191P4D12B

Each peptide is a portion of SEQID NO: 23; each start position isspecified, the length of peptide is

15 amino acids, and the endposition for each peptide is the

start position plus fourteen.[PosI 123456789012345 Fs~r

[JRLRLRVMVPPLPSLN 30[11RVMVPPLPSLNPGPA L9[0LRLRVMVPPLPSLNP

QARLRL RVMVPp~S~~[]AQARLRVMVP 18EIIGSFQARLRLRMVP1

GS1FQARLRLRVMVPP I17Ejfl RLRVMVPPLPSLNPG 16gI2 FPAGSFQARLRLRVMF15

2LRVMVPPLPSLNPGP 1[278RRMVpPL1

I TableXLVI-V12-HLADRBI-0101-1II 1 Smers-1 91 P401 2B

00

00

FTableXLVI-V14-HL11A-DRBI-o101-]

Each peptide Is a portion of SEQID NO: 29; each start position isspecified, the length of peptide is

amino acids, and the endposition for each peptide is theIstart position plus fourteen.

[Posl 123456789012345 sce]A ASLVAG T-L S-VHHC A C r4

TableXLVII-V1 -HLA-DRBI-0301-1 Smers-191 P4DI 28

Each peptide is a portion of SEQ ID~NO: 3; each start position Is

specified, the length of peptide is

amino acids, and the end

position plus fourteen.Posl 12345678024 [scorel178 1APSVTWDTEvKG1TS] 29I~227 HPGLLQ RTHL 1281411TVVLGQDALP FJ[27

73791 AQQMTQ E TL] 7251141 AWLLLLLLLASFTGR] 231

290 PSGVRVDGDTLGFPP J 2313 9 VVTVLQD LCFIiI

1703PPRNPLDGVLN F 221247 EASVRGLEDQNLWHI If-221117 RNAVQADEGEYECRV][ 21J142 RLRVLVPPPLP ]211233 DQRITHILHVSF-LAE 11211325 1DSQVTV0VDED] 211738] ASVVWGVIAALLFC]21F3491 SVVWVGVIMLLFOL]21Z--16GAEMWGPEAWLLLL]L 20

17561 GPALEEGQGLTLAAS 2012421 VSFLAESR ED ]20249 SVIRGLEDQLHG] 202921 GVRV0DTL FPP 2] 0

135 VVVGVIMLFCL] 2013521 WGVIALF LW] 20113531 VGVIAALLFCLLVW 20~363 LLWWVLMSRYHRR] 20i

1126 ECRVSTFPAGSFQAR] 1913021 FPPLTEHSGIYVC] 91328 VTVDVLDPQEDSGKQ][ 19~136511VVWVLMSRYHRRKA][ 191387 EEELTLTRENSIRRL E]19lI 77 QELALLHSKYGLHVS .j 18]

TableXLVII-V1-HLA-DRBI-0301-11Smers-1 911P40D1 2B

Each peptide is a portion of SEQ IDNO: 3; each start position is

specified, the length of peptide is15 amino acids, and the end

posilion for each peptide is the startLposition plus fourteen. I

E~ 1234568024 1IsrF1III SVLLRNAVQA0E1265 IGAMLKOLSEGQPP F7i81286 DGPLPSGVRV DT] 7813-191 NEFSSRDSQVTDVL] 7Dj1329TVDVLDPQDKV] ThI-1433CSVMSEEPEGRSYST] F 1I

VREIETQTELLPG ]18[7]JGLHVSPAYEGRVQ Liz-7[97] R'/EQPPPPRNLG 17B1 ILHVSFILAEASG 12-55jDQNLWHIGREGAMLKj 1711311 GIYVCHVSNEFSRD] F71IE DPQEDSGKQV-DLVS-A][E36 BVVLMVSRYHRRAQ[ 7jI381 IQMTQKYEEETLR[ F 17E4011LHSHHTDPRSQPEES1[ 1l1 EESVGLRAEGPL I[ 17H~I YSTLTTVREIETQTE F[ 17K~jDEG1KQAMNHFVQEN [17F479] K QA MN H FVQ ENGTI[ 171471 TLRAKPTGNGYN [17DI LGAEMWGPALL I[ 161

EAWLLLLLLLST nt16Ej DAKLPCFYRG DSGQItZE~j VDAGEGAQELHS l[:16F1i-4 AGSFQARLRLRVLVP I[16FEI~LRNAVQADEGEC j[15F130] STFPAGSFQALL j 15gi~j FPAGSFQARLRLRVL 1[]15

9 SRsAAvSEFHLVPS I15~94 LC HPLQDQR I15~F2-36 ITHILHVSFLAEASV 1[15

[JAMNHF VQENGT LRAK I 5F15]_WLLLLLLLASF GRC j 4

LLLLg4 ASFTGRCPA I 4I1ELAIIHSKYGLHVSP [4

r1709 DGSVLILRNAVQADEG1 41

1ll~ GSVLRNVQAGE 14

TableXLVII-V1 -HLA-DRB1 -0301-l5mers-1 91 P4012

Each peptide is a portion of SEQ IDNO: 3; each start position is

specified, the length of peptide is15 amino acids, and the end

position for each peptide is the startposition plus fourteen.

IPos F123456789012345 ]scorel144 RVLVPPLPSLNPGPA F14

280 1YNWTRLDGPLPSGVR Jt.1411342 QVDLVSASVV V [1413-56 IMLLFCLLVVL [141360 LFCLLVVVVVLMS-RY 1[14F48] LTTVREIETQTELLS It 144I49 TTVREIETQTLS It57 Q-TELLSPGSGRAEEE I[ 141

Tab~eXLVII-V2-HLA-DRBI -0301-]l5mers-191P4D12B J

Each peptide is a portion of SEQID NO: 5; each start position is

specified, the length of peptide is15 amino acids, and the end

position for each peptide is the-start position plus fourteen.

[Posj 123456789012345 score][D TVVLGQDAKLPCYR [:jA[]jJVVIVLGQDAKLPCLI 2i72[DIDAKLPCLYRGDSGEQ -1-6D I VTWLGQDAKLPCLY F7J

[TableXLVII-W-HLA-DRBI -0301-l5mers-191P4D12B

Each peptide Is a portion of SEQI0 NO: 15; each start position isspecified, the length of peptide is

15 amino acids, and the endposition for each peptide is the

start position plus fourteen.[Ps123456789012345 scorel

[~LHSHHT0PRSQSEEP 17[IRRLHSHHTDP SOS Il1l

LI1RSQSEEPEGRSYSTL 9~ HTDPRSQSEEPEGRSF19

SHHTDPRSQSEEPEG12 PRS-QSEEPEGRSYST138J

1SQSEEPEGRSYSTLT EII81

Tab~eXLVII-Vg9HLA..DRBI -0301-1 Smers-1 91 P40128

00

00

Each peptide is a portion of SEQ IDNO: 19; each start position is

specified, the length of peptide is15 amino acids, and the end

position for each peptide Is the startposition plus fourteen.

[81 GILLRITFNF FLFF251M121 QGVNSCDCERGYFQG 24i

YFYFFLEESYA 23~[61 LAGILLRITFNFFLF7 22[27] AGILLRITNFF [211[91 LFFFLPFPLWFFIY )[211

LLRITFNFF2F0L201 FFF-PFPLW F 20 z

[74 SHYVAQAGLELL-GSS F20L-931 FRFIQCLLLGLLVR )20

9[7 QCLLLGLLVPQ CLLLGLLVPQQ i[Z2G

[161 NFFLFFFLPFPL 1 9[s[241 PFPLWFFIYFY-FYF ][191

IFPLWFFYYFFF F7[ 9h751] GLELLGSS-NPPASAS [19[681 AGTLSVHHAEFIfI[901 KKAFRFIQCLLLGLL] [199[2 AFRFIQCLLLGLLKV [19[1 4 TFNFFLFFPPL [181[26 PLVFYY F -[18.

[29 VFFFFFENE [18)[12RITNFFFFFLPFP [7

221 FLPFPLVVFFIYFYF [17128 WFIFYYFL EM- 1[ 7

[7911 FESFTKRKKKLKKAF 17)[82 FTKRKKKLKKFF 17)

86 KKKLKKAFRFIQGCLL [17)27 LWFFIYFYF FFL 16)

F76] CACFESFTKRKKL [1615AILITNFI9

1 33 15FFLEEHV M41 IEMESHYVAQAGLEL-L 15sI78 C-FESFTKRKKKLKKA[ L-891 LKKAFRFIQCLLLGL )[15)[l11 GVNSCDCEGFI [1511-] FCDCRYQIMA7hF96 IQCLLLGLLVPL [14)

RRLADLITN) a[49 QALLLS9PA

1101 LGLK RPLQHQGV[[13

TabieXLVII-V9-HLA-DRB1 -0301. l5mers-191P4D12B

Each peptide is a portion of SEQ IDNO: 19; each start position Is

specified, the length of peptide Is15 amino acids, and the end.

position for each peptide is the startposition plus fourteen.

[Po 12345678901 2347 [scorel[101 LGLLKVRPLOQGV j[ 13[103 1LLKVRPLQHQGVN-SC]113

36j FYFFLEMVESHYVQA 112F37jYFFLEMESHY-VAQAG)[ 1239 FLEMESHYVAAG E l1252j LELLGSSNPPASA7SL 12

[674 ASLVAGTLSVHHCAC J[ 12[106VRPLQHQGVNSCDCE2

1TableXL VII-VI0HADB-311l5mers-191P4D12B

Each peptide Is a portion of SEQID NO: 21; each start position is

specified, the length of peptide Is15 amino acids, and the end

position for each peptide is thestart position plus fourteen.

[Posj 123456789012345] soe112 GELGTSMVVVVLG-Q 12~[I iAGELGTSDWTL i

LASFTGRCPAGELG 17012]ASFTGRCPA GELGTS 912] FTGROPAGELTD E11A113l ELGTSD-VVTV-vLGQ-D I[TabIeXLVII-V1 I-HLA-DRBI-0301-

1 5mers-191P34D12BEach peptide is a portion of SEQID NO: 23; each start position is

specified, the length of pepfide is15 amino acids, and the end

position for each peptide is thestart position plus fourteen.

[Po 12457801345 Fscr[1 -l]RLRVMVPPLPSLNGLP[2]AGSFQARLRLMp LIP)[2]FPAGSFQARLRLkV-M 7Th[1 2 LRVMVPPLPSLNPGPf141I 13) RVMVPPLPSLNPGPA 14[2]RQARLRLRvmvPPLPS. 13

2]RLRLRVMVPPLPSLN L_1212I SFQARLRLRVMPPL

8 8IALLVVPPLPSLI iMVPPLPSLNPGPA&lEF1

F TableXLVII V1 2-HLA-DRB1-0301-1l15mers-191P4D12B3

Each peptide Is a portion of SEQID NO: 25; each start position Is~lspecified, the length of peptide Is

15 amino acids, and the endposition for each peptide is the

start position plus fourteen.[Ps123456789012-34S scorel

[2 CSVMIS E E PEGqCSYST 181[2]SCS VMSEEPEGCSYS1-2

SVMSEEPEGCSYSTL 5505VMSEEPEGCSY ElSEEPEGCSYSTLTTV

TabieXLVII-VI 3-HLA-DRB1-0301-)5mers-191P4D12B

Each peptide Is a portion of SEQID NO: 27; each start position isspecified, the length of peptide Is

15 amino acids, and the endposition for each peptide is the

start position pius fourteen.[Po 123456789012345 scr[10 TVDVLA0PQEDSK ZIP)[2]DSQV1VDVLADPQE 2 2[ii VDVLADPQEDSGKQV[1j 6

TabeXLVII-V1 4-HLA-DRBI-0301-1 Smers-1 91 P401 2B

Each peptide Is a portion of SEQID NO: 29; each start position isspecified, the length of peptide is

15 amino acids, and the endposition for each peptide Is the

start position plus fourteen.

g 1I 123456789012345 scor2] GLELL GSSNPPASA 19)

12]LELLGSSNPPA SASL 12)

15 JASLVAGTLSVHHCAC 12[14 ISASLVAGTLSVHHCAil2] LGSSN PPASASLVAG

IMiP-PASASLVAGTLSVH

TableXLVIII-VI-HLA-DRB1-0401 1 Smers-1 91 P4D12B

00

00

Each peptide is a portion of SEQ IDNO: 3; each start position is

specified, the length of peptide is 15amino acids, and the end position

for each peptide Is the start positionplus fourteen.

[Posl 123456789012345 jIsc~i

1205 TSEFHLVSRM Q 28z~12-99 ITLGFPPLTTEHSGY ]281f 47 DAKLPCFY RGDSGEQ[ 26111621 GQGLTLMASCTAEGS 1L26I2-55 DQNLWHIGREG-AMLK][ 26~3-11 IGIYVCHVSNEFSSRD 1126

1395 ENSIRRLHHTP [261

14-151 SVGLRAE GHPDS LKD 26Z~F4 5 DEGIKQAMNHFVQ-E-N 1261

F-71AEMWGPEALLL 12211 PEAWLLLLLAF ]221

FI501 LPCFYRGDSGEVG] 22IF511 PCFYRGDSEVQ] F221rl180 I SVTWDTEVKGT SSR 22

193 SRSFKHSRS TE] 221241 HVSFLAEASVRGLED 1[22

1358 ALLFCLLVVVM 11223781 TQKYEEELTLTEN F[221

441GRSYSTTVET 1221[13 EAWULLLLST 1201[151 WLLLLLLAFRCI 20111 LLLLLLLAFGC I201I 371 SDVTVVLGQDAKL][7F.591I G EQ VG Q VAWAR-VDAG][ 20

76 iAQELALLHSKYGLHV][F 201871GLHVSPAYGVQ1 201

FI1-111 SVLLRNAVQADEE [201I44 RVLVPPLPLPP [20

F1-] VPPLPSLN AE [201

1184 DTEVKGTfSSRSK- 1201211 SMAVTSEFHLVSR 20i~

M281 GQPLTCWSHPGLLQ] 2011227 HPGLLQQTHL F201

1233 5,5THIHVFLA 12-391 ILHVSFLAVRL]201242 VSFLAESVRGLEIJQ [L20247 EASVRGLEDQLH .[20

251LWHIGREGAMLKCS ]2o

l26] EGAMLKCLSEGQPPP J[ 203021 FPPLTTEHSGIYVCH I[ 20

TableXLVlll-V1-HLA-DRBI-4115mers-191P4D12B

Each peptide is a portion of SEQ IDNO: 3; each start position is

specified, the length of peptide is 15amino acids, and the end position

for each peptide Is the start positionplus fourteen.

Igos 1234567890124 [oVel1325DSQVTVDVLDPQD 201340 GKQVDLVSASVWG l[ 20

342 QVDLVSASVVVV 201

E34 SASVVVVGVIAALF j[2011R941 SVVWGVIM O 1201352 WGVIAALLFC LLWV Fl20j

I53 VGVIMALLFCL LVWV FI 201357 MALLFCLLWVLM 20Z~13-601 LFCLLVVWVVLMSRY]1201361] FCLLVVVVVLMSRYH][ 201

1364 LWWVVLMSRY HRRK] 20113-68 IVVLMSRYHRRK AQQM[ E~13891 ELTLTRENSIRRLI-S 1 2011424 PDSLKDNSSCSVMSE 274-33 ICSVMSEEPEGRSYST]1[:

1445 YSTLTTVREIEQT ]20]

44-8] LTTVREIETQEL II 20IRj QTELLSPGSGAE 11201479 KQAMNHFVQENGTLR Fl 204-831 NHFVQENGTLRAKPTEIL291 28 1RCPAGELETSDVV1781 i~[29 OPAGELETSDVVT ]181

331 ELETSDVVT:-VLGQD I[ A[38j DVTWLGQDAKLPC ]18[j HVSPAYEGRVEQPPP Ill j.8F1 3 PPRNPLDGSVLRNA jIf LDVLLRNAVQj[ F-18

I 8 LDGSVLLRNA VQAE I[ZiIg1 ADEGEYECRVSTFPA IDiL IN1 GEYECRVSTFPAGS7FF 118

1i RVSTFPAGSFQA RLR 1118PGPALEEGQGLTLAA i

[i§90 -TfSS FHSAAV II 18

M291 QPLTOWVSHPGQ =1 1813081 EH-SGIYVCHVSES]1

Eg CHVSN EFSSR SQVT 18131 N-EFSSRDSQVTVDVL ][18

1 328 VTVDVLDPQEDSGKQF][ 81331 DLQESQV L 8

TableXLVI -1 -HLA-DRB1-0401-l5mers-191P4D12B

Each peptide is a portion of SEQ IDNO: 3; each start position is

specified, the length of peptide is amino acids, and the end position

for each pep tide Is the start positionplus fourteen.

Posl 123456789012345 re3391 SGKQVDLVSAS-VVVV I[ 1-8133 RYHRRKAQQMTQKYE[ -IF 7

386] YEEELTLTRENSIRR 1[181392 LTRENSIRRLHSHHT][ 7407 DPRSQPEESVLE] F1 814231 HPDSLKDNSSVS] 18i

1435 VMSEEPEGRSYSTLT 1 181449 TTVREIETQTLS I[Z8I441 IETQTELLSPGRAIii1472 EDQDEGIKQAMNHFV 111811341 AGSFQARLRLVV F117113181 SNEFSSRDSQVTVDV 1171[64 QVAWARVDAGEGAE]I

83I HSKYGLHVSP AYEGR ]f162561 QNLWHIGREGMK 16~

1279 SYNWTRLDGPLPSGV[ IF16113101 SGIYVCHVSNEFSS 1[]6

1482 MNHFVQENGTRK] jj176367 WVVLMSRYHRRKQ]

PLSLGAEMWGPAW] 74j76] GAEMWGPAWLLLLL [14[14 AWLLLLLLLAS~fTGR 14.[17 LLLLLLASFTRP F1141

[18 LLLLLASFTGRCPA 114[19 LLLLASFTGRAE114

31j AGELETSDVVTWVLG I~36 T -SDVVTVVLGQDAKL] F14

39q VVTWVLGQDAKLPCF ]IF-14411 TWLGQDAKLPCFYR 3[ 762 jVGQVAWARVDAGEGA][ 14

95 EGRVEQPPPPRNPLD[ JF14111051 RNPLDGSVLL-RNAVQ][ 14LI 1RNAVQADEGEYECRV[ F17[i 261 ECRVSTFPAGSFQARI 1[ 141[140 RLRLRVLVPPLPSLN I. 74[142 RLRVLVPPLPSLNPG [F141[143 LRVLVPPLPSLNPGP I1141[1-56 GPALEEGQLLA IL 4[-164fLTLAASCTAEGSPA 1114

00

00

TableXLVIII-VI -HLA-DRBI .0401 15mers-191 P4D12B

Each peptide Is a portion of SEQ IDNO: 3; each start po 'sition is

specified, theilength of peptide Is 15amino acids, and the end position

Ifor each peptide Is the start positionpius fourteen.

[Pos 1234567890124 scoreI17 8APSVTWDTEVKGTTS F7I1207 EFHLVPSRSM-NGQPL] 74~213 SRSMNGQ-PLTCW-SH][ 1721 LTOWSHPLQQ 1[4~228 PGLLQD-RITHILHV] [14

237 LTHILHVSFA~V ]F 141250 VIRGLEDQNWR] r1 4!265 GALCLRQP 14

268 LKCLSEGQPPPS-YN-W][ i1282 I GPLPGVRVD]7i

DG LPSGVIRVDDTL]j

F290 PSGVRVDGDTLGFPP[14

[Y92GRDDLFPL [4F327 QVTV0VLDPQEDSK[4[3301 VDVLDPQEDs-GKQ-VDJ[ 14[i 8]ASVVWGVIAALLFC ][14i350 VVVVGVIM-ALLFCLL -]1

1356 IAALLFCLLV-VVVVL ][j411362LLVVVVVLMS-RYHR[]14363 LLWWVSYR [141365VVVVLSYRK

387 EEELTLTRENSIRRL Df14398 IRRLHSHHTPSP] 141

142SCSVMSEEPEGRSYS ]1414RITTLS~

TalXVIII-V2-HLA-DRB1 -0401-[Tab e rs 9P4D12B

Each peptide is a portion of SEQ IDNO: 5; each start position is

specified, the length of peptide is 15amino acids, and the end position

for each peptide Is the start positionplus fourteen.

IEos 12345678-9012345 scoejI DAKLPCLRGSE 26~~

[1-3PCLYRGOSGEQVGQV FT2[l1 LPCLYRGDSGEQVGQJ[ 20Li1] VVTVVLGQDAKLPCL ED3 TVLGQDAKLCY 14i

TableXLVIII-V2-HLA-DRB1-0401-1 Smers-1 91 P4D12B

Each peptide is a portion of SEQ 10NO: 5; each start position is

specified, the length of peptide is 15amino acids, and the end position

for each peptide is the start positionplus fourteen.

[Po 124568902345 score

[15 LYRGDSGEQVGQvAW 71j2]

[TableXLVIlk-v7.HLADRBI-0401-]

Each peptide Is a portion of SEQID NO: 15; each start position isspecified, the length of peptide is

15 amino acids, and the endpostion for each peptidle Is the

start position plus fourteen.[E[I 123456789012345-]s~r[D LHSHHTDPRSQSE1p8]I S~ SQ SEE P EG RSYSTLT LF71!

[-2]IRLHSHHTDPRQ 14[12PRSSEEEGSYST12

[TbeXLVI I kV9HLADRB1-0401. JEach peptide is a portion of SEQ ID)

NO: 19; each start position isspecified, the length of peptide is

15 amino acids, and the endiposition for each peptide Is the startposition plus fourtee.

[Po 123456789012345 scr[37 YFFLEMVESHYVAQAG [F 26[86 KKKLKKAFRFIQCLL 1I 26[103 LLKVRPLQHQG-vNS-cJ 26

[2 RITFNFFLFFFLPFP I22117 FFLFFFLPFPLWFF 221[Al YFYFYFFLEME-SHYV][ 221

36I FYFFLEMESHYVAQA] IF22

[7NJ CACFESFTKRKKKLK]IF 22!Lg1 KKAFRFIQCLLLGLL ]22r i1RGYFQDGIFMVQMAAP7WEf 22f

[~RELLAGJLLRITFNF 1120[GILLRITFNFFLFFF [201

161 [NFFLF FFLPFPL VVF [-20]4 SHYVAQAGLELLGSS D

:49 QAGLELLGSSNPPAS 2051_LELSNIAA L2a l

TableXLVIII-V9-HLA-DRB1 -0401-l15mers-191124D1213

Each peptide is a portion of SEQ ID~NO: 19; each start position is

specified, the length of peptide is15 amino acids, and the end

position for each peptide is the startposition plus fourteen.

IPos 123456789012345 1FSC70]F931 FRFIQOLLLGLLKvR jF 598 CLLLGLLKVRLQHQ][ [41! EMESHYVAQAGLELL J[ T 8

62J ASASLVAGTLSVHHC IF-181I 73VHHCACFESFTK-RKK 1181

891 LKKAFRFIQCLLLGL 11-18[141 TFNFFLFFFLPFPLV [[F16[15 FNFFLFFFLPFPLW 1L 16![18j FLFFFLPFPLWFFI j-1i6]

[22j FLPFPLWFFYFF [161[28 FFIYFYFYFFLEM J[16

3011 FFIYFYFYFFLES ][16[311 FIYFYFYFFLEMESH 196I 321 IYFYFYFFLEMESHY 1[ 161

3YFYFFLEMESHYVAQ]j[ 16~[43 ESHYVAQAGLELLG-S] [i6

AFRFIQLLLG-L-L-KV J120 ERYFGIMQPW][ 17

[AGILLRITFNFFL-F7FE]D.i[24j PFPLWFFIYFYFYF 14[25j FPLWFFIYFYFYFF 1 14~

LFFIYFYFYFFL 4129j VFFIYFYFYFFLEME [14E439 FLEMESHYVAQAGLE ]~141

52g LELLGSNPSS 1464l ASLVAGTLSVHHCACII.I70I TLSVHHCACFESFTK J[14

[97 QCLLLGLVLQ II 1i4I[100 LLGLLKVRPLQHQGV JIL

Ej LLAGILLRITFNFFL I[ 172El21 FFLPFPLWFFIYFY 12

461 YVAQAGLELLGSSNP][ 12147 VAQAGLELLGSSNPP] IF12!48jAQAGLELLGSSNPPAj[

55 LGS S ASL:VAG]

00

00

TableXLVlIl-V9-HLA-DRBI -0401-1 5ners-1 91 P4012B

rEach peptide Is a portion of SEQ IDNO: 19; each start position Is

specified, the length of peptide isamino acids, and the end

position for each peptide is the startposition plus fourteen. I

[Pos 1234567890124 [scorel[5-61 GSSNPPASASL VAGT I[ 121[57 SSNPPASASLAGLj12

PPASASLVAGTLSVH F-1 j[611 PASASLVAGTLSVH]-iI1-21[661 LVAGTLS-VHHCACFE Jj 1267 VAGTLSV HHCAC FESF 121751 HCACFE-SFTKRKK-KL 111217 ACFESFTKK K [12

F941 RFIQCLLLLLVR 112951 FIQCLLLGLVP 1121

1704] LKVRPLQ GNSDj F-111081PLQHQGVNCD E[ i1714VNSCDCERGYFQGF [12111881 DCERGYF-QGIFMQAA L1211122GYFQGIFMQMPWEG 1112

TabeXLVIII-V1 0-HLA-DRB1 -1T401-15mers-1iM1i 1

Each peptide is a portion of SEQID NO: 21; each start position is

specified, the length of peptide isamino acids, and the end

position for each peptide is thestart position plus fourteen.

[Pos 112345678901-2345 sreRCPAGELTDT r-1-8

[11 AGELGTSVTL 14~I 2] FTGRCPAGELGTSDAF 1j2,

CPAGELG-TSDV'vVV L112 GELGTSDW-MVVLGQ EZ I

TabIeXLVIII-VI 1-HLA-DRB1-10401-l5mers-191 P4D1 28

Each peptide Is a portion of SEQID NO: 23; each start position is

specified, the length of peptide isamino acids, and the end

position for each peptide is thestart position plus fourteen.

[Po0s51 1123456789012345 1score]

TableXLVIII-V1 1-HLA-DRB1-0401-1 Smers-1 91 P401 28

Each peptide Is a portion of SEQID NO: 23; each start position Is

specified, the length of peptide is15 amino acids, and the end

position for each peptide is thestart position plus fourteen.j

[EIj 123456789012345 so1-[2]AGSFQARLRL MV 171[11 IRLRVMVPPLPLG F71[7jAJLRVMVPPLPSNG 14[2]FPAGSFQARRL MZii[2]GSFQARLRL-RVMVPP 172

ARLRLRVMVPPLS EI12[jI LRLRVMVPPLPSLN

FTableXLIl-V1 2-HLA-DRB1 -0401-5mers-191P4D 128

Each peptide is a portion of SEQID NO: 25; each start position isspecified, the length of peptide Is

15 amino acids, and the endposition for each peptide is theLstart position plus fourteen.

E l12,34567890123457][cr[RI GCSYSTLTTVRE:lET 2I2

CSVMSEEPEGCSS F20SCSVMSEEPEOSYS

[21 IDNSSCSVMSEEPEGC 2[27 VMSEEPEGCSYSTLT2[2]MSEEPEGCSYSTLTT][12[7J EEPEGCSYSTTTR 1[El EPEGCSYSTLTTVE][12

TabIeXLV1II-V1 3-HLA-DRBI-10401-1 5mers-1 91 P401 2B

Each peptide is a portion of SEQID NO: 27; each start position isspecified, the length of peptide is

15 amino acids, and the endposition for each peptide is theIstart position plus fourteen.

1234567890124 Fsor[gI~TVDVLADPQEDSGKQ F 276

VLADPQEDSGK VO 18i12] DSQVTVDVLADPQED 14

QVTVDVLADPQEDSG 14[D FSSRDSQVTVDVLAD F12[23 ISSRDsQVTVDVLADpI 12[2]SQVTVDVLADPQDS DJ2

14 LADPQDEDSGKVD)LV 12

TabIeXLVIII-V14-HLA-DRB1 -1I 0401-1 Smers-191 P4DI2B J

Each peptide Is a portion of SEQID NO: 29; each start position isspecified, the length of peptide is

15 amino acids, and the endposition for each peptide is the

start position plus fourteen.[Pos 123456789012345 ]scorel[2]GLELLGSSNPPASAS [EN[1-3ASASLVAGTLSVHH 8

LELLGSSNPPASS 14[15 ASLVAGTLSVHHCAC[2]LGSSNPPASASLVAG 2[2]GSSNPPASASLVAGT 12j[2]SSNPPASASLVAGTL 1

71 PPASASLVAGTLS-VH] 71

,[12 PASASLVAGTLSVHHjF12

TableXLIX-V1-HLA-DRB1-1 101-115Smers-1 91NP412B3

Each peptide is a portion of SEQ IDNO: 3; each start position is

specified, the length of peptide is amino acids, and the end position

for each peptide is the start positionplus fourteen.I

I 123456789012345 Iscore1255 NLHIGRE-MLKI 26279 SYNWTRLDGLSG ]F [12 PEAWLLLLLLA F I2-3120-1]1 SAAVTSEFHLVPSRS 1L.23~

164 QVAWARVAEGQI 22[140 RLRLRVLVPPSL 1122E218 GQPLTCWVSHPGLLQ ll2g123 DQRITH1LHVSFLAE- 1221286 DGPLPSGVRVDGDTL Jf221

29TLGFPPT SI F1221138 LMSRYHRRA J F221

I 37l SDVVTVVLGQDKPf 21112611 IGREGAMLKCLSEGQ 1[21E

13FCLLVVWVLMSRYH 1121lI DAKLPCFYRGDSGEQI1 201

113 AGSFQARLRLRVV 11801 SVWDTEVKGTTSSR IL720365 WWVLMSRYHRRKA fl201

13-861 YEEELTLTRENSIRR 1120[39 LRENSIRRLHSHHT II

00

00

TableXLIX-V1 -HLA-DRBl -1 101-l5mers-191P4D12B

Each peptide is a portion of SEQ IDNO: 3; each start position is

specified, the length of peptide Is 15amino acids, and the end position

for each peptide is the start positionplus fourteen.

(Po s 11234567890123451 s ore14F1 SGLRAEGHPDSLKD [20(3471 SASVWVVGVIMALLF [19[3581 ALLFCLLVVVVVLMS IF 9[13 EAWLLLLLLLASFTG ]F718~[161 LLLLLLLASfT GRCP] I8~F76 A Q ELA LL HS KYGL H-V II j1891jSPAYEGRV EQPPPPRI F181

1122 EGEYECRVST-FPAGS] 1l8[T11RVLVPPLPSLNPGPA 11 18]

Fj147 VPPLPSLN-P-GPA-LEE 11812411 HVSFLAEAS-VRGLED 118]

1265 GAMLKCLSEGQPPPS ]jil111 GIYVCHVSNEFSSRD] 118442 GRSYSTLTTVREIET IF18(274 VTSEFHLVPSRSMNG ]7i1-205 TSEFHLVPSRSMNGQ]F173671 VVVLMSRYHRRKAQQ][-171

1190O TTSSRSFKH-SRSAAV I16277 PPSYNWTRLD-G-PLPS 16 71346 VSASVVVVGVIMALL ][76360 LFCLLVVVVVLMSRYJF14871 QENGTLRAKP-TGNGI J[ 161

GAQELALLHSKYGLH]F151Il-0h7] PLOGSVLLRNAVQAD] IF71F17-81 APSVTWDEVGT] F 1711921 SSRSFKHSSAT [151219 QPLTCWSPGLQ 157

(23-01 LLQDQRITLHF 15i343 VDLVSASWVA j-1i5362 CLLWVVWMRH IF- iiF36] LLVVVVVLMSRYHRR [151411 QPEESVGLRAEGHPD 1-5F4- J EGIKQAMNFEG [15

1VEGTRKT 5 i

LLFTCAGEL I[14j LETSDVVTVVLGQ DA l[-14

M61 TSDVVTVVLGQDAKL I[ 14F-411 TVVLGQDAKLPCFYR l[ 141 59 GEQVGQVAARDG j

TableXLIX-V1-HLA-DRBI-1 101-1 5mers-1 91 P4D1 2B

Each peptide Is a portion of SEQ IDNO: 3; each start position is

specified, the length of peptide Is 15amino acids, and the end position

for each peptide is the start positionplus fourteen.

[Pos 1 1234567890124 F Re[61I QVG QVAWA R VDAGEG L-1h][81LLHSKYGLHVSPAYE IF 141

[1381 QARLRLRVL VPPLPSI .1N16 GQGLTLMASCTAEGS114[181 VTWDTEVKGTTSSRS ]D14[184 DTEVKGTTSSRSKH ][14[2271 HPGLLQDQRITHILH 141(2521 GLEDQNLWHIGREG-A][ 12-761 PPPSYNWTR LDGPLP ]Iij

(290 PSGVRVDGDTLGFPP EE(3081 EHSGIYVCHVSNE:FS ][141350 WWVGVIMLLFC7LL ][14135 MLLFCLLVVVVVLM 1411364 LVVVVVLMSRYHRR] 141

397 SIRRLHSHHT DPRSQ ]Li 4F40] LHSHHTDPRS QPEESF 74(420 AEGHPDSLKDNSSCS] 141433 CSVMSEEPEGR-SYST][ 1 I

143 VMSEEPEGRSYSTLT][ 141445 YSTLTTVREI1ETQTE:][ 14454 IETQTELLSPGSRA] 14

1457 QTELLSPGSG EE[14

1479KQAMNHFVENTL] 744831 NHFVQENGTLRAKT i 14111 LLLLASFTGRCPG [13I q VTVVLGQDAKLPCFY DI13

85 JKYGLHVSPAYEGRVE f[ 131 06 NPLDGSVLLRNAVQA Jj[ 313-711 FQARLRLRVLVPLP 13

215j SMNGQPLTCVVSHPG [131237 THILHVSFLAEASVR [_13327 QVTVDVLDPQ DSG 233740 GKQVDLVSASWV [13

I~SVVVVGVFMALLFCL I

411VREIETQTELLS-PGS 11 13DI LSLGAEMWGPEAWLLIF1712

TableXLIX-VI-HLA-DRB1-1 101-I 5mers-1 91 P4D1 2B

Each peptide Is a portion of SEQ IDNO; 3; each start position is

specified, the length of peptide is amino acids, and the end position

for each peptide is the start positionplus fourteen.

[PoI 1234567890124 e[22 LASFTGRCPAGELET F 7

[62 VGQVAWARVDAGEGA 7h[73 GEGAQELALHYG] 12[82 LHSKYGLHVSA E12[83 HSKYGLHVSPAYEGR IF 12[92 PAYEGRVEQPPPPRN 1 121[109 DGSVLLRNAVQADEG ]1 12[11 VLLRNAVQ EEE112[123 GEYEORVSTFPG F 112[141 LRLRVLVPPLSN 12[153 LNIPGPALEEGQ FT ]12[1591 LEEGQGLTLAASCTA 111211764 GLTLAASCTAGP 11121

120 EFHLVPSRSMNGQPL I112]jITHILHVSFLAEASV Jj12

129ILHVSFLAEASVRGL 1_212EASVRGLEDQNLW-HI 12

(26 LKCLSEGQPPPS-YNW 12g(2-92 GVRVDGDTLGFPL 112

(3SGIYVCHVSNEFS 1LJ2I13RDSQVTVDVLPQD] 12

1329 TVDVLD)PQEDSGKQV][ Eg1337 EDSGKQVDLVSASW][ 1213-95 ENSIRRLHSHH TDPR ][1214131 EESVGLRAEGHPDSLI][ j2I421l EGHPDSLKDNSFV] 12

1429 DNSSCSVMSEP F-1-214481 LTTVREIETQT-E-LLS ][F1211455 ETQTELLSIPG SGRAE][ 12(489 NGTLRAKPTGN-GIYI ][12

TableXL1-11V2-HLA-DRB1-1 101-l5mers-191P4D12B

Each peptide is a portion of SEQID NO: 5; each start position is

specified, the length of peptide is15 amino acids, and the end

position for each peptide is thestart position plus fourteen.I~o 12345678901 2345-]Scrl

9 DAKLPCLYRGDSE

00

00

1VLGDKLPCLYRI 14

vi-wi-VVVLGQAKLPCLYFj

ITabIeXLIX-W7-HLA-DRBI-1 101 l5mers-191 P4012B

Each peptide is a portion of SEQID NO: 15; each start position isspecified, the length of peptide Is

amino acids, and the endposition for each peptide is the

start position plus fourteen.

[Pos 1123456789012345 scorelIiI1 SIRRLNSHHTDPRS -1-4171 jLH-SHHTOPRSQSEEP 14[14 ISQSEEPEGRSYSTLT 14~

IRRLHSHHTDPRSQSE 8I~[12 PRSQSEEPGSS F78

F21IRRLHSNHTDPRSQS 61

F_ 81HTDIPIRSQISEEPE 61

110 TOPRSQSEEPEGRSY Mfj

TableXLIX-V9-HLA-DRBI-1 101-l5mers-191P4012Bj

Each peptide is a portion of SEQ IDNO: 19; each start position is

specified, the length of peptide isamino adids, and the end

position for each peptide Is the start___position plus fourteen.

7PosI 12345678024 scorel

97 QCLLLGLLKVRP LQH 28[1_211RGYFQG:F MQMAPWE 22~

[37 YFFLEMESHYVAQAG I] 21![79 FESFTKRKLKFI 21

[76CCEFKKKK1 201[1_03 ILLKVRPLQHQG-VNS-C] 20

221 FLPFPLVFIFF] 19[17j FFLFFFLPFPLWFF F1_i.491 QAGLELLGSSNPPAS [Ir

7.66I LVAGTLSVHAF [jF51F FYFYFFLE MESHYVAF1117!

FKKFRFIQCLLLGLL 7

F[120 ER GY F QGIFMQAAP-W][ 171'FNFFLFFFLPFPLWV ][16

33 YFYFYFFLEMESHYV lE 161[36 FYF FLEMESHYVAQA] 16

161KKKLKKFICL] 1532 RELLAGILIFF]T41ELLAGILLRITFNFF ][14

Tab~eXLIX-V9-HLA-DRB1 -1101 -11 Smers-191 P40128

Each peptide Is a portion of SEQ IDNO: 19; each start position is

specified, the length of peptide is15 amino acids, and the end

position for each peptide is the startI position plus fourteen.

[Pos [123456789012345- [coreI[7VAGTLSVHHCACFES[14[3TKRI<KKLKKAFRFIQ][ 141IiHQGVNSCDCERGYFQ][ 14

[26j PLWFFIYFYFYFFL] 13]

F61] PASASLVAGTLSV7HH 13I93 FRFIQCLLLGLLKVR 1398 CLLLGLLKVRPLQQ D__13

TbIeXLIX-VI 0-HLA-DRBI-1 101-[T 15mers-191P4D128

Each peptide Is a portion of SEQID NO: 21; each start position isspecified, the length of peptide is

1amino acids, and the endposition for each peptide Is the

start position plus fourteen.jEgF 123456789012345 I crjj1IjJLGTSDVVTWLGQDA 4

72LASFTGRCPAGELGT 1T2[gELGTSDVVTVWLG FZ9I[11 LLASFTGRCPAGELGiii7

S-FT GR C P A GELG TSD 137[3 TGRCPAGELGTSDW 16

R RCP A GE LG TSDVVT VL

I ]BAGELGTSDYVVTWLG E96

[TableXLIX-V1 1 -HLA-DR1-1101-l5mners-191P4D12B

Each peptide is a portion of SEQID NO: 23; each start position Isspecified, the length of peptide is

15 amino acids, and the endposition for each peptide is the

start position plus fourteen.Pos 12345 6789012 345 Fs-o-e

[3RLRLRVMVPPLPSLN Ii[3AGSFQARLRLRVMVP LI

DI 3VVPPLPP 18

7[QRLRLRV MVPPLPSE]I

I~ F FQRLRLRVMVPPLP L-ii3

7FFPAGSFQARLRLV Zi1P

TabIeXLIX-V12-HLA-DRB1-1 101-1l5mers-191P4012B37

Each peptide is a porton of SEQID NO: 25; each start position isspecified, the length of peptide is

15 amino acids, and the endposition for each peptide is the

start position plus fourteen.

Posj 123456789012345 I score[14 GCSYSTLT1VREE ZIP][3 DNSSCSVMSEEPEGCI 172~[31CSVMSEEPEGCSYST 1

NSSCSVMSEEPEGCS Lii

LTabIeXLIX-V13-HLA-DRB1-1 1011 Smers-1 91 P02

Each peptide is a portion of SEQID NO: 27; each start position isspecified, the length of peptide is

15 amino acids, and the endposition for each peptide is the

start position plus fourteen.

[Ps 23456789012345 e

[3 jDSQVTVDVLADPQED F-7

I QVTVDVLAD)PQEDSG II3[10 TVDVLADPQEDSK 12I[illVDVLADPQEDSGKV i[3 SRDSQVTVDVADPQ IF 17[m jADPQEDSGKQVDLVS DI

STabIeXLIX-V14-HLA-DRB1-1 101-1 Smers-1 91P4031 2BEach peptide is a portion of SEQID NO: 3; each start position is

specified, the length of peptide is15 amino acids, and the end

position for each pepide is thestart position plus fourteen.

[Pos 123456789012345 Iscre[12 PASASLVAGTLSVHHjF_ 1I3I 71GLELLGSSNPPASAS

I LELLGSSNPPASASLF-121[[EIiiPPASASLV TLH 11F3 8SSNPPASASLVAGTL I 14 SASLVAGTLSVIIO 13fI AGLELLGSSNPP-ASA E31

E3 ELLGSSNPPAAL 116[3 LLGSSNPPASASLA 1[3 jSNPPASASLVAGTS161[Is ASLVAGTLSVH=HCAC 136

2008202217 20 May 2008

Table L: Properties of 191P4D12(b)

00

00

Ig1P4D12(b)B v.1ORFProtein lengthTransmembrane region

Signal PeptidePIMolecular weightLocalization

Motifs

BioinformaticProgramORF finder

TM PredHMMTopSosulTMHMMSignal Pp1/MW toolp1/MW toolPSORT

PSORTI11PfamPrints

Blocks

http:Ilwww.ch.embnet.org/hftp://www.enzim.hulhmmtop/http:Ilwww.genome.ad.jp/SOSuiIhftp://www.cbs.dtu.dk/servicesTMHMMhttp:Ilwww.cbs.dtu.dkservices/SignaIP/hftp://www.expas y.ch/tools/http://www.expasy.ch/tools/http:/Ipsort.nibb.ac.jp/

httpJ/psor~nibb.ac.jp/http://www.sanger.ac.uk/Pfam/http:llwww.biochem.ucl.ac.uk/

http:/Iwww.blocks.fhcrc.org/

Outcome264-1796

2 TM, aa 14-30, 351 -3701 TM, aa 347-3712 TM, aa 14-31, 347-3691 TM, aa 350-372yes, cleaved aa 31-32pl 5.2755.4 kDa46% plasma membrane39.1 cytoplasmic, 21 nuclearImmunoglobulin domainCadherin signatureIg domain, Herpesviwusglycoprotein D

Bioinformaticv.6 Program URL OutcomeORF ORE finderProtein lengthTransmembrane region

Signal PeptidepIMolecular weightLocalization

Motifs

TM PredHMMTopSosuiTMHMMSignal Pp1/MW toolp1/MW toolPSORT

PSORT 11PfamPrints

Blocks

http://www.ch.embnetorg/http:/lwww.enzim.hulhmmtop/http://www.genome.ad.jp/SOSuV/http://www.cbs.dtu.dk/servicesrrMHMMhttpJ/www.cbs.dtu.dk/services/SignaIP/http://www.expasy.ch/toolsIhttpJ/www.expasy.ch/tools/http://psort.nibb.ac.jp/

http://psort.nibb.ac.jp/http://www.sanger. ac.uk/Pfam/http://www.biochem.ucl.ac.ukl

http:f/www.blocks fiicrc-org/

295 asI TM, aa 135-1561 TMV, aa 132-1561 TM, aa 132-1541 TM, aa 135-157nonepl 5.2832.6 k~a70% plasma membrane,20% endoplasmic reticulum39% cytoplasmic, 21%nuclearImmunoglobulin domainnone

Herpesvirus glycoprotein D

00

00

Table LI: Exon boundaries of transcript 191 P4D12(b) v.1

Exon Number Start End Length

1 2 342 341

2 343 702 360

3 703 993 291

4 994 1114 12111115 1263 149

6 1264 1420 157

7 1421 1496 76

8 1497 1571

9 1572 3459 1888

Table UlI(a). Nucleotide sequence of transcript variant 191 P4DI 2(b) v.6 (SEQ ID NO: 105)ggccgtcgttacggcttctttcccctagtgcagttccttaagctggagact ctaccgagggcgaaggcgccttacgagggtcctgcgcaa.ccgccggcagtgaatcctggctgagggcaggccgttccttgccgcagcataccaaaggatttgaagaccaaagggcagcctacgagtggaacgtctgccattgacccccatgggtgtgatgataccatcgccagggagaaaggagagtgtgctctgtgatagatagaaacatcaggatgagggccaagccggcctgcctcttgggggcctcttgacctttcaccatgcattgtgtgtgtgctgtcatatcgggcaacactaaagcaggtaggtggagactggtgtgaggggtCCCtgggttgggcctgCtaatactgctCtgtatttttttcaggctggc

gttggccacagggggtagctgagacccaagttcaagtctgctcagacgtgggactccggcccaggaactaccgcgtggagcgcagtgcagcttccaggcgtccagcactacccagccccccaagcactccgaatgggcagcacccacatcaaatctgtggccctccctcatggggacacttgtcagcaatggaagactctcgccgcactcgcgcaaggccctccatccggagggctgagagagtgaagagac agac tgaaaggcatcaaacacgggcaatccttccctagccttaaacacacctccaaccgcaggtcactgaggggtgacagagtcaagtgtcagggtttttttctcagagtggctcagaaacctgtctccagccagagggcatgtacatcgaatcacttatttatttttcttgaactcc

gcgtgggaagacggctgggttgcgagaggcctactgctgggtaactgtgggagcaagtgggcgctactgccagccgccgcgcggatgaggcggctgcggcgaagagggccagcgtgacctcgctctgctgccactgacttctccacgtgtcaca ttggcatacaactggattgggctttcgagttctcctgggaagcaggttgttctgcccagcagatgaaggctgcattgc cgagggc ccccgagggccctgctgtctccaggc catgaggcatctacagcctggctccccccatttctcttctgttcagtgtgtgtgctgtccgtggagaactgtggtggcgtgtgtgccccagagcacccaggtgtgctaccacttcct tgaactgtattttctgtattaattttttatttttattttgggCtcaag

cagctctggggtgtagaacgaagaactctgcatcatttactgctgggccaggcaagtggcactccaaataccccacgcaagcgagtacgatccgagtgctagggcctgacgggacacggaccgtcacctcgtgtggtgtcccttccttgcgagaaggagccacggctggaccccactgaccaagggattctggacctagtttCtggtggtcccagaaatacccatcacacaccctgataggcagttactccaggctctggaccattttgttcaatgggcgttctgttgactgcggaagatt cgggagggcatgtgtgcctggggtgactggtatgtgccatcatgtggctgtattaatgacgggcatagcggagccatggtacagaagccaatatacatgtcttttttttttttttagagcaatcctcct

ggagctcggagggccggggccagcttcctgaggccggtgcggacgcaaaaatgggctcggcgggcttcatccccctggacgtgccgggtcggtgCCtCCCCC tggCagcCCggtcaaaggcagagttccacc cat c ctgg ctgaggcctcttatgctcaagtgggcctctgcac tgagcactcaggtcactgtcagcctcgggtggtggtgtgaggaggagggaccccaggtctcaaggaccacgctgaccgcgggccgagt caggagaatgggacacctgatgggagattgctccccatctccaccaattgtgtgagtgttgtccgtggtcgggatttgagtgtgtgacctgcagaggt ttggagctggagggcaagtgtCtCtgCCCtCCgCCgggagcttcttgccctatggagtctccCt cagocct

gctcccgatctggggctgggccttctgggtc ccgcgggtgC tgcC Ctgc tgtggacgcgggtgagcccggggCtcagtgcagcaccttccctgccctcactcctgcacagacaacgtccattggtgcctactgctccagggtgaggggcctgcctgagtgcccagtggggagcggcatctgtggatgttcgtggtggtggctcatgtcccctgaccctgaagccagccggaacagtagctacggtgaggggaggaggaaggggaccctacgtctgacccattagctcatcccactgactggagtctctcctgactgactggtgtattatggtggttgcgttctgcctgaaggaggagagaatctgcctccgaagcagccatggtggcctcttcttgcaggttccattagtactatgttgcccctagtagc

120180240300360420480540600660720780840900960

102010801140120012601320138014401500156016201680174018001860192019802040210021602220228023402400246025202580

tgggacttta agtgtacacc actgtgcctg ctttgaatcc tttacgaaga gaaaaaaaaa 2640

attaaagaaa gcctttagat ttatccaatg tttactactg ggattgctta aagtgaggCC 2700

cctccaacac cagggggtta attcctgtga ttgtgaaagg ggCtacttcc aaggcatctt 2760

00 catgcaggca gccccttggg agggcacctg agagctggta gagtctgaaa ttagggatgt 2820

C) gagcctcgtg gttactgagt aaggtaaaat tgcatccacc attgtttgtg ataccttagg 2880

C) gaattgcttg gacctggtga caagggctcc tgttcaatag tggtgttggg gagagagaga 2940

gcagtgatta tagaccgaga gagtaggagt tgaggtgagg tgaaggaggt gctgggggtg 3000Sagaatgtcgc ctttccccct gggttttgga tcactaattc aaggctcttc tggatgtttc 3060

tctgggttgg ggctggagtt caatgaggtt tatttttagc tggcccaccc agatacactc 3120

agccagaata cctagattta gtacccaaac tcttcttagt ctgaaatctg ctggatttct 3180

ggcctaaggg agaggctccc atccttcgtt ccccagccag cctaggactt cgaatgtgga 3240

gcctgaagat ctaagatcct aacatgtaca ttttatgtaa atatgtgcat atttgtacat 3300aaaatgatat tctgttttta aataaacaga caaaacttga aaaa 3344

Table 1.lll(a). Nucleotide sequence alignment of 191P4D12(b) M. (SEQ ID NO: 106) and 19113012(b) v.6 (SEQ ID NO:107).

ci V.1 1 gGCCGTCGTTGTTGGCCACAGCGTGGGAAGCAGCTCTGGGGGAGCTCGGA

ci V.6 1 ggccgtcgttgttggccacagcgtggaagcagctctgggggagctcgga 00

V.1 51 GCTCCCGATCACGGCTTCTTGCGGGTAGCTACGGCTGGGTGTGTAGAACG 100

ci V.6 51 gctcccgatcacggcttcttgggggtagctacggctgggtgtgtagaacg 100

V.1 101 GGGCCGGGGCTGGGGCTGGGTCCCCTAGTGGAGACCCAAGTGCGAGAGGC 150

V.6 101 gggccggggctggggctgggtcccctagtggagacccaagtgcgagaggc 150

V.1 151 AAGAACTCTGCAGCTTCCTGCCTTCTGGGTCAGTTCCTTATTCAAGTCTG 200

V.6 151 aagaactctgcagcttcctgccttctgggtcagttccttattcaagt-- 197

V.1 201 CAGCCGGCTCCCAGGGAGATCTCGGTGGAACTTCAGAAACGCTGGGCAGT 250

V.6 197

V.1 251 CTGCCTTTCAACCATGCCCCTGTCCCTGGGAGCCGAGATGTGGGGGCCTG 300

V.6 197

V.1 301 AGGCCTGGCTGCTGCTGCTGCTACTGCTGGCATCATTTACAGGCCGGTGC 350

V.6 ctgctactgctggcatcatttacaggccggtgc 230

V. 1 351 CCCGCGGGTGAGCTGGAGACCTCAGACGTGGTAACTGTGGTGCTGGGCCA 400

V. 6 231 cccgcgggtgagctggagacctcagacgtggtaactgtggtgctgggcca 280

V. 1 401 GGACGCAAAACTGCCCTGCTTCTACCGAGGGGACTCCGGCGAGCAAGTGG 450

V. 6 281 ggacgcaaaactgccctgcttctaccgaggggactccggcgagcaagtgg 330

V. 1 451 GGCAAGTGGCATGGGCTCGGGTGGACGCGGGCGAAGGCGCCCAGGAACTA 500

V.6 331 ggcaagtggcatgggctcgggtggacgcgggcgaaggcgcccaggaacta 380

v.1 501 GCGCTACTGCACTCCAAATACGGGCTTCATGTGAGCCCGGCTTACGAGGG 550

V.6 381 gcgctactgcactccaaatacgggcttcatgtgagcccggcttacgaggg 430

V.1 551 CCGCGTGGAGCAGCCGCCGCCCCCACGCAACCCCCTGGACGGCTCAGTGC 600

235

V.6 431 ccgcgtggagcagccgccgcccccacgcaaccccctggacggctcagtgc 480

00 V.1 601 TCCTGCGCAACGCAGTGCAGGCGGATGAGGGCGAGTACGAGTGCCGGGTC 650

V.6 481 tcctgcgcaacgcagtgcaggcggatgagggcgagtacgagtgccgggtc 530

V.1 651 AGCACCTTCCCCGCCGGCAGCTTCCAGGCGCGGCTGCGGCTCCGAGTGCT 700

S V.6 531 agcaccttccccgccggcagcttccaggcgcggctgcggctccgagtgct 580

V.1 701 GGTGCCTCCCCTGCCCTCACTGAATCCTGGTCCAGCACTAGAAGAGGGCC 750

V.6 581 ggtgcctcccctgccctcactgaatcctggtccagcactagaagagggcc 630

V.1 751 AGGGCCTGACCCTGGCAGCCTCCTGCACAGCTGAGGGCAGCCCAGCCCCC 800

ri V.6 631 agggcctgaccctggcagcctcctgcacagctgagggcagcccagccccc 680

V.1 801 AGCGTGACCTGGGACACGGAGGTCAAAGGCACAACGTCCAGCCGTTCCTT 850

00 V.6 681 agcgtgacctgggacacggaggtcaaaggcacaacgtccagccgttcctt 730

V. 1 851 CAAGCACTCCCGCTCTGCTGCCGTCACCTCAGAGTTCCACTTGGTGCCTA 900

V.6 731 caagcactcccgctctgctgccgtcacctcagagttccacttggtgccta 780

V.1 901 GCCGCAGCATGAATGGGCAGCCACTGACTTGTGTGGTGTCCCATCCTGGC 950

V.6 781 gccgcagcatgaatgggcagccactgacttgtgtggtgtcccatcctggc 830

V. 1 951 CTGCTCCAGGACCAAAGGATCACCCACATCCTCCACGTGTCCTTCCTTGC 1000

V.6 831 ctgctccaggaccaaaggatcacccacatcctccacgtgtccttccttgc 880

V.1 1001 TGAGGCCTCTGTGAGGGGCCTTGAAGACCA-AAATCTGTGGCACATTGGCA 1050

'V.6 881 tgaggcctctgtgaggggccttgaagaccaaaatctgtggcacatcggca 930

V.1 1051 GAGAAGGAGCTATGCTCAAGTGCCTGAGTGAAGGGCAGCCCCCTCCCTCA 1100

V.6 931 gagaaggagctatgctcaagtgcctgagtgaagggcagccccctccctca 980

V.1 1101 TACAACTGGACACGGCTGGATGGGCCTCTGCCCAGTGGGGTACGAGTGGA 1150

V.6 981 tacaactggacacggctggatgggcctctgcccagtggggtacgagtgga 1030

V.1 1151 TGGGGACACTTTGGGCTTTCCCCCACTGACCACTGAGCACAGCGGCATCT 1200

V.6 1031 tggggacactttgggctttcccccactgaccactgagcacagcggcatct 1080

V.1 1201 ACGTCTGCCATGTCAGCAATGAGTTCTCCTCAAGGGATTCTCAGGTCACT 1250

V.6 1081 acgtctgccatgtcagcaatgagttctcctcaagggattctcaggtcact 1130

V.1 1251 GTGGATGTTCTTGACCCCCAGGAAGACTCTGGGAAGCAGGTGGACCTAGT 1300

V.6 1131 gtggatgttcttgacccccaggaagactctgggaagcaggtggacctagt 1180

V. 1 1301 GTCAGCCTCGGTGGTGGTGGTGGGTGTGATCGCCGCACTCTTGTTCTGCC 1350

V.6 1181 gtcagcctcggtggtggtggtgggtgtgatcgccgcactcttgttctgcc 1230

V.1 1351 TTCTGGTGGTGGTGGTGGTGCTCATGTCCCGATACCATCGGCGCAAGGCC 1400

V.6 1231 ttctggtggtggtggtggtgctcatgtcccgataccatcggcgcaaggcc 1280

00 V.1 1401 CAGCAGATGACCCAGAAATATGAGGAGTGAGCTGACCCTGACCAGGGAGAA 1450

S V.6 1281 cagcagatgacccagaaatatgaggaggagctgaccctgaccagggagaa 1330

V.1 1451 CTCCATCCGGAGGCTGCATTCCCATCACACGGACCCCAGGAGCCAGCCGG 1500

VA6 1331 ctccatccggaggctgcattcccatcacacggaccccaggagccagccgg 1380

V.1 1501 AGGAGAGTGTAGGGCTGAGAGCCGAGGGCCACCCTGATAGTCTCAAGGAC 1550

V.6 1381 aggagagtgtagggctgagagccgagggccaccctgatagtctcaaggac 1430

V.1 1551 AACAGTAGCTGCTCTGTGATGAGTGAAGAGCCCGAGGGCCGCAGTTACTC 1600

V.6 1431 aacagtagctgctctgtgatgagtgaagagcccgagggccgcagttactc 1480

V.1 1601 CACGCTGACCACGGTGAGGGAGATAGAAACACAGACTGAACTGCTGTCTC 1650

S V.6 1481 cacgctgaccacggtgagggagatagaaacacagactgaactgctgtctc 1530

(1 V.1 1651 CAGGCTCTGGGCGGGCCGAGGAGGAGGAAGATCAGGATGAAGGCATCA 1700

V.6 1531 caggctctgggcgggccgaggaggaggaagatcaggatgaaggcatcaaa 1580

V.1 1701 CAGGCCATGAACCATTTTGTTCAGGAGAATGGGACCCTACGGGCCAAGCC 1750

V.6; 1581 caggccatgaaccattttgttcaggagaatgggaccctacgggccaagcc 1630

V.1 1751 CACGGGCAATGGCATCTACATCAATGG7GCGGGGACACCTGGTCTGACCA 1800

V.6 1631 cacgggcaatggcatctacatcaatgggcggggacacctggtctgaccca 1680

V.1 1801 GGCCTGCCTCCCTTCCCTAGGCCTGGCTCCTTCTGTTGACATGGGAGATT 1850

V.6 1681 ggcctgcctcccttccctaggcctggctccttctgttgacatgggagatt 1730

V.1 1851 TTAGCTCATCTTGGGGGCCTCCTTA-AACACCCCCATTCTTGCGGAAGAT 1900

V.6 1731 ttagctcatcttgggggcctccttaaacacccccatttcttgcggaagat 1780

V.1 1901 GCTCCCCATCCCACTGACTGCTTGACCTTTACCTCCAACCCTTCTGTTCA 1950

V.6 1781 gctccccatcccactgactgcttgacctttacctccaacccttctgttca 1830

V.1 1951 TCGGGAGGGCTCCACCAATTGAGTCTCTCCCACCATGCATGCAGGTCACT 2000

V.6 1831 tcgggagggctccaccaattgagtctctcccaccatgcatgcaggtcact 1880

V.1 2001 GTGTGTGTGCATGTGTGCCTGTGTGAGTGTTrGACTGACTGTGTGTGTGTG 2050

V.6 1881 gtgtgtgtgcatgtgtgcctgtgtgagtgttgactgactgtgtgtgtgtg 1930

V.1 2051 GAGGGGTGACTGTCCGTGGAGGGGTGACTGTGTCCGTGGTGTGTATTATG 2100

VA6 1931 gaggggtgactgtccgtggaggggtgactgtgtccgtggtgtgtattatg 1980

V.1 2101 CTGTCATATCAGAGTCAAGTGAACTGTGGTGTATGTGCCACGGGATTTGA 2150

V.6 1981 ctgtcatatcagagtcaagtgaactgtggtgtatgtgccacgggatttga 2030

V.1 2151 GTGGTTGCGTGGGCAACACTGTCAGGGTTTGGCGTGTGTGTCATGTGiGCT 2200

00 V.6 2031 gtggttgcgtgggcaacactgtcagggtttggcgtgtgtgtcatgtggct 2080

V.1 2201 GTGTGTGACCTCTGCCTGAAAAAGCAGGTATTTTCTCAGACCCCAGAGCA 2250

V. 6 2081 gtgtgtgacctctgcctgaaaaagcaggtattttctcagaccccagagca 2130

V.1 2251 GTATTAATGATGCAGAGGTTGGAGGAGAGAGGTGGAGACTGTGGCTCAGA 2300

V. 2131 gttatagaagtggaaagga acggtaa 2180

V.1 230 CCCAGGGTGCGGCATAGCGGAGCTII ATIIIIIICGIITGIIIG 235V.6 2181 cccaggtgtgcgggcatagctggagctggaatctgcctccggtgtgaggg 2230

CI V.1 2351 AACCTGTCTCCTACCACTTCGGAGCCATGGGGGGCAAGTGTGAAGCAGCCA 2400

V.6 2231 aacctgtctcctaccacttcggagccatgggggcaagtgtgaagcagcca 2280

00 V.1 2401 GTCCCTGGGTCAGCCAGAGGCTTGAACTGTTACAGAAGCCCTCTGCCCTC 2450

V.6 2281 gtccctgggtcagccagaggcttgaactgttacagaagccctctgccctc 2330

V.1 2451 TGGTGGCCTCTGGGCCTGCTGCATGTACATATTTTCTGTAAATATACATG 2500

V.6 2331 tggtggcctctgggcctgctgcatgtacatattttctgtaaatatacatg 2380

V.1 2501 CGCCGGGAGCTTCTTGCAGGAATACTGCTCCGAATCACTTTTAATTTTTT 2550

V.6 2381 cgccgggagcttcttgcaggaatactgctccgaatcacttttaatttttt 2430

V.1 2551 TCTTTTTTTTTTCTTGCCCTTTCCATTAGTTGTATTTTTTATTTATTTTT 2600

V.6 2431 tcttttttttttcttgccctttccattagttgtattttttatttattttt 2480

V.1 2601 ATTTTTATTTTTTTTTAGAGATGGAGTCTCACTATGTTGCTCAGGCTGGC 2650

V.6 2481 atttttatttttttttagagatggagtctcactatgttgctcaggctggc 2530

V.1 2651 CTTGAACTCCTGGGCTCAAGCAATCCTCCTGCCTCAGCCTCCCTAGTAGC 2700

V.6 2531 cttgaactcctgggctcaagcaatcctcctgcctcagcctccctagtagc 2580

V.1 2701 TGGGACTTTAAGTGTACACCACTGTGCCTGCTTTGAATCCTTTACGAAGA 2750

V.6 2581 tgggactttaagtgtacaccactgtgcctgctttgaatcctttacgaaga 2630

V.1 2751 GAAAAAAATTAAAGAAAGCCTTTAGATTTATCCAATGTTTACTACTG 2800

V.6 2631 gaaaaaaaaaattaaagaaagcctttagatttatccaatgtttactactg 2680

V.1 2801 GGATTGCTTAAAGTGAGGCCCCTCCAACACCAGGGGGTTAATTCCTGTGA 2850

V.6 2681 ggattgcttaaagtgaggcccctccaacaccagggggttaattcctgtga 2730

V. 1 2851 TTGTGAAAGGGGCTACTTCCAAGGCATCTTCATGCAGGCAGCCCCTTGGG 2900

V.6 2731 ttgtgaaaggggctacttccaaggcatcttcatgcaggcagccccttggg 2780

V.1 2901 AGGGCACCTGAGAGCTGGTAGAGTCTGAAATTAGGGATGTGAGCCTCGTG 2950

V.6 2781 agggcacctgagagctggtagagtctgaaattagggatgtgagcctcgtg 2830

238

V.1 2951 GTTACTGAGTAAGGTAAAATTGCATCCACCATTGTTTGTGATACCTTAGG 3000

00 V.6 2831 gttactgagtaaggtaaaattgcatccaccattgtttgtgataccttagg 2880

V.1 3001 GAATTGCTTGGACCTGGTGACAAGGGCTCCTGTTCAATAGTGGTGTTGGG 3050

V.6 2881 gaattgcttggacctggtgacaagggctcctgttcaatagtggtgttggg 2930

V.1 3051. GAGAGAGAGAGCAGTGATTATAGACCGAGAGAGTAGGAGTTGAGGTGAGG 3100

S V.6 291gagagagagagcagtgattatagaccgagagagtaggagttgaggtgagg 2980

V.1 30 TGAAGGAGGTGCTGGGGGTGAGAATGTCGCCTTTCCCCCTGGGTTTTGGA 3150

V.6 981tgaaggaggtgctgggggtgagaatgtcgcctttccccctgggttttgga 3030

V.1 151TCACTAATTCAAGGCTCTTCTGGATGTTTCTCTGGGTTGGGGCTGGAGTT 3200

V6 3031 tcactaattcaaggctcttctggatgtttctctgggttggggctggagtt 3080

00S V.1 3201 CAATGAGGTTTATTTTTAGCTGGCCCACCCAGATACACTCAGCCAGAATA 3250

C] V.6 3081 caatgaggtttatttttagctggcccacccagatacactcagccagaata 3130

V.1 3251 CCTAGATTTAGTACCCAAACTCTTCTTAGTCTGAAATCTGCTGGATTTCT 3300

V.6 3131 cctagatttagtacccaaactcttcttagtctgaaatctgctggatttct 3180

V.1 3301 GGCCTAAGGGAGAGGCTCCCATCCTTCGTTCCCCAGCCAGCCTAGGACTT 3350

V.6 3181 ggcctaagggagaggctcccatccttcgttccccagccagcctaggactt 3230

V.1 3351 CGAATGTGGAGCCTGAAGATCTAAGATCCTAACATGTACATTTTATGTAA 3400

V.6 3231 cgaatgtggagcctgaagatctaagatcctaacatgtacattttatgtaa 3280

V.1 3401 ATATGTGCATATTTGTACATAAAATGATATTCTGTTTTTAAATAAACAGA 3450

V.6 3281 atatgtgcatatttgtacataaaatgatattctgtttttaaataaacaga 3330

V.1 3451 CAAAACTTGaaaaa 3464

V.6 3331 caaaacttgaaaaa 3344

Table LiV(a). Peptide sequences of protein coded by 191P4012(b) v.6 (SEQ ID NO: 108)NNGQPLTCVV SHPGLLQDQR ITHILHVSFL AEASVRGLED QNLjWHIGREG AMLKCLSEGQ PPPSYNWTRL DGPLPSGVRV DGDTLGFPPL TTEHSGIY'VC IiVSNEFSSRfl SQVTVDVLDP 120QEDSGKQVDL VSASVVVVGV IAALLFCLLV VVVVLMSRYH RRKAQQMTQK YEEELTLTRE 180NSIRRLHSHH TDPRSQPEES VGLRAEGHPD SLKDNSSCSV MSEEPEGRSY STLTTVREIE 240

TQTELLSPGS GRAEEEEDQD EGIKQAMNHF VQE1NGTLRAK PTGNGIYING RGHLV 295

Table LV(a). Amino acid sequence alignment of 19113012(b) M. (SEQ ID NO: 109) and 191P4D12(b) v.6 (SEQ ID NO:110)V.1 216 MNGQPLTCVVSHPGLLQDQRITHILHVSFLAEASVRGLEDQNLWHIGREG 265

V.6 1 MNGQPLTCVVSHPGLLQDQRITHILHVSFLAEASVRGLEDQNLWHIGREG

V.1 266 AMLKCLSEGQPPPSYNWTRILDGPLPSGVRVDGDTLGFPPLTTEHSGIYVC 315

V. 6 51 AMLKCLSEGQPPPSYNWTRLDGPLPSGVRVDGDTLGFPPLTTEHSGIYVC 100

V. 1 316 1VSNESSRflQVTVDVLDPQEDSGKQVDLVSASvvvVGVIAALLFCLLV 365

239

I 1 1 I1 1 1 1 I1 1 11 1 Ii I1 11 1 IIIIIIIIIIIIIIIII II II I II V.6 101 IIVSNEFSSRDSQVTVDVLDPQEDSGKQVDLVSASVVVVGVIAAIJLFCLLV

V.1 366 VVVVLMSRYHRRKAQQMTQKYEEELTLTRENSIRRLHSHHTDPRSQPEES

V.6 151 VVVVLMSRYHRRKAQQMTQKYEEELTIJTRENSIRpTRSHHJTDPRSQPEES

V. 1 416 VGLRAEGH-PDSLKNSSCSVMSEEPEGRSYSTLTT=REIETQTELLSPGS

V.6 201 VGLRAEGHPDSLKDNSSCSVMSEEPEGRSYSTLTI'VREIETQTELLSPGS

V.1 466 GRAEEEEDQDEGIKQAHFVQENGTLRAkKPTOGIYINGRGHLV

V.6 251 GRAEEEEDQDEGIKQAVNHFVQENGTLRAJCPTGNGIYINGRGHLV

150

415

200U

465

250

Table 111(b). Nucleotide sequence of transcript variant 191 P4DI 2(b) v.7 (SEQ ID NO:ggccgtcgttacggcttctttcccctagtgcagttccttagc tgggcagtaggcctggctagctggagactctaccgagggcgaaggcgccttacgagggtcctgcgcaaccgccggcagtgaatcctggctgagggcaggccgttccttgccgcagcata cc aaagga tttgaagaccaaagggcagcct acgagtggaacgtctgccattgacccccatgggtgtgatgataccatcgccagggagaaaagagcccgactgaactgcttcaaacaggcgcaatggcatcc taggcctyaacaccCCCacaacccttcttcactgtgtggtgactgtcccaagtgaactggtttggcgttcagaccccatcagacccaggtctcctaccagaggcttgatacatattttcacttttaattttttattttactcctgggcacaccactgt

gttggccacagggggt agc tgagacccaagttcaagtctgctgcctttcagctgctgctgctcagacgtgggact ccggcccaggaactaccgcgtggagcgcagtgcagcttccaggcgtccagcactacccagccccccaagcactccgaatgggcagcacccacatcaaatctgtggccctccctcatggggacacttgtcagcaatggaagactctcgccgcactcgcgcaaggccctccatccgggggccgcagtgtctccaggccatgaaccatctacatcaatgctccttctgtttcttgcgggttcatcgggtgtgcatgtggtggaggggtgtggtgtatggtgtgtcatggagcagtattgtgtgcgggcacttcggagcactgttacagCtgtaaatatttttttcttttatttttttttcaagcaatcgcctgctttg

gcgtgggaagacggctgggt

tgcgagaggccagccggctcaccatgccccctactgctgggtaactgtgggagcaagtgggcgctactgccagccgccgcgcggatgaggcggctgcggcgaagagggccagcgtgacctcgctctgctgccactgacttCtccacgtgtcacattggcatacaactggattgggctttcgagttctcctgggaagcaggttgttctgcccagcagatgaaggctgcatttactccacgctctgggcgggtttgttcagggggcggggacttgacatgggaagatgctccagggctccactgcctgtgtggactgtgtcctgccacgggatggctgtgtgaatgatgcagatagctggagCatgggggcaaagccctctgacatgcgccgtttttttctttagagatggaCtcctgcctcaatcctttac

cagctctggggtgtagaacgaagaactctgccagggagattgtccctgggcatcatttactgctgggccaggcaagtggcactccaaataccccacgcaagcgagtacgatccgagtgctagggcctgacgggacacggaccgtcacctcgtgtggtgtcccttccttgcgagaaggagccacggctggaccccactgaccaagggattctggacctagtttctggtggtcccagaaatacccatcacactgaccacggtccgaggaggaagaatgggacacctggtctgagattttagcccatcccactcaattgagtcagtgttgactgtggtgtgtatttgagtggttgacctctgcaggt tggaggctggaatctgagtgtgaagcccctctggtgggagcttcttgccCtttccagtctcactatagcctccctagaagagaaaa

ggagctcggagggccggggccagcttcctgctcggtggaaagccgagatgaggccggtgcggacgcaaaaatgggctcggc ggg ct t catccccctggacgtgccgggtcggtgCCtCCCcctggcagccggtcaaaggcagagttccacccatcctggctgaggcctcttatgctcaagtgggcctctgcac tgagcactcaggtcactgtcagcctcgggtggtggtgtgaggaggagggaccccagggagggagataggaagatcagcctacgggccacccaggccttcatcttggggactgcttgatctcccaccagactgtgtgtttatgctgtctgcgtgggcaCtgaaaaagcagagaggtggcctccggtgtagccagtcccgcctctgggcgcaggaatacttagttgtatgttgctcagggtagctgggaaaaaaattaa

111)gctcccgatctggggctgggcc tt ctgggtcttcagaaactgggggcctgCCCgCgggtgctgccctgctgtggacgcgggtgagcccggggctcagtgcagcaccttccctgccctcactcctgcacagacaacgtccattggtgcctac tgctccagggtgaggggcctgcctgagtgcccagtggggagcggcatctgtggatgttcgtggtggtggctcatgtcccctgaccctgaagccagagtgg~aacacagagatgaaggcaaagcccacgggCCtCCCttCggcctccttaCCtttacctctgcatgcagggtgtggaggga tat cagag tacactgtcagaggtattttcagactgtggcgagggaaccttgggtcagccctgctgcatgtgctccgaattttttatttaCtggcct tgactttaagtgtagaaagcctt

120180240300360420480540600660720780840900960

10201080114012001260132013801440150015601620168017401800186019201980204021002160222022802340240024602520258026402700

tagatttatc caatgtttac tactgggatt gcttaaagtg aggcccctcc aacaccaggg 2760ggttaattCc tgtgattgtg aaaggggcta cttccaaggc atcttcatgc aggcagcccc 2820ttggagggc acctgagagc tggtaga~tc tgaaattagg gatgtgagcc tcgtggttac 2880

00 tgagtaaggt aaaattgcat ccaccattgt ttgtgatacc ttagggaatt gcttggacct 2940ggtgacaagg gctcctgttc aatagtggtg ttggggagag agagagcagt gattatagac 3000

S cgagagagta ggagttgagg tgaggtgaag gaggtgctgg gggtgagaat gtcgcctttc 3060S cccctgggtt ttggatcact aattcaaggc tcttctggat gtttctctgg gttggggctg 3120

gagttcaatg aggtttattt ttagctggcc cacccagata cactcagcca gaatacctag 3180S atttagtacc caaactcttc ttagtctgaa atctgctgga tttctggcct aagggagagg 3240S ctcccatcct tcgttcccca gccagcctag gacttcgaat gtggagcctg aagatctaag 3300

atcctaacat gtacatttta tgtaaatatg tgcatatttg tacataaaat gatattctgt 3360S ttttaaataa acagacaaaa cttgaaaaa 3389

Table 1-11(b). Nucleotide sequence alignment of 191P4D12(b) v.1 (SEQ ID NO: 112) and 191P4D12(b) v.7 (SEQ ID NO:113)V.1 1 gGCCGTCGTTGTTGGCCACAGCGTGGGAAGCAGCTCTGGGGGAGCTCGGA s0

V.7 1 1111111111111111ggaacacttgggagtcga

00 .1 51 GCTCCCGATCACGGCTTCTTGGGGGTAGCTACGGCT(GQTGTGTAGAACG 100

S V.7 51 gctcccgatcacggcttcttgggggtagctacggctgggtgtgtagaacg 100

V. 1 2.01 GGGCCGGGGCTGGGGCTGOGTCCCCTAGTGGAGACCCAAGTGCGAGAGGC 150

V.7 101 gggccggggctggggctgggtcccctagtggagacccaagtgcgagaggc 150

V.1 151 AAGAACTCTGCAGCTTCCTGCCTTCTGGGTCAGTTCCTTATTCAAGTCTG 200

V.7 151 aagaactctgcagcttcctgccttctgggtcagttccttattcaagtctg 200

V.1 201 CAGCCGGCTCCCAGGGAGATCTCGGTGGAACTTCAGAAACGCTGGGCAGT 250

V.7 201 cagccggctcccagggagatctcggtggaacttcagaaacgctgggcagt 250

V.1 251 CTGCCTTTCAACCATGCCCCTGTCCCTGGGAGCCGAGATGTGGGGGCCTG 300

V.7 251 ctgcctttcaaccatgcccctgtccctgggagccgagatgtgggggcctg 300

V.1 301 AGGCCTGGCTGCTGCTGCTGCTACTGCTGGCATCATTTACAGGCCGGTGC 350

V.7 301 aggcctggctgctgctgctgctactgctggcatcatttacaggccggtgc 350

V.1 351 CCCGCGGGTGAGCTGGAGACCTCAGACGTGGTAACTGTGGTGCTGGGCCA 400

V.7 351 cccgcgggtgagctggagacctcagacgtggtaactgtggtgctgggcca 400

V.1 401 GGACGCAAAACTGCCCTGCTTCTACCGAGGGGACTCCGGCGAGCAAGTGG 450

V.7 401 ggacgcaaaactgccctgcttctaccgaggggactccggcgagcaagtgg 450

V. 1 451 GGCAAGTGGCATGGGCTCGGGTGGACGCGGGCGAAGGCGCCCAGGAACTA 500

V.7 451 ggcaagtggcatgggctcgggtggacgcgggcgaaggcgcccaggaacta 500

V.1 501 GCGCTACTGCACTCCAAATACGGGCTTCATGTGAGCCCGGCTTACGAGGG 550

V.7 501 gcgctactgcactccaaatacgggcttcatgtgagcccggcttacgaggg 550

V.1 551. CCGCGTGGAGCAGCCGCCGCCCCCACGCAACCCCCTGGACGGCTCAGTGC 600

V.7 551 ccgcgtggagcagccgccgcccccacgcaaccccctggacggctcagtgc 600

V.1 601 TCCTGCGCAACGCAGTGCAGGCGGATGAGGGCGAGTACGAGTGCCGGGTC 650

00 V.7 601 tcctgcgcaacgcagtgcaggcggatgagggcgagtacgagtgccgggtc 650

S V.1 651 AGCACCTTCCCCGCCGGCAGCTTCCAGGCGCGGCGCGGCTCCGAGTGCT 700

S V.7 651 agcaccttccccgccggcagcttccaggcgcggctgcggctccgagtgct 700

V.1 701 GGTGCCTCCCCTGCCCTCACTGAATCCTGGTCCAGCACTAGAAGAGGGCC 750

V.7 701 ggtgcctcccctgccctcactgaatcctggtccagcactagaagagggdc 750

V.1 751 AGGGCCTGACCCTGGCAGCCTCCTGCACAGCTGAGGGCAGCCCAGCCCCC 800

V.7 751 aggcgccgcgcctcaacgggaccgcc 800

V.1 801 AGCGTGACCTGGGACACGGAGGTCAGGCACACGTCCAGCCGTTCCTT 850

S V.7 801 agggctgaagagcaagaactcgctct 85000

S V.1 851 CAAGCACTCCCGCTCTGCTGCCGTCACCTCAGAGTTCCACTTGGTGCCTA 900

V.7 8351 cagatcgttcgctactaatcatgtct 900

V.1 901 GCCGCAGCATGAATGGGCAGCCACTGACTTGTGTGGTGTCCCATCCTGGC 950

V.7 901 gcgactatgcgccgatgggttcactg 950

V.1 951 CTGCTCCAGGACCAAGGATCACCCACATCCTCCACGTGTCCTTCCTTGC 1000

V.7 951 ctccagcaagtacactccaggctctg 2000

V.1 1001 TGAGGCCTCTGTGAGGGGCCTTGAAGACCAAATCTGTGGCACATTGGCA 1050

V.7 1001 tggctttaggctagacaacggcctgc 1050

V.1 1051 GAAGACAGTAGGCGATAGGACCCCCC 1100

V7 1051 gaagacagtaggcgataggacccccc 1100

V.1 1101 TACACTGGACACGGCTGGATGGGCCTCTGCCCGTGGGGTACGAGTGGA 1150

V.7 1101 taacgaagcgaggcttccgggtcatg 1150

V.1 1251 TGGGGACACTTTGGGCTTTCCCCCACTGACCACTGAGCACAGCGGCATCT 1200

V.7 1151 tggaattgctcccctaccggaacgac 1200

V.1 1201 ACGTCTGCCATGTCAGCAATGAGTTCTCCTCAGGGATTCTCAGGTCACT 1250

V.7 1201 acttcagcgcaggttccaggtccgtat 1250

V.2 1252 GTGGATGTTCTTGACCCCCAGGAGACTCTGGGJGCAGGTGGACCTAGT 1300

V.7 1251 gtgttctaccagaaccggacgtgctg 1300

V.1 1301 GTCAGCCTCGGTGGTGGTGGTGGTGTGATCGCCGCACTCTTGTTCTGCC 1350

V.7 1301 gtactgtggtggggtaccgattgttc 1350

V.1 1351 TTCTGGTGGTGGTGGTGGTGCTCATGTCCCGATACATCGGCGCAAGGC 1400

242

V.7 1351 ttctggtggtggtggtggtgctcatgtcccgataccatcggcgcaaggcc 1400

V.1 1401 CAGCAGATGACCCAGAAATATGAGGAGGAGCTGACCCTGACCAGGGAGAA 1450

00 V.7 1402. cagcagatgacccagaaatatgaggaggagctgaccctgaccagggagaa 1450

V.1 1451 CTCCATCCGGAGGCTGCATTCCCATCACACGGACCCCAGGAGCCAGCCGG 1500

V.7 1451 ctccatccggaggctgeattcccatcacacggaccccaggagcca 1495

S V.1 1501 AGGAGAGTGTAGGGCTGAGAGCCGAGGGCCACCCTGATAGTCTCAAGGAC 1550

C1 V.7 1495

V.1 1551 AACAGTAGCTGCTCTGTGATGAGTGAAGAGCCCGAGGGCCGCAGTTACTC 1600

V.'7 gagtgaagagcccgagggccgcagttactc 1525

V.1 1601 CACGCTGACCACGGTGAGGGAGATAGAAACACAGACTGAACTGCTGTCTC 1650

00 V.7 1526 cacgctgaccacggtgagggagatagaaacacagactgaactgctgtctc 1575

V.1 1651 CAGGCTCTGGGCGGGCCGAGGAGGAGGAAGATCAGGATGAAGGCATCAAA 1700

V.7 1576 caggctctgggcgggccgaggaggaggaagatcaggatgaaggcatcaaa 1625

V.1 1701 CAGGCCATGAACCATTTTGTTCAGGAGAATGGGACCCTACGGGCCAAQCC 1750

V.7 1626 caggccatgaaccattttgttcaggagaatgggaccctacgggccaagcc 1675

V.1 1751 CACGGGCAATGGCATCTACATCAATGGGCGGGGACACCTGGTCTGACCCA 1800

V.7 1676 cacgggcaatggcatctacatcaatgggcggggacacctggtctgaccca 1725

V.1. 1801 GGCCTGCCTCCCTTCCCTAGGCCTGGCTCCTTCTGTTGACATGGGAGATT 1850

V. 7 1726 ggcctgcctcccttccctaggcctggctccttctgttgacatgggagatt 1775

V.1 1851 TTAGCTCATCTTGGGGGCCTCCTTAAACACCCCCATTTCTTGCGGAAGAT 1900

V.7 1776 ttagctcatcttgggggcctccttaaacacccccatttcttgcggaagat 182S

V.1 1901 GCTCCCCATCCCACTGACTGCTTGACCTTTACCTCCAACCCTTCTGTTCA 1950

V.7 1826 gctccccatcccactgactgcttgacctttacctccaacccttctgttca 1875

V.1 1951 TCGGGAGGGCTCCACCAATTGAGTCTCTCCCACCATGCATGCAGGTCACT 2000

V.7 1876 tcgggayggctccaccaattgagtctctcccaccatgcatgcaggtcact 1925

V.1 2001 GTGTGTGTGCATGTGTGCCTGTGTGAGTGTTGACTGACTGTGTGTGTGTG 2050

V.7 1926 gtgtgtgtgcatgtgtgcctgtgtgagtgttgaCtgactgtgtgtgtgtg 1975

V.1 2051 GAGGGGTGACTGTCCGTGGAGGGGTGACTGTGTCCGTGGTGTGTATTATG 2100

V.7 1976 gaggggtgactgtccgtggaggggtgactgtgtccgtggtgtgtattatg 2025

V.1 2101 CTGTCATATCAGAGTCAAGTGAACTGTGGTGTATGTGCCACGGGATTTGA 2150

V.7 2026 ctgtcatatcagagtcaagtgaactgtggtgtatgtgccacgggatttga 2075

V.2 2151 OTGGTTGCGTGGOCAACACTGTCAGGGTTTGGCGTGTGTGTCATGTGGCT 2200

I II I111111111111 111111 IIIII1111 IIIII IIIII IIIII 1V.7 20*76 gtggttgCgtgggcaacactgtcagggtttggcgtgtgtgtcatgtggct 2125

00 V.1 2201 GTTTACCGCGAAGCGT= CCGCCAAC 2250

V.7 2126 gtgtgtgacctctgcctgaaaaagcaggtattttctcagaccccagagca 2175

S V.1L 2251. GTATTAATGATGCAGAGGTTGGAGGAGAGAGGTGGAGACTGTGGCTCAGA 2300

V.7 2176 gtattaatgatgcagaggttggaggagagaggtggagactgtggctcaga 2225

V.1 2301 CCCAGGTGTGCGGGCATAGCTGGAGCTGGAATCTGCCTCCGGTGTGAGGG 2350

V.7 2226 cccaggtgtgcgggcatagctggagctggaatctgcctccggtgtgaggg 2275

V.1 2351 AACCTGTCTCCTACCACTTCGGAGCCATGGGGGCAAGTGTGAAGCAGCCA 2400

V.7 2276 aacctgtctcctaccacttcggagccatgggggcaagtgtgaagcagcca 2325

CI V.1 2401 GTCCCTGGGTCAGCCAGAGGCTTGAACTGTTACAGAAGCCCTCTGCCCTC 2450

V.7 2326 gtccctgggtcagccagaggcttgaactgttacagaagccctctgccctc 2375

V.1 2451 TGGTGGCCTCTGGGCCTGCTGCATGTACATATTTCTGTATATACATG 2500

V. 7 2376 tgtgccggcgtcttaaattttattct 2425

V.1 2501 CGCGACTTGAGAATGTCATATTATTT 2550

V. 7 2426 cgcgacttgagaatgtcatattattt 2475

V. 1 2551 TCTTTTTTTTTTCTTGCCCTTTCCATTAGTTGTATTTTTTATTTATTTTT 2600

V.7 2476 tcttttttgcttcttgtttttatatt 2525

V.1 2601 ATTTTTATTTTTTTTTAGAGATGGAGTCTCACTATGTTGCTCAGGCTGGC 2650

V.7 2526 atttttatttttttttagagatggagtctcactatgttgctcaggctggc 2575

V.1 2651 CTTGAACTCCTGGGCTCAAGCATCCTCCTGCCTCAGCCTCCCTAGTAGC 2700

V.7 2576 cttgaactcctgggctcaagcaatcctcctgcctcagcctccctagtagc 2625

V.1 2702. TGGGACTTTAAGTGTACACCACTGTGCCTGCTrGTCCTTTACGAAGA 2750

V. 7 2626 tggsactttaagtgtacaccactgtgcctgctttgaatcctttacgaaga 2675

V.1 2751 GAAAAAATTAAAGAAAGCCTTTAGATTTATCCAATGTTTACTACTG 2800

V. 7 2676 gaaaaataaaacttaatacatttcat 2725

V.1 2801 GGATTGCTTAAAGTGAGGCCCCTCCACACCAGGGGGTTAATTCCTGTGA 2850

V.7 2726 ggattgcttaaagtgaggcccctzccaacaccagggggttaattcctgtga 2775

V.1 2851 TTGTGAAAGGGGCTACTTCCGGCATC~TAGCAGGCAGCCCCTTGGG 2900

V.7 2776 tttaaggtctcagattctcgcgcctg 2825

V.1 2901 AGGGCACCTGAGAGCTGGTAGAGTCTGAAATTAGGGATGTGAGCCTCGTG 2950

V.7 2826 aggacgggtgaattgatagagggcct 2875

V.1 2951. GTTACTGAGTAAGGTAAAATTGCATCCACCATTGTTTGTGATACCTTAGG 3000

V.7 2876 gttactgagtaaggtaaaattgcatccaccattgtttgtgataccttagg 2925

00) V.1 3001 GAATTGCTTGGACCTGGTGACAAGGGCTCCTGTTCAATAGTGGTGTTGGG 3050

V.7 2926 gaattgcttggacctggtgacaagggctcctgttcaatagtggtgttggg 2975

V.1 3051 GAGAGAGAGAGCAGTGATTATAGACCGAGAGAGTAGGAGTTGAGGTGAGG 3100

V.7 2976 gagagagagagcagtgattatagaccgagagagtaggagttgaggtgagg 3025

V.1 3101 TGAAGGAGGTGCTGGGGGTGAGAATGTCGCCTTTCCCCCTGGGTTTTGGA 3150

V.7 3026 tgaaggaggtgctgggggtgagaatgtcgcctttccccctgggttttgga 3075

V.1 3151. TCACTAATTCAAGGCTCTTCTGGATGTTTCTCTGGGTTGGGGCTGGAGTT 3200

C] V.7 3076 tcactaattcaaggctcttctggatgtttctctgggttggggctggagtt 3125

V. 1 3201 CAATGAGGTTTATTTTTAGCTGGCCCACCCAGATACACTCAGCCAGAAA 325000V.7 3126 caatgaggtttatttttagctggcccacccagatacactcagccagaata 3175

V.1 3251 CCTAGATTTAGTACCCAAACTCTTCTTAGTCTGAAATCTGCTGGATTTCT 3300

V.7 3176 cctagatttagtacccaaactcttcttagtctgaaatctgctggatttct 3225

V.1 3301 GGCCTAAGGGAGAGGCTCCCATCCTTCGTTCCCCAGCCAGCCTAGGACTT 3350

V.7 3226 ggcctaagggagaggctcccatccttcgttccccagccagcctaggactt 3275

V.1 3351 CGAATGTGGAGCCTGAAGATCTAAGATCCTAACATGTACATTTTATGTAA 3400

V.7 3276 cgaatgtggagcctgaagatctaagatcctaacatgtacattttatgtaa 3325

V.1 3401 ATATGTGCATATTTGTACATAAAATGATATTCTGTTTTTAAATAAACAGA 3450

V.7 3326 atatgtgcatatttgtacataaaatgatattctgtttttaaataaacaga 3375

V.1 3451 CAAAACTTGaaaaa 3464

V.7 3376 caaaacttgaaaaa 3389

Table LIV(b). Peptide sequences of protein coded by 191P4DI2(b) v.7 (SEQ ID NO: 114)MPIJSLGAEMW GPEAWLLLLL LLASFTGRCP AGELETSDVV TVVLGQDAKL PCFYRGDSGE QVGQVAWARV DAGEGAQELA LLHSKYGLHV SPAYEGRVEQ PPPPIUNPLDG SVLLRNAVQA 120DEGEYECRVS TFPAGSFQAR LRLjRVLVPPL PSLNPGPALE EGQGLTLAAS CTAEGSPAPS 180VTWflTEVKGT TSSRSFKHSR SAAVTSEFHL VPSRSMNGQP LTCVVSHPGL LQDQRITHIL 240IIVSFLAEASV RGLEDQNLWH IGREGAMLKC LSEGQPPPSY NWTRLDGPLP SGVRVDGDTL 300GFPPLTTEHS GIYVCHVSNE FSSRDSQVTV DVLDPQEDSG KQVD)LVSASV VVVGVIAALL 360FCLLVVVVVL MSRYHRRKAQ QMTQKYEEEL TLTRENSIRR LHSRHTDPRS QSEEPEGRSY 420STLTTVREIE TQTELLSPGS GRAEEEEDQD EGIKQAmNHp VQEUGTLRAK PTGNGIYING 480RGHLV 485

Table LV(b). Amino acid sequence alignment of 191 P4DI2(b) vM (SEQ ID NO: 115) and 191P4D12(b) v.7 (SEQ ID NO:116).V.1 1 MPLSLGAEMWGPEAWLLLLLLLASPTGRCPAGELETSDVVTVVLGQDAXKL

V.7 1 MPLSLGAEMWGPEAWLLLLLLLASFTGRCPAGELETSDVVTVVLGQDAKcL

V.1 51 PCFYRGDSGEQVGQVAWARVDAGEGAQELALL1.SKYCLHVSPAYEGRVEQ 100

00

V.7 51 PCFYRGDSGEQVGQVWAVDAGEGAQELLHMS1GCLHSPAYEGRVEQ

V.1 101 PPPNLGVLNVAEEECVTPGFALLVVP

V.7 101 PPPPRPLDGSVLLRAVQADEGEYECRVSTPAGSFQARJLRLRVLVPPL

V.1 151 PSLNPGPALEEGQGLTLAASCTAEGSPAPSVTWDTEVKGTTSRSFHSR

V.7 151 PSLNPGPALEEGQGLTLAASCTAEGSPAPSVTWDTEVJXGTTSSRSFKHSR

V.1 201 SAAVTSEFHLVPSRSMNGQPLTCVVSHPGLLQDQRITHILVSFMASV

V.7 201 SAAVTSEFHLVPSRSMNGQPLTCVVSHPGLLQDQRITHILHVSFLAEASV

V.1 251 RGIJEDQNLWHIGREGALKCLSEGQPPPSYWTRLDGPLPSGVRVDGDTL

V.7 251 RGLEDQNLWHIGREGAMLKCLSEGQPPPSWTRLDGPLPSGVVGDTL

V.1 301 GFPPLTTEHSGIYVCHVSNEFSSRDSQVVDVLDPEDSGKQIDLVSASV

V.7 301 GFPPLTTEHSGIYVCHVSNEFSSPJJSQVTVDVIDPQEDSGKQVJDLVSASV

V.1 351 VVGIALCLVVLSYRRAQTKBETTESR

V.7 351 VVVGVIAALLFCLLVVVVVLMSRYHRRKAQQMTQKYEEELTLTRENSIRR

V.1 401 LHSHHTDPRSQPEESVGLRAEGI{PDSLKDNSSCSVMSEEPEGRSYSTLTT

V.7 401 SEEPEGRSYSTLTT

V.1 451 VRITTLSGGAEEQEIQMHVEGLA TW

V.7 426 VRITTLSGGAEEQEGKANFQNTRKTN

100

150

150

200

200

250

250

300

300

350

350

400

400

450

425

Soo

475

V.1 501 IYINGRGHLV

IllIhIiIV.7 476 IYINGRGHLV

Table LII(c). Nucleotide sequence of transcript variant 191 P4DI2(b) v.8 (SEQ ID NO:ggc cgtcgttacggcttctttCCCCtagtgcagttccttagctgggcagtaggcctggctagc tggagactctaccgagggcgaaggcgccttacgagggtcctgcgcaac cgccggcagtgaatcctggctgagggcaggccgttccttgccgcagcataccaaaggatttgaagaccaaagggcagcctacgagtggaacgtctgccattgacccccatgggtgtgat

9ttggccacagggggtagctgagacccaagttcaagtctgctgcctttcagctgctgctgCtcagacgtgggactccggcccaggaactaccgcgtggagcgcagtgcagcttccaggcgtccagcactaCccagccccccaagcactccgaatgggcagcacccacatcaaatctgtggccCtcCctcatggggacacfrtgtcagcaatggaagactctCgCC9Cactc

gcgtgggaagacggctgggttgcgagaggcc agc cggct caccatgccccc tactgctgggtaactgtgggagcaagtgggcgctactgcCagccgccgcgcggatgaggcggctgcggcgaagagggccagcgtgacctcgctctgctgccactgacttCtCCaCgtgtcacattggcatacaactggattgggctttcgagttctcctgggaagcaggttgttctgcc

cagctctggggtgtagaacgaagaactctgccagggagattgtccctgggcatcatttactgctgggccaggcaagtggcactccaaataccccacgcaagcgagtacgatccgagtgctagggcctgacgggacacggaccgtcacctcgtgtggtgtcccttccttgcgagaaggagccacggctggaccccactgacCaagggattctggacctagtttctggtggt

ggagctcggagggCCggggCcagcttcctgCtcggtggaaagccgagatgaggccggtgcggacgcaaaaatgggctcggcgggcttcatCCCcctggacgtgccgggtcggtSCCtccccctggcagccggtcaaaggcagagttccacccatcctggctgaggcctcttatgctcaagtgggcctctgcactgagcactcaggtcactgt Cagcctcgggtggtggtg

117)gCtCCCgatctggggctgggcct tctgggtcttcagaaactgggggcctgCccgcgggtgctgccctgctgtggacgcgggtgagcccggggctcagtgcagcaccttccCtgccctCaCtcctgcacagacaacgtccattggtgcctactgctccagggtgaggggcctgcctgagtgCccagtggggagcggcatctgtggatgttcgtggtggtggctcatgtccc

120180240300360420480540600660720780840900960

1020108011401200126013201380

00

00

gataccatcgccagggagaaaggagagtgtgctctgtgatagatagaaacatcaggatgagggccaagccggcctgcctcttgggggCCtcttgacctttcaccatgcattgtgtgtgtgctgtcatatcgggcaacactaaagcaggtaggtggagactggtgtgagggtccctgggttgggcctgctaatactgctctgtattttt~ttcaggctggctgggactttaattaaagaaacctccaacaccatgcaggcagagCCtCgtggtgattatagatgtcgccttgggttggggccagaatacctctaagggagatgaagatctaatgatattct

gcgcaaggccctccatccggagggctgagagagtgaagagacagactgaaaggcatcaaacacgggcaatcct tcc ctagccttaaacacacctccaaccgcaggtcactgaggggtgacagagtcaagtgtcagggtttttttctcagagtggctcagaaacctgtctcc agccagagggcatgtacatcgaatcacttatttatttttcttgaactccagtgtacaccgcctttagatcagggggttagccccttgggctggtgacaaaccgagagagtccccctgggtggagttcaaagatttagtaggctcccatcagatcctaacgtttttaaat

cagcagatgaaggctgcattgccgagggcccccgagggccctgctgtctccaggccatgaggcatctacagcctggctccccccatttctcttctgttcagtgtgtgtgctgtccgtggagaactgtggtggcgtgtgtgccccagagcacccaggtgtgctaccacttccttgaactgtattttctgtattaattttttatttttattttgggc tcaagactgtgcctgttatccaatgattcctgtgaagggcacctggggctcctgttaggagt tgattttggatcatgaggtttatcccaaactctCttcgttCCCatgtacattt

cccagaaatacccatcacacacc ctgataggcagt tactccaggctctggaccattttgttcaatggggttctgttgactgcggaagattcgggagggcatgtgtgcctggggtgactggtatgtgccatcatgtggctqtattaatgacgggcatagcggagccatggtacagaagccaatatacatgtcttttttttttttttagagcaatcctcctctttgaatcctttactactgttgtgaaaggagagctggtatcaatagtggggtgaggtgactaattcaagttttagctggtcttagtctgcagccagccttatgtaaata

tgaggaggaggyac cc cagytctcaaggaccacgctgaccgcgggccgagtcaggagaatgggacacctgatgggagattgctccccatctccaccaattgtgtgagtgttgtccgtggtcgggatttgagtgtgtgacctgcagaggtttggagctggagggcaagtgtCtCtgCCCtCcgccgggagcttcttgccctatggagtctcgcctcagccttt tacgaagaggattgcttaggctacttccgagtctgaaatgttggggagaggaggtgctgctcttctggcccacccagaaaatctgctgaggacttcgatgtgcatatt

ctgaccctgaagccagccggaacagtagctacggtgaggggaggaggaagg ggaccc tacgtctgacccattagctcatcccactgactggagtCtCtcctgactgactggtgtattatggtggttgcgttctgcctgaaggaggagagaatctgcctccgaagcagccatgg tggCc t cttcttgcaggttccattagtactatgttgcccctagtagcgaaaaaaaaaaagtgaggccaaggcatcttttagggatgtagagagagcagggggtgagaatgtttctcttacactcagcgatttctggcatgtggagcctgtacataaa

144015001.5601620168017401800186019201980204021002160222022802340240024602520258026402700276028202880294030003060312031803240330033603401aaacagacaa aacttgaaaa a

Table 1.1II(c). Nucleotlde sequence alignment of 191P4D12(b) v.1 (SEQ ID NO: 118) and 191P4D12Q,) v.8 (SEQ ID NO:119)V.1 1 gGCCGTCGTTGTTGGCCACAGCGTGGGAAGCAGCTCTGGGGGAGCTCGGA

V.8 1 ggccgtcgttgttggccacagcgtgggaagcagctctgggggagctcgga s0

V.1 51 GCTCCCGATCACGGCTTCTTGGGGGTAGCTACGGCTGGGTGTGTAGAACG 100

V.8 51 gctcccgatcacggcttcttgggggtagctacggctgggtgtgtagaacg 100

V.1 101 GGGCCGGGGCTGGGGCTGGGTCCCCTAGTGGAGACCCAAGTGCGAGAGGC 150

V.8 101- gggccggggctggggctgggtcccctagtggagacccaagtgcgagaggc 150

V.1 151 AAGAACTCTGCAGCTTCCTG3CCTTCTGGGTCAGTTCCTTATTCAAGTCTG 200

V.8 151 aagaactctgcagcttcctgccttctgggtcagttccttattcaagtctg 200

V.1 201 CAGCCGGCTCCCAGGAGATCTCGGTGGAACTTCAGAALACGCTGGGCAGT 250

V.8 201 cagccggctcccagggagatctcggtggaacttcagaaacgctgggcagt 250

V.1 251 CTGCCTTTCAACCATGCCCCTGTCCCTGGGAGCCGAGATGTGGGGGCCTG 300

V.8 251 ctgcctttcaaccatgcccctgtccctgggagccgagatgtgggggcctg 300

V.1 301 AGGCCTGGCTGCTGCTGCTGCTACTGCTGGCATCATTTACAGGCC-GGTGC 350

V. 8 301 aggcctggctgctg'ctgctgctactgctggcatcatttacaggccggtgc 350

00 V.1 353. CCCGCGGGTGAGCTGGAGACCTCAGACGTGGTAACTGTGGTGCTGWCCA 400

V.8 351 cccgcgggtgagctggagacctcagacgtggtaactgtggtgctgggcca 400

V.1 401 GGACGCAAAACTGCCCTGCTTCTACCGAGGGGACTCCGGCGAGCAAGTGG 450

V.8 401 ggacgcaaaactgccctgcttctaccgaggggactccggcgagcaagtgg 450

451 GGCAAGTGGCATGGGCTOGGGTGGACGCGGGCGAGGCGCCCAGGAACTA 500

V.8 451 ggaggctgccgtgcggggaggcagat 500

V.3. 501 GCGCTACTGCACTCCAAATACGGGCTTCATGTGAGCCCGGCTTACGAGGG 550

501 gcgctactgcactccaaatacgggcttcatgtgagcccggcttacgaggg 550

C1 V.1 551 CCGCGTGGAGCAGCCGCCGCCCCCACGCAACCCCCTGGACGGCTCAGTGC 600

V.8 551 ccgcgtggagcagccgccgcccccacgcaaccccctggacggctcagtgc 600

V.1 601 TCCTGCGCAACGCAGTGCAGGCGGATGAGGGCGAGTACGAGTGCCGGGTC 650

V. 8 601 tcctgcgcaacgcagtgcaggcggatgagggcgagtacgagtgcc9gggtc 650

V. 1 651 AGCACCTTCCCCGCCGGCAGCTTCCAGCGCGGCTGCGGCTCCGAGTGCT 700

V.8 651 agcaccttccccgccggcagcttccaggcgcggctgcggctccgagtgct 700

V.1 701 GGGCCCTCCCCGATCGCACCAAGWC 750

V. 8 701 gggccctccccgaccgtcgatgaagc 750

V.*1 751 AGGGCCTGACCCTGGCAGCCTCCTGCACAGCTGAGGGCAGCCCA.GCCCCC 800

V. 8 751 aggcgccgcgcctcaacgggaccgcc 800

V.1 801 AGCGTGACCTGGGACACGGAGGTAGOCACACGTCCAGCCGTTCCTT 850

V. 8 801 agggctgaagagcaagaactcgctct 850

V.1 851 CAAGCACTCCCGCTCTGCTGCCGTCACCTCAGAGTTCCACTTGGTGCCTA 900

V-8 851 111111111 11111111111111111111111111111111111111 V.1 901 GCCGCAGCATGA.TGGGCGCCACTGACTTGTGTGGTGTCCCTCCTGG3C 950

V. 8 901 gccgcagcatgaatgggcagccactgacttgtgtggtgt~ccatcctggc 950

V.1 951 CTGCTCCAGGACCAAAGGATCACCCACTCCTCCACG3TGTCCTTCCTTGC 1000

V.8 951 ctccagcaagtacactccaggctctg 1000

V.1 1001 TGGCTTTAGGCTAGCAATTTOCCTGC 1050

V.8 1001 tggctttaggctagacaacggcctgc 1050

V.1 1051 GAGAAGGAGCTATGCTCAGTGCCTGAGTGAGG GCCCCCTCCCTC!A 1100

V. 8 1051 gaagacagtaggcgataggacccccc 1100

V.1 1101 TACAACTGGACACGGCTGGATGGGCCTCTGCCCAGTGGGGTACGAGTOGA 1150

V.8 1101 tacaactggacacggctggatgggcctctgcccagtggggtacgagtgga 1150

00V.1 1151 TGGGGACACTTTGGGCTTTCCCCCACTGACCACTGAGCACAG.CGGCATCT 1200

C] V.8 1151 tggggacactttgggctttcccccactgaccactgagcacagcggcatct 1200

V.1 1201 ACGTCTGCCATGTCAGCAATGAGTTCTCCTCAAGGGATTCTCAGGTCACT 1250

SV. 8 1201 acgtctgccatgtcagCaatgagttctcctcaagggattctCaggtcact 1250

V.1 1251 GTGGATGTTCTTGACCCCCAGGAAGACTCTGGGAAGCAGGTGGACCTAGT 1300

V. 8 1251 gtggatgttcttgacccccaggaagactctgggaagcaggtggacctagt 1300

V.1 1301 GTCAGCCTCGGTGGTGGTGGTGGGTGTGATCGCCGCACTCTIGTTCTGCC 1350

V.8 1301 gtcagcctcggtggtggtggtgggtgtgatcgccgcactcttgttctgcc 1350

00 V.1 1351 VTCTGGTGGTGGTGGTGGTGCTCATGTCCCGATACCATCGGCGCAAGGCC 1400

0 V.8 1351 ttctggtggtggtggtggtgctcatgtcccgataccatcggcgcaaggcc 1400

V.1 1401 CAGCAGATGACCCAGAAATATGAGGAGGAGCTGACCCTGACCAGGGAGAA 1450

V.8 1401 cagcagatgacccagaaatatgaggaggagctgacctgaccagggagaa 1450

V.1 1451 CTCCATCCGGAGGCTGCATTCCCATCACACGGACCCCAGGAGCCAGCCGG 1500

V.8 1451 ctccatccggaggctgcattcccatcacacggaccccaggagccagccgg 1500

V.1 1501 AGGAGAGTGTAGGGCTGAGAGCCGAGGGOCACCCTGATAGTCTCAAGGAC 1550

V.8 1501 aggagagtgtagggctgagagccgagggccaccctgatagtctcaaggac 1550

V.1 1551 AACAGTAGCTGCTCTGTGATGATGAAGA~.GCCCGAGGGCCGCAGTTACTC 1600

V.8 1551 aacagtagctgctctgtgatgatgaagagcccgagggccgcagttactc 1600

V.1 1601 CACGCTGACCACGGTGAGGGAGATAGAAACACAGACTGAACTGCTGTCTC 1650

V.8 1601 cacgctgaccacggtgagggagatagaaacacagactgaactgctgtctc 1650

V.1 1651 CAGGCTCTGGGCGGGCCGAGGAGGAGGAAGATCAGGATGAAGGCATCAAA 1700

V. 8 1651 caggctctgggcgggccgaggaggaggaagatcaggatgaaggcatcaaa 1700

V.1 1701 CAGGCCATGAACCATTTTGTTCAGGAGAATGGGACCCTACGGGCCAAGCC 1750

V.8 1701 caggccatgaaccattttgttcaggagaatgggaccctacgggccaagcc 1750

V.1 1751 CACGGGCAATGGCATCTACATCAATGGGCGGGGACAOCTGGTCTGACCCA 1800

V.8 1751 cacgggcaatggcatctacatcaatgggcggggacacctggtctgaccca 1800

V.1 1801 GGCCTGCCTCCCTTCCCTAGGCCTGGCTCCTTCTGTTGACATGGOAGATT 1850

V.8 1801 ggcctgcctcccttccctaggcctggctccttctgttgacatgggagatt 1850

V.1 1851 TTAGCTCATCTTGGGGGCCTCCTTAAACACCCCCATTTCTTGCGGAAGAT 1900

V.8 1851 ttagctcatcttgggggcctccttaaacacccccatttcttgcggaagat 1900

249

V. .1 1901 GCTCCCCATCCCACTGACTGCTTGACCTTTACCTCCAACCCTTCTGTTCA 1950

00V.8 1901 gctccccatcccactgactgcttgacctttacctccaacccttctgttca 1950

V.1 1951 TCGGGAGGGCTCCACCAATTGAGTCTCTCCCACCATGCATGCAGGTCACT 2000

V.8 1951 tcgggagggctccaccaattgagtctctcccaccatgcatgcaggtcact 2000

SV.1. 2001 GTGTGTGTGCATGTGTGCCTGTGTGAGTGTTGACTGACTGTGTGTGTGTG 2050

VA 001gtgtgtgtgcatgtgtgcctgtgtgagtgttgactgactgtgtgtgtgtg 2050

V.1 2051 GAGGGGTGACTGTCCGTGGAGGGGTGACTGTGTCCGTGGTGTGTATTATG 2100

r-V.8 2051 gaggggtgactgtccgtggaggggtgactgtgtccgtggtgtgtattatg 2100

(iV.1. 2102. CTGTCATATCAGAGTCAAGTOAACTGTGGTGTATGTGCCACGGGATTTGA 21.50

(iV.8 2101 ctgtcatatcagagtcaagtgaactgtggtgtatgtgccacgggatttga 215000V. 1 2151 GTGGTTGCGTGGGCAACACTOTCAGGGTTTGGCGTGTGTGTCATGTGGCT 2200

V. 8 2151 gtggttgcgtgggcaacact~tcagggtttggcgtgtgtgtcatgtggct 2200

V. 1 2201 GTGTGTGACCTCTGCCTGAAAAAGCAGGTATTTTCTCAGACCCCAGAGCA 2250

V. 8 2201 gtgtgtgacctctgcctgaaaaagcaggtattttctcagaccccagagca 2250

V. 1 2251 GTATTAATGATGCAGAGGTTc zGAGGAGAGAGGTGGAGACTGTGGCTCAGA 2300

V. 8 2251 gtattaatgatgcagaggtt(-gaggagagaggtggagacegtggctcaga 2300

V. 1 2301 CCCAkGGTGTGCGGGCATAGCTGGAGCTGJ JATCTGCCTCCGGTGTG;AGGG 2350

V. 8 2301 cccaggtgtgcgggcatagctggagctggaatctgcctccggtgtgaggg9 2350

V.1 2351 AACCTGTCTCCTACCACTTCGGAGCCATOGGGGCAAGTGTGAAGCAGCCA 2400

V.8 2351 aacctgtctcctaccacttcggagccatgggggcaagtgtgaagcagcca 2400

V.1 2401 GTCCCTGGGTCAGCCAGAGGCTTGACTQTTAAGAGCCCTCTGCCCTC 2450

V.8 2401 gtccctgggtcagccagaggcttgaact~ttacagaagccctctgccctc 2450

V.1 2451 TGGTGGCCTCTGGGCCTGCTGCATGTACTATTTCTGTATATACATG 2500

V.8 2451 tggtggcctctgggcctgctgcatgtacatattttctgtaaatatacatg 2500

V.1 2501 CGCCGGGAGCTTCTTGCAGGAATACTGCTCCGATCACTTTTAATTTTTT 2550

V.8 2501 cgccgggagcttcttgcaggaatactgctccgaatcacttttaattttt 2550

V.1 2551 TCTTTTTTTTTTCTTGCCCTTTCCATTAGTTGTATTTTTTATTTATTTTT 2600

V. 8 2551 tcttttttgcttcttgtttttatatt 2600

V.1 2601 ATTTTTATTTTTTTTTAGAGATGGAGTCTCACTATGTTGCTCAGGCTGGC 2650

V. 8 2601 atttttatttttttttagagatggagtctcactatgttgctcaggctggc 2650

V.1 2651 CTTGAACTCCTGGGCTCAAGCAATCCTCCTGCCTCAGCCTCCCTAGTAGC 2700

250

V.8 2651 cttgaactcctgggctcaagcaatcctcctgcctcagcctccctagtagc 2700

V.1 2701 TGGGACTTTAAGTGTACACCACTGTGCCTGCTTTGAATCCTTTACGAAGA 2750

00111 ~lIIIfI ffl 111SV.8 2701 tgggactttaagtgtacaccactgtgcctgctttgaatcctttacgaaga 2750

ClV.1 2751 GAAAAbAAATTAAAGAAAGCCTTTAATTTATCCAATGTTTACTACTG 2800

Ct V.8 2751 Saaaaaaaaaattaaagaaagcctttagatttatccaatgtttactactg 2800

SV.1 2 801 GGATTGCTTAAAGTGAGGCCCCTCCAACACCAGGGGGTTAATTCCTGTGA 2850

CIV.8 2801 ygattgcttaaagtgaggcccctccaacaccagggggttaattcctgtga 2850

V.1 2851 TTGTGAAAGGGGCTACTTCCAAGGCATCTTCATGCAGGCAGCCCCTTGGG 2900

V.8 2851 ttgtgaaaggggctacttccaaggcatcttcatgcaggcagccccttggg 2900

V.1 2901 AGGGCACCTGAGAGCTGGTAGAGTCTGAAATTAGGGATGTGAGCCTCG;TG 2950

00 V.8 2901 agggcacctgagagctggtagagtctgaaattagggatgtgagcctcgtg 2950

SV.1 2951 GTTACTGAGTAAGGTAAAATTGCATCCACCATTGTTTGTGATACCTTAGG 3000

V.8 2951 2950

V.1 3001 GAATTGCTTGGACCTGGTGACAAGGGCTCCTGTTCAATAGTGGTGTTGGG 3050

V.8 ctggtgacaagggctcctgttcaatagtggtgttggg 2987

V.1 3051 GAGAGAGAGAGCAGTGATTATAGACCGAGAGAGTAGGAGTTGAGGTGAGG 3100

V.8 2988 gagagagagagcagtgattatagaccgagagagtaggagttgaggtgagg 3037

V.1 3101 TGAAGGAGGTGCTGGGGGTGAGAAJTGTCGCCTTTCCCCCTGGGTTTTGGA 3150

V.8 3038 tgaaggaggtgctgggggtgagaatgtcgcctttcccctgggttttgga 3087

V.1 3151 TCACTAATTCAAGGCTCTTCTGGATGTTTCTCTGGGTTGGGGCTGGAGTT 3200

V.8 3088 tcactaattcaaggctcttctggatgtttctctgggttggggctggagtt 3137

V.1 3201 CAATGAGGTTTATTTTTAGCTGGCCCPLCCCAGATACACTCAGCCAGAATA 3250

V.8 3138 caatgaggtttatttttagctggcccacccagatacactcagccagaata 3187

V.1 3251 CCTAGATTTAGTACCCAAACTCTTCTTAGTCTGAAATCTGCTGGATTTCT 3300

V.8 3188 cctagatttagtacccaaactcttcttagtctgaaatctgctggatttct 3237

V.1 3301 GGCCTAAGGGAGAGGCTCCCATCCTTCGTTCCCCAGCCAGCCTAGGACTT 3350

V.8 3238 ggcctaagggagaggctcccatccttcgttccccagccagcctaggactt 3287

V.1 3351 CGAATGTOGAGCCTGAAGATCTAAGATCCTAACATGTACATTTTATGT4A 3400

V.8 3288 cgaatgtggagcctgaagatctaagatcctaacatgtacattttatgtaa 3337

V.1 3401 ATATGTGCATATTTGTACATAAAATGATATTCTGTTTTTAAATAAACAGA 3450

V.8 3338 atatgtgcatatttgtacataaaatgatattctgtttttaaataaacaga 3387

V.1 3451 CAAAACTTGaaaaa 3464

V.8 3388 caaaacttgaaaaa 3401

00Table LIV(c). Peptide sequences of protein coded by 1919P01 2(b) v.8 (SEQ ID NO: 120)MPLSLGAEMW GPEAWLLLLL LLASFTGRCP AGELETSDVV TVVLGQDAKL PCFYRGDSGE QVGQVAWARV DAGEGAQELA LLHSKYGLHV SPAYEGRVEQ PPPPRNPLD)G SVLjLRNAVQA 120DEGEYECRVS TFPAGSFQAR LRLRVLVPPIL PSLNJPGPALE EGQGILTLAAS CTAEGSPAPS 180VTWDTEVKGT TSSRSFKHSR SAAVTSEPHL VPSRSMNGQP LTCVVSHPGL LQDQRITHIL 240

SHVSFLAEASV RGLEDQNLWH IGREGAMLKC LSEGQPPPSY NWTRLDGPLP SGVRVDGDTL 300GFPPLTTEHS GIYVCHVSNE FSSRDSQVTV DVLDPQEDSG KQVDLVSASV VVVGVIAALL 360

ciFCLLVVVVVL MSRYHRRKAQ QMTQKYEEEL TLTRENSIRR LHSHHTDPRS QPEESVGLRA 420EGHPDSLKDbI SSCSVMSEEP EGRSYSTLTT VREIETQTEL LSPGSGRAEE EEDQDEGIKQ 480ANNHFVQENG TLRAKPTGNG IYINGRGHLV 510

Table LV(c). Amino acid sequence alignment of 191 P401(b) v.1 (SEQ ID NO: 121) and 191 P4D12(b) v.8 (SEQ ID NO:c]122)CiV-1 1 MPLSLGAEMWGPEAWLLLLLLLASFTGRCPAGELETSDVVTVVLGQDAKcL

N V.8 1 MPLSLGAEMWGPEAWLLLLLLLASFTGRCPAGELETSDVVTVVLGQDAKL so00

V. 1 51 PCFYRGDSGEQVGQVAWARVDAGEGAQELALLHSI(YGLHVSPAYEGRVEQ 100

V.8 51 PCFYRGDSGEQVGQVAWARVDAGEGAQELALLHSKYGLHVSPAYEGRVEQ 100

V. 1 101 PPPPRNPLDGSVLLRNAVQADEGEYECRVSTFPAGSFQARLRLRVTJVPPL 150

V. 8 101 PPPPRNPLDGSVLLRNAVQAflEGEYECRVSTFPAGSFQARLRLRVLVPPL 150

V.1 151 PSLNPGPAIIEEGQGLTLAASCTAEGSPAPSVTWDTEVKGTTSSRSFKHSR 200

V.8 151 PSLUIPGPALEEGQGLTLAASCTAEGSPAPSVTWDTEVKGTTSSRSFKHSR 200

V.1 201 SAAVTSEPHLVPSRSMNGQPLTCVVSHPGIJLQDQRITHILHVSFLAEASV 250

V.8 201 SAAVTSEPHLiVPSRSMNGQPLTCVVSHPGLLQDQRITHILHVSFLAEASV 250

V.1 251 RGLEDQNLWHIGREGAMLKCLSEGQPPPSYNWTR jDGPLPSGVRVDGDTL 300

V.8 251 RGLEDQNLWf{IGREGAM~LKCLSEGQPPPSYNWTRLDGPLPSGVRVDGDTL 300

V.1 301 GFPPLTTEHSGIYVCHVSNEFSSRDSQVTVDVLDPQEDSGKQVDLVSASV 350

V.8 301 GFPPLTTEHSGIYVCHVSbNEFSSRlSQVTVDVLDPQEDSGKQVDLVSASV 350

1 351 VVVGVIAALLFCLLVVVVVLMSRYHRRKAQQMvTQKYEEELTLTRENSIRR 400

V.8 351 VVVGVIAALLFCLLVVVVVLMSRYHRRKAQQMTQKYEEELTLTRENSIRR 400

V.1 401 LHSHHTDPRSQPEESVGLRAEGHPDSLKDNSSCSVMSEEPEGRSYSTLTT 450

V. 8 401 LHSHHTDPRSQPEESVGLRABGHPDSLKDNSSCSVMSEEPEGRSYSTLTT 450

V. 1 451. VREIETQTELLSPGSGRABEEEDQDEGIKQAMNHFVQENGTLRAKPTGNG 500

V.8 451 VREIETQTELLSPGSGRAEEEEDQDEGIKQAMNHFVQEGTLRACPTGNG 500

V.1 501 IYINGRGHLV 510

V.8 501 IYINGRGHLV 510

Table 1-1I(d). Nucleotide sequence of transcript variant 191P4D12(b) v.9 (SEQ ID NO: 123)

252

00

00

gtCtgaCCCattagctcatcccactgactggagtctctcctgactgactggtgtattatggtggttgcgttctgcctgaaggaggagagaatctgcctccgaagcagccatggtggcctcttcttgcaggttccattagtactatgttgcccctagtagcgaaaaaaaaaaagtgaggccaaggqcatcttttagggatgtataccttagggagagagagagCtgggggtgtggatgtttcag ata cac tcctggatttctcgaatgtggaatttgtacat

ggcctgCCtCttgggggCCtcttgacctttcaccatgcattgtgtgtgtgctgtcatatcgggcaacactaaagcaggtaggtggagactggtgtgagggtccctgggttgggCCtgCtaatactgctctgtatttttttcaggctggctgggactttaattaaagaaacctccaacaccatgcaggca,gagcctcgtggaattgcttggcagtgattaagaatgtcgctCtgggttggagccagaataggcctaaggggcctgaagataaaatgatat

cct tccc tagccttaaacacacctccaacc.gcaggtcactgaggggtgacagagtcaagtgtcagggtttttttctcagagtggctcagaaacctgtctccagccagagggcatgtacatcgaatcacttatttatttttcttgaactccagtgtacaccgcctttagatcagggggttagCCCCttggggttact~agtgacctggtgatagaccyagaCtttcCCCCtggctggagttcctagatttaagaggctcccctaagatccttctgttttta

gCCtggCtccccccatttctcttctgttcagtgtgtgtgctgtccgtggagaactgtggtggCgtgtgtgccccagagcaCCaggtgtgctaccacttccttgaactgtatt~t t ctgt attaattttttatttttattttgggctcaagactgtgcctgttatccaatgattcctgtgaagggcacctgaaggtaaaatcaagggct ccgagtaggagtgggttttggacaatgaggtgtacccaaacatccttcgttaacatgtacaaataaacaga

ttCtgttgaCtgcggaagattcgggagggcatgtgtgc~tggggtgactggtatgtgccatcatgtggctgtattaatgacgggcatagcggagccatggtacagaagccaatatacatgtctttttttttttttt agagcaatcctcctctttgaatcctttactactgt tgtgaaaggagagctggtatgcatccacctgttcaata9tgaggtgaggtcactaattctatttttagctcttcttagtccccagccagttttatgtaacaaaacttg

atgggagattgctccccatctccaccaattgtgtgagtgttgtccgtggtcgggatttgagtgtgtgacctgcagaggtttggagctggagggcaagtgtCtCtgCCCtCcgccgggagcttCttgccctatggagtctcgcctcagccttttacgaagaggattgcttaggctacttccgagtctgaaaattgtttgtgtggtgttgggtgaaggaggtaaggctcttCtggcccaccctgaaatctgcctaggacttatatgtgcat

120180240300360420480540600660720780840900960

102010801140120012601320138014401500156016201669

Table 1-11(d). Nucleotide sequence alignment of 19P4D1(b) v.1 (SEQ ID NO: 124) and 191P4D1(b) v.9 (SEQ ID NO:125)v.1 1791 GTCTGACCCAGGCCTGCCTCCCTTCCC!TAGGCCTGGCTCCTTCTGTTGAC 1840

V. 9 1 gtctgacccaggcctgcctcccttccctaggcctggctccttctgttgac

v.1 1841 ATGGGAGATTTTAGCTCATCTTGGGGGCCTCCTTAAACACCCCCATTTCT 1890

V.9 51 atgggagattttagctcatcttgggggcctccttaaacacccccatttct 100

v.1 1891 TGCOGAAGATGCTCCCCATCCCACTG1ACTGCTTGACCTTTACCTCCAACC 1940

v.9 101 tgcggaagatgctccccatcccactgactgcttgacctttacctccaacc 150

v.1 1941 CTTCTGTTCATCGGGAGGGCTCCACCAATTGAGTCTCTCCCACCATGCAT 1990

v.9 151 cttctgttcatcgggagggctccaccaattgagtctctCCCaccatgcat 200

v.1 1991 GCAGGTCACTGTGTGTGTGCATGTGTGCCTGTGTGAGTGTTGACTGACTG 2040

v.9 201 gcaggtcactgtgtgtgtgcatgtgtgcctgtgtgagtgttgactgactg 250

v.1 2041 TGTGTGTGTGGAGGGGTGACTGTCCGTGGAGGGGTGACTGTGTCCGTGGT 2090

v.9 251 tgtgtgtgtggaggggtgactgtccgtggaggggtgactgtgtccgtggt 300

v.1 2091 GTGTATTATGCTGTCATATCAGAGTCAAGTGAACTGTGGTGTATGTGCCA 2140

v.9 301 gtgtattatgctgtcatatcagagtcaagtgaactgtggtgtatgtgcca 350

v.1 2141 CGGGATTTGAGTGGTTGCGTGGGCAACACTGTCAGGGTTTGGCGTGTGTG 2190

v.9 351 cgggatttgagtggttgcgtgggcaacactgtcagggtttggcgtgtgtg 400

v.1 2191 TCATGTGGCTGTGTGTGACCTCTGCCTGAAAAAGCAGGTAT2TTCTCAGA 2240

00 v.9 401. tcatgtggctgtgtgtgacctctgcctgaaaaagcaggtattttctcaga 450

v.1 2241 CCCCAGAGCAGTATTAATGATGCAGAGGTTGGAGGAGAGAGGTGGAGACT 2290

v.9 :51 500ggatttagtcgggtggaaagtggc o

Sv.1 221GTGGCTCAGACCCAGGTGTGCGGGCATAGCTGGAGCTGGAATCTGCCTCC 2340

v.9 501 gtggctcagacccaggtgtgcgggcatagctggagctggaatctgcctcc 550

v.1 2341 GGTGTGAGGGAACCTGTCTCCTACCACTTCGGAGCCATGGGGGCAAGTGT 2390

551 ggtgtgagggaacctgtctcctaccacttcggagccatgggggcaagtgt 600

2391 GAAGCAGCCAGTCCCTGGGTcAGccAG.AGGCTTGAACTGTTACAGAAGCC 2440

v.9 601 gaagcagccagtccctgggtcagccagaggcttgaactgttacagaagcc 65000

v.1 2441 CTCTGCCCTCTGGTGGCCTCTGGGCCTGCTGCATGTACATATTTTCTGTA 2490

v.9 2651 cttcccgtgccggcgtcttctttcga 700

v. 291AATATACATGCGCCGGGAGCTTCTTGCAGGAATACTGCTCCGAATCACTT 254 0

v.9 701 aatatacatgcgccgggagcttcttgcaggaatactgctccgaatcactt 750

v.1 2541 TTAATTTTTTTCTTTTTTTTTI'CTTGCCCTTTCCATTAGTTGTATTTTTT 2590

v.9 751 ttaatttttttcttttttttttcttgccctttccattagttgtatttttt 800

v.1 2591 ATTTATTTTTATTTTrATTTTTTTTTAGAGATGGAGTCTCACTATGTTGC 2640

v.9 801 atttatttttatttttatttttttttagagatggagtctcactatgttgc 850

v. 1 2641 TCAGGCTcGGCCTTGAACTCCTGGGCTCAAGCAATCCTCCTGCCTCAGCCT 2690

v.9 851 tcaggctggccttgaactcctgggctcaagcaatcctcctgcctcagcct 900

V.1 2691 CCCTAGTAGCTGGGACTTTAAGTGTACACCACTGTGCCTGCTTTGAATCC 2740

v.9 901 ccctagtagctgggactttaagtgtacaccactgtgcctgctttgaatcc 950

v.1 2741 TTTACGAAGAGAAAAAATTAAAGAAAGCCTTTAGATTTATCCAATG 2790

v. 9 951 tttacyaagagaaaaaaaaaattaaagaaagcctttagatttatccaatg 1000

v.1 2791 TTTACTACTGGGATTGCTTAAAGTGAGGCCCCTCCAACACCAGGGGGTTA 2840

V.9 1001 tttactactgggattgcttaaagtgaggcccctccaacaccagggggtta 1050

v.1 2841 ATTCCTGTGATTGTGAAAGGGGCTACTTCCAAGGCATCTTCATGCAGGCA 2890

v-9 1051 attcctgtgattgtgaaaggggctacttccaaggcatcttcatgcaggca 1100

v.1 2891 GCCCCTTGGGAGGGCACCTGAGAGCTGGTAGAGTCTGATTAGGGATGT 2940

v. 9 1101 gccccttgggagggcacctgagagctggtagagtctgaaattagggatgt 1150

v.1 2941 GAGCCTCGTGGTTACTGAGTAAGGTAALAATTGCATCCACCATTGTTTGTG 2990

254

v.9 1151 gagcctcgtggttactgagtaa99taaaattgcatccaccattgtttgtg 120o

v.1 2991 ATACCTTAGGGAATTGCTTGGACCTGGTGACAAGGGCTCCTGTTCAATAG 3040

Sv.9 1201 ataccttagggaattgcttggacctggtgacaaggctcctgttcaatag 1250

Clv.1 3041 TGGTGTTGGGGAGAGAGAGAGCAGTGATTATALGACCGAGAGAGTAGGAGT 3090

C~v.9 1-251 tggtgttggggagagagagagcagtgattatagaccgagagagtaggagt 1300

v.1 3091 TGAGGTGAGGTGAAGGAGQTGCTGGGGGTGAGAATGTCGCCTTTCCCCCT 3140

v.9 1301 tgaggtgaggtgaaggaggtgctgggggtgagaatgtcgcctttccccct 1350

v.1 3141 GGGTTTTGGATCACTAATTCAAGGCTCTTCTGGATGTTTCTCTOGGTTGG 3190

v.9 1351 gggttttggatcactaattcaaggctcttctggatgtttctctggttgg 1400

.1 3191 GGCTGGAGTTCAATGAGGTTTATTTTTAGCTGGCCCACCCAGATACACTC 3240

00 v.9 1401 ggctggagttcaatgaggtttatttttagctggCCCaccagatacactc 1450

-v.1 3241 AGCCAGAATACCTAGATTTAGTACCCAAACTCTTCTTAGTCTGATCTG 3290

v.9 1451 agccagaatacctagatttagtacccaaactcttcttagtctgaaatctg 1500

v. 1 3291 CTGGATTTCTGGCCTAAGGGAGAGGCTCCCATCCTTCGTTCCCCAGCCAG 3340

v. 9 1501 ctggatttctggcctaagggagaggctcccatccttcgttCcccagccag 1550

v.1 3341 CCTAGGACTTCGAATGTGGAGCCTGAAGATCTAAGATCCTAACATGTACA 3390

v.9 1551 cctaggacttcgaatgtggagcctgaagatctaagatcctaacatgtaca 1600

v.1 3391 TTTTATGTAAATATGTGCATATTTGTACATAAAATGATATTCTGTTTTA 3440

v.1 3441 AATAAACAGACAAAACTTG 3459

v.9 1651 aataaacagacaaaacttg 1669

Table LIV(d). Peptide sequences of protein coded by 19112012(b) v.9 (SEQ ID NO: 128)MRRELLAGIL ILRITFNFFLF FFLPFPLVVF FIYFYFYFFL EMESHYVAQA GLELLGSSNP

PASASLVAGT LSVHHCACFE SFTKRKKKLK KAFRFIQCLL LGLLKVRPLQ HQGVNSCDCR 120

RGYFQGIFMQ AAPWEGT 137

Table LV(d). Amino acid sequence alignment of 1911241312(b) v.1 and 19113012(b) v.9

(NO SIGNIFICANT MATCH)

CLAIMS:

00 1. A composition that comprises, consists essentially of, or consists of:

O a) a peptide of eight, nine, ten, or eleven contiguous amino acids of a protein of Figure 2;

b) a peptide of Tables VIII-XXI;

c) a peptide of Tables XXII to XLV; or,

d) a peptide of Tables XLVI to XLIX.

1 2. A composition of claim 1 that comprises a protein related to a protein of Figure 2.

3. A protein of claim 2 that is at least 90, 91,92, 93, 94, 95, 96, 97, 98, or 99% homologous to an entire

=K amino acid sequence shown in Figure 2.

i 4. A composition of claim 1 wherein the substance comprises a CTL polypeptide or an analog thereof, from

00 the amino acid sequence of a protein of Figure 2.

A composition of claim 4 further limited by a proviso that the epitope is not an entire amino acid

sequence of Figure 2.

6. A composition of claim 1 further limited by a proviso that the polypeptide Is not an entire amino acid

sequence of a protein of Figure 2.

7. A composition of claim 1 that comprises an antibody polypeptide epitope from an amino acid sequence of

Figure 2.

8. A composition of claim 7 further limited by a proviso that the epitope is not an entire amino acid

sequence of Figure 2.

9. A composition of claim 7 wherein the antibody epitope comprises a peptide region of at least 5 amino

acids of Figure 2 in any whole number increment up to the end of said peptide, wherein the epitope comprises an amino acid

position selected from:

a) an amino acid position having a value greater than 0.5 in the Hydrophilicity profile of Figure

b) an amino acid position having a value less than 0.5 In the Hydropathicity profile of Figure 6;

c) an amino acid position having a value greater than 0.5 in the Percent Accessible Residues profile of

Figure 7;

d) an amino acid position having a value greater than 0.5 in the Average Flexibility profile of Figure 8;

e) an amino acid position having a value greater than 0.5 in the Beta-tur profile of Figure 9;

f) a combination of at least two of a) through e);

g) a combination of at least three of a) through e);

h) a combination of at least four of a) through or

I) a combination of five of a) through e).

A polynucleotide that encodes a protein of claim 1.

11. A polynucleotide of claim 10 that comprises a nucleic acid molecule set forth in Figure 2.

00O 12. A polynucleotide of claim 10 further limited by a proviso that the encoded protein is not an entire amino

C< acid sequence of Figure 2.

13. A composition of claim 11 wherein the substance comprises a polynucleotide that comprises a coding

sequence of a nucleic acid sequence of Figure 2.

14. A polynuceotide of claim 11 that further comprises an additional nucleotide sequence that encodes an

S additional peptide of claim 1.

rC 15. A composition comprising a polynucleotide that is fully complementary to a polynucleotide of claim 0

0 16. A method of generating a mammalian immune response directed to a protein of Figure 2, the method

0 comprising:

exposing cells of the mammal's immune system to a portion of

a) a 191P4D12(b)-related protein and/or

b) a nucleotide sequence that encodes said protein,

whereby an immune response is generated to said protein.

17. A method of generating an immune response of claim 16, said method comprising:

providing a 191P4D12(b)-related protein that comprises at least one T cell or at least one B cell epitope; and,

contacting the epitope with a mammalian immune system T cell or B cell respectively, whereby the T cell or B cell

is activated.

18. A method of claim 17 wherein the immune system cell is a B cell, whereby the induced B cell generates

antibodies that specifically bind to the 191P4D12(b)-related protein.

19. A method of claim 17 wherein the immune system cell is a T cell that is a cytotoxic T cell (CTL), whereby

the activated CTL kills an autologous cell that expresses the 191P4D12(b)-related protein.

A method of claim 17 wherein the immune system cell is a T cell that is a helper T cell (HTL), whereby

the activated HTL secretes cytokines that facilitate the cytotoxic activity of a cytotoxic T cell (CTL) or the antibody-producing

activity of a B cell.

21. A method for detecting, in a sample, the presence of a 191P4D12(b)-related protein or a 191P4D12(b)-

related polynucleotide, comprising steps of:

contacting the sample with a substance that specifically binds to the 191P4D12(b)-related protein or to the

191P4D12(b)-related polynucleotide, respectively; and,

determining that there is a complex of the substance with the 191P4D12(b)-related protein or the substance with

the 191P4D12(b)-related polynucleotide, respectively.

22. A method of claim 21 for detecting the presence of a 191P4D12(b)-related protein in a sample

OO comprising steps of:

contacting the sample with an antibody or fragment thereof either of which specifically bind to the 191P4D12(b)-

1 related protein; and,

determining that there is a complex of the antibody or fragment thereof and the 191P4D12(b)-related protein.

23. A method of claim 21 further comprising a step of:

taking the sample from a patient who has or who is suspected of having cancer.

24. A method of claim 21 for detecting the presence of a protein of Figure 2 mRNA in a sample comprising:

CN producing cDNA from the sample by reverse transcription using at least one primer;

Samplifying the cDNA so produced using 191P4D12(b) polynucleotides as sense and antisense primers, wherein

the 191P4D12(b) polynucleotides used as the sense and antisense primers serve to amplify a 191P4D12(b) cDNA; and,

0 detecting the presence of the amplified 191P4D12(b) cDNA.

A method of claim 21 for monitoring one or more 191P4D12(b) gene products In a biological sample from

a patient who has or who is suspected of having cancer, the method comprising:

determining the status of one or more 191P4D12(b) gene products expressed by cells in a tissue sample from an

individual;

comparing the status so determined to the status of one or more 191P4012(b) gene products in a corresponding

normal sample; and,

identifying the presence of one or more aberrant gene products of 191P4D12(b) in the sample relative to thenormal sample.

26. The method of claim 25 further comprising a step of determining if there are one or more elevated geneproducts of a 191P4D12(b) mRNA or a 191P4D12(b) protein, whereby the presence of one or more elevated gene products

in the test sample relative to the normal tissue sample indicates the presence or status of a cancer.

27. A method of claim 26 wherein the cancer occurs in a tissue set forth in Table I.

28. A composition comprising:

a substance that a) modulates the status of a protein of Figure 2, or b) a molecule that is modulated by a protein ofFigure 2, whereby the status of a cell that expresses a protein of Figure 2 is modulated.

29. A composition of claim 28, further comprising a physiologically acceptable carrier.

A pharmaceutical composition that comprises the composition of claim 28 In a human unit dose form.

31. A composition of claim 28 wherein the substance comprises an antibody or fragment thereof thatspecifically binds to a protein of Figure 2.

258

32. An antibody or fragment thereof of claim 31, which is monoclonal.

33. An antibody of claim 31, which is a human antibody, a humanized antibody or a chimeric antibody.00

34. A non-human transgenic animal that produces an antibody of claim 31.

A hybridoma that produces an antibody of claim 32.

LC 36. A method of delivering a cytotoxic agent or a diagnostic agent to a cell that expresses a protein of Figure

2, said method coriprising:

providing the cytotoxic agent or the diagnostic agent conjugated to an antibody or fragment thereof of claim 4; and,

exposing the cell to the antibody-agent or fragment-agent conjugate.

37. A composition of claim 28 wherein the substance comprises a polynucleotide that encodes an antibody

00 or fragment thereof, either of which immunospecifically bind to a protein of Figure 2.

38. A composition of claim 28 wherein the substance comprises a) a ribozyme that cleaves a polynucleotide

having a 191P4D12(b) coding sequence, or b) a nucleic acid molecule that encodes the ribozyme; and, a physiologically

acceptable carrier.

39. A composition of claim 28 wherein the substance comprises human T cells, wherein said T cells

specifically recognize a 191P4D12(b) peptide subsequence in the context of a particular HLA molecule.

A method of inhibiting growth of cancer cells that express a protein of Figure 2, the method comprising:

administering to the cells the composition of claim 28.

41. A method of claim 40 of Inhibiting growth of cancer cells that express a protein of Figure 2, the method

comprising steps of:

administering to said cells an antibody or fragment thereof, either of which specifically bind to a 191P4D12(b)-

related protein.

42. A method of claim 40 of inhibiting growth of cancer cells that express a protein of Figure 2, the method

comprising steps of:

administering to said cells a 191P4012(b)-related protein.

43. A method of claim 40 of inhibiting growth of cancer cells that express a protein of Figure 2, the method

comprising steps of:

administering to said cells a polynudeotide comprising a coding sequence for a 191P4012(b)-related protein or

comprising a polynucleotide complementary to a coding sequence for a 191P4D12(b)-related protein.

44. A method of claim 40 of inhibiting growth of cancer cells that express a protein of Figure 2, the method

comprising steps of:

I

administering to said cells a ribozyme that cleaves a polynucleotide that encodes a protein of Figure 2.

A method of claim 40 of inhibiting growth of cancer cells that express a protein of Figure 2 and a00 particular HLA molecule, the method comprising steps of:

0administering human T cells to said cancer cells, wherein said T cells specifically recognize a peptide subsequenceof a protein of Figure 2 while the subsequence is in the context of the particular HLA molecule.

46. A method of claim 40, the method comprising steps of:

Sadministering a vector that delivers a nucleotide that encodes a single chain monoclonal antibody, whereby theencoded single chain antibody is expressed intracellularly within cancer cells that express a protein of Figure 2.

00

CO

CO0

C

Figure 1: 19P4D)12(b) SSH sequence of 223 nucleotides. (SEQ ID NO: 1)

1 GATCACTAAT TCAAGGCTCT TCTGGATGTT TCTCTGGGTT GGGGCTGG.G TTCAATGAGG00

61 TTTATTTTTA GCTGGCCCAC CCAGATACAC TCAGCCAGAA TACCTAGATT TAGTACCCAA

121 ACTCTTCTTA GTCTGAAATC TGCTGGATTT CTGGCCTAAG GGAGAGGCTC CCATCCTTCG

181 TTCCCCAGCC AGCCTAGGAC TTCGAATGTG GAGCCTGAAG ATC

00

Figure 2:

00 ~Figure 2A. The cDNA (SEQ ID. NO.: 2) and amino acid sequence (SEQ ID. NO.: 3) of 191 P4D1 2(b) v.11 cloneW A. The start methionine is underlined. The open reading frame extends from nucleic acid 264-1796 Including the stop codon.

121 tcctggaacagggggtagattcgtctctcgg

C-]181 catctatagdgacgcccagaaccggactaaa

1 M P L S L G A E M W G P E241 gcggattcttacAGCCTTCTGACGGTTGGCT

14 AW LL LL L L L AS T G RC P AG ECl301 AGGCCTGGCTGCTGCTGCTGCTACTGCTGGCATCATTACAGGCCGGTGCCCCGCGGGTG

cI34 L ET S D V V T VV L G Q D A K L P C F00 361 AGTGGCTAAGGTATTGTCGGCGAGAACGCTC

54 Y RG D S GE Q VG Q VA WA RV DA G

74 E G A Q E L A L L H S K Y 0 L H V S P A481 GCAGCCCGACACCATCATCATCGCTAGGGCG

94 Y E G R V E Q P P P P R N P L D G S V L541 CTAGGGCCTGGACGCCCCCCACCTGC3CCGG

114 L R N A V Q A D E G 2 Y E C R V S T P P601 TCCTGCGCAACGCAGTGCAGGCGGATGAGGGCGAGTACGAGTGCCGTAGC!CCTTCC

134 A G SFP Q A R L R L R VL V P P L P S L661 CCGCCGGCAGCTTCCAGGCGCGGCTGCGGCTCCGAGGCTGGTGCCTCCCCTGCCCTCAC

154 N P G P A LE EGOQ G.b T LbAA SC T A721 TGATCCTGGTCCAGCACTAGAAGAGGCCAGGGCCTGACCCTGGCAGCCTCCTGCACAG

174 E G S P A P S V T W D T E V K G T T S S781 CTGAGGGCAGCCCAGCCCCCAGCGTGACCTGGACACGGAGGTCWGGCACACGTCCA

194 R S F K H S R S A A V T S E F H L V P G841 GCCGTTCCtTCAGCACTCCCGCTCTGCTGCCGTCACCTCAGAGTCCACTTGGTGCCTA

214 R S M N G Q P L T C V V S H P G L L Q D9021 GCCGCAGCATGAATGGGCAGCCACTGACTTGTGTTGTCCCATCCTGCCTGCTCCAGO

234 Q R I T H I L H V S F L A E A S V R G L961 ACCAAAGGATCACCCACATCCTCACGTGTCCTCCTTGCTGAGCCTCTGTQAGGGC

254 E D Q N L W H I G R E G A M L K C L S E1021 TTGAAGACCAAAATCTGTGGCACATTGGCAGAGAAGGAGCTATGCTCAGTGCCTGAGTG7

274 G Q P P P S Y N W T R L D2 G P L P S a V1081 AAGCGCCTCTAAACGACCGTGTGCTTCCGGG

294 R V D2 G D T L G F P P L T T E H S G I. y1141 TAGGGAGGAATTGCTCCCATACCGGAACGAC

314 V C H V S N E F S S R D S Q V T V D V L

1201 ACGTCTGCCATGTCAGCAATGAGTTCTCCTCAAGGGATTCTCAGGTCACTGT'GGATGTTC

334 D P Q E D S G K Q V D L V S A. S V V V V

00 1261 TTGACCCCCAGGAAGACTCTGGGAAGCAGGTGGACCTAGTGTCAGCCTCGGITGGTGGTGG

354 QGV I A A L L F C L L V VV V VL M S R

1321 TGGGTGTGATCGCCGCACTCTTGTTCTGCCTTCTGGTGGTGGTGGTGGTGCTICATGTCCC

374 Y HR RK AQ Q MT QK Y EE E L TL T

S 1381 GATACCATCGGCOCAAGGCCCAGCAGATGACCCAGAAATATGAGGAGGAGCTGACCCTGA

394 R E NS I R RL H SH HT D PR S Q P E

Cl1441 CCAGGGAGAACTCCATCCGGAGGCTGCATTCCCATCACACGACCCCAGGACiC:CAGCCGG

414 9 S V G L R A E G H P D S L K D N S S C

is501 AGGAGAGTGTAGGGCTGAGAGCCGAGGGCCACCCTGATAGTCTCAAGGACAkC!AGTAGCT

434 S V MS E E P EG R S Y S T L T T V R E

1561 GCTCTGTGATGAGTGAAGAGCCCGAGGGCCGCAGTTACTCCACGCTGACCAC.GGTGAGGG

Cl 454 1 E T Q T E LLS P G S G R AE E E E D00

1621 AGATAGAAACACAGACTGAACTGCTGTCTCCAGGCTCTGGGCGGGCCGAGGAkGGAGGAAG

474 Q D E G IK Q A M N H F V Q E N G T L R

1681 ATCAGGATGAAGGCATCAAACAGGCCATGAACCATTTTGTTCAGGAGAATGGGACCCTAC

494 A K P T G N G I Y I N G R G H L V*

1741 GGGCCAAGCCCACGGGCAATGGCATCTACATCAATGGGCGGGGACACCTGGCTGAccca

1801 ggcctgcctcccttccctaggcctggctccttctgttgacatgggagattt',:agctcatc

1861 ttgggggcctccttaaacacccccatttcttgcggaagatgctccccatcccactgactg

1921 cttgacctttacctccaacccttctgttcatcgggagggctccaccaattgalgtctctcc

1981 caccatgcatgcaggtcactgtytgtgtgcatgtgtgcctgtgtgagtgttgactgactg

2041 tgtgtgtgtggaggggtgactgtccgtggaggggtgactgtgtccgtggtgtgtattatg

2101 ctgtcatatcagagtcaagtgaactgtggtgtatgtgccacgggatttgagtggttgcgt

2161 gggcaacactgtcagggtttggcgtgtgtgtcatgtggctgtgtgtgacctctgcctgaa

2221 aaagcaggtattttctcagaccccagagcagtattaatgatgcagaggttggaggagaga

2281 ggtggagactgtggctcagacccaggtgtgcgggcatagctggagctggaatctgcctcc

2341 ggtgtgagggaacctgtctcctaccacttcggagccatgggggcaagtgtgaagcagcca

2401 gtccctgggtcagccagaggcttgaactgttacagaagccctctgccctctggtggcctc

2461 tgggcctgctgcatgtacatattttctgtaaatatacatgcgccgggagcttcttgcagg

2521 aatactgctccgaatcacttttaatttttttcttttttttttcttgccctttccattagt

2581 tgtattttttatttatttttatttttatttttttttagagatggagtctcactatgttgc

2641 tcaggctggccttgaactcctgggctcaagcaatcctcctgcctcagcctccctagtagc

2701 tgggactttaagtgtacaccactgtgcctgctttgaatctttacgaagagaaaaaaaaa

2761 attaaagaaagcctttagatttatccaatgtttactactgggattgcttaaagtgaggcc

2821 cctccaacaccagggggttaattcctgtgattgtgaaagyggctacttccaaggcatctt

2881 catgcaggcagccccttgggagggcacctgagagctggtagagtctgaaattagggatgt

2941 gagcctcgtggttactgagtaaggtaaaattgcatccaccattgtttgtgataccttagg

3001 gaattgcttggacctggtgacaagggctcctgttcaatatggtgttggggagagagaga

3 06.1 gcagtgattatagaccgagagagtaggagttgaggtgaggtgaaggaggtgctgggggtg

3121 agaatgtcgcctttccccctgggttttggatcactaattcaaggctcttctggatgtttc

3181 tctgggttggggctggagttcaatgaggtttatttttagctgg~ccacccagatacactc

3241 agccagaatacctagatttagtacccaaactcttcttagtctgaaatctgctggatttct

00 331gctagaagtcactctccacactgatcattg331Cctagaagtcct)tgtc~g~aCtgat~attg3361 gcctgaagatctaagatcctaacatgtacattttatgtaaatatgtgcatatttgtacat

3421 aaaatgatattctgtttttaaataaacagacaaaacttgaaaaa

Figure 213. The cDNA, (SEQ ID. NO. 4) and amino acid sequence (SEQ ID. NO. 5) of 191 P4DI12(b) v.2. The

start methionine is underlined. The open reading frame extends from nucleic acid 264-1796 including the stop codon.

1 ggccgtcgttgttggccacagcgtgggaagcagctctgggggagctcggagctcccgatc

61 acggcttcttgggggtagctacggctgggtgtgtagaacggggccggggctggggctggg

.121 tccccztagtggagacccaagtgcgagaggcaagaactctgcagcttcctgccttctgggt

181 cagttccttattcaagtctgcagccggctcccagggagatctcggtggaacttcagaaac

00 1 M4 P L S LG A E M W G P E

241 gctgggcagtctgcctttcaaccATGCCCCTGTCCCTGGGAGCCGAGATGTGGGGGCCTG

14 A WL L L L L L L AS F T G R C PA G E

301 AGGCCTGGCTGCTGCTGCTGCTACTGCTGGCATCATTTACAGGCCGGTGCCCCGCGGGTG

34 L E T S D V V T V V L G Q D A K L P C L

361 AGCTGGAGACCTCAGACGTGGTAACTGTGGTGCTGGGCCAGGACGCAAAACTGCCCTGCC

54 Y R G D S G E Q V G Q V A W A R V D A G

421 TCTACCGAGGGGACTCCGGCGAGCAAGTGGGGCAAGTGGCATGGGCTCGGGTGGACGCGG

74 E G A Q E L A L L H S K Y G L H V S P A

481 GCGAAGGCGCCCAGGAACTAGCGCTACTGCACTCCAAATACGGGCTTCATGTGAGCCCGG

94 Y E G R V E Q P P P P R N P L D G S V L

541 CTTACGAGGGCCGCGTGGAGCAGCCGCCGCCCCCACGCAACCCCCTGGACGGCTCAGTGC

114 L R N A V Q A D E G E Y E C R V S T F P

601 TCCTGCGCAACGCAGTGCAGGCGGATGAGGGCGAGTACGAGTGCCGGGTCAGCACCTTCC

134 A G S F Q A R L R L R V L V P P L P S L

661 CCGCCGGCAGCTTCCAGGCGCGGCTGCGGCTCCGAGTGCTGGTGCCTCCCCTGCCCTCAC

154 N P G P A L E E G Q G L T L A A S C T A

721 TGAATCCTGGTCCAGCACTAGAAGAGGGCCAGGGCCTGACCCTGGCAGCCTCCTGCACAG

174 E G S P A P S V T W D T E V K G T T S S

781 CTGAGGGCAGCCCAGCCCCCAGCGTGACCTGGGACACGGAGGTCAAAGGCACAACGTCCA

194 R S F K H S R S A A V T S E F H L V P S

841 GCCGTTCCTTCAAGCACTCCCGCTCTGCTGCCGTCACCTCAGAGTTCCACTTGGTGCCTA

214 R S M N G Q P L T.C VV S H P G L L Q D

901 GCCGCAGCATGAATGGGCAGCCACTGACTTGTGTGGTGTCCCATCCTGGCCTGCTCCAGG

234 Q R I T H I L H V S F L A E A S V R G L

961 ACCAAAGGATCACCCACATCCTCCACGTGTCCTTCCTTGCTGAGGCCTCTGTGAGGGGCC

254 E D Q N L W H I G R E G A M L K C L S E

1021 TTGAAGACCAAAATCTGTGGCACATTGGCAGAGAAGGAGCTATGCTCAAGTGCCTGAGTG

274 G Q P P P S Y N W T R L D G P L P S G V

1081 AAGGGCAGCCCCCTCCCTCATACAACTGGACACGGCTGGATGGGCCTCTGCCCAGTGGGG

294 R V D G D T L G F P P L T T E H S G I Y

00 1141a TACGAGTGGATGGGGACACTTTGGGCTTTCCCCCACTGACCACTGAGCACkGCGGCATCT

314 V C H V S N' E F S S R D S Q V T V D V L

c-I 1201 ACGTCTGCCATGTCAGCAATGAGTTCTCCTCAAGGGATTCTCAGGTCACTGTGGATGTTC

334 D P Q E D S G K QV D L V S A S V V VV

1261 TTGACCCCCAGGAAGACTCTGGGAAGCAGGTGGACCTAGTGTCAGCCTCGGTGGTGGTGG

354 G V I A A L L F C L L V V V V V L M S R

c-I1321 TGGGTGTGATCGCCGCACTCTTGTTCTGCCTTCTGGTGGTGGTGGTGGTGCTCATGTCCC374 Y H R R K A Q Q M T 0 K Y E E E L T L T

1381 GATACCATCGGCGCAAGGCCCAGCAGATGACCCAGAAATATGAGGAGGAGCTGACCCTGA

c-I394 R E N S I R R L H S H H T D P R S Q P E

1441 CCAGGGAGAACTCCATCCGGAGGCTGCATTCCCATCACACGGACCCCAGGAGCCAGCCGG

N 414 E SV GL RA E GHP D S L K DN S S C00

1501 AGGAGAGTGTAGGGCTGAGAGCCGAGGGCCACCCTGATAGTCTCAAGGACACAGTAGCT

-I434 S V M S E E PE G R S Y S T L T T VR E

1561 GCCGGTATAGGCGGGCGATATCCCGCAGTAG

454 I E T Q T E L L S P G S G R A E E E E D

1621 AGATAGAAACACAGACTGAACTGCTGTCTCCAGGCTCTGGGCGGGCCGAGGAGGAGGAAG

474 Q. D E G I K QA M NH F V Q E N G-TL R

1681 ATCAGGATGAAGGCATCAAACAGGCCATGAACCATTTTGTTCAGGAGAAT'GGGACCCTAC

494 A K P T G N G I Y I N G R G H L V

1741 GGGCCAAGCCCACGGGCAATGGCATCTACATCAATGGGCGGGGACACCTGGTCTGAccca

1801 ggcctgcctcccttccctaggcctggctccttctgttgacatgggagattttagctcatc

1861 ttgggggcctccttaaacaccccatttcttgcggaagatgctccccat(ccactgactg

1921 cttgacctttacctccaacccttctgttcatcgggagggctccaccaatt~gagtctctcc

1981 caccatgcatgcaggtcactgtgtgtgtgcatgtgtgcctgtgtgagtgttgactgactg

2041 tgtgtgtgtggaggggtgactgtccgtggaggggtgactgtgtccgtggtgtgtattatg

2101 ctgtcatatcagagtcaagtgaactgtggtgtatgtgccacgggatttgi31gtggttgcgt

2161 gggcaacactgtcagggtttggcgtgtgtgtcatgtggctgtgtgtga~c4tctgctgaa

2221 aaagcaggtattttctcagaccccagagcagtattaatgatgcagaggttggaggagaga

2281 ggtggagactgtggctcagacccaggtgtgcgggcatagctggagctggaatctgcctcc

2341 ggtgtgagggaacctgtctcctaccacttcggagccatgggggcaagtgtgaagcagcca

2401 gtccctgggtcagccagaggcttgaactgttacagaagccctctgccctctggtggcctc

2461 tgggcctgctgcatgtacatattttctgtaaatatacatgcccgggagcttcttgcagg

2521 aatactgctccgaatcacttttaatttttttcttttttttttcttgccctttccattagt

2581 tgtattttttatttatttttatttttatttttttttagagatggagtctcactatgttgc

2641 tcaggctggccttgaactcctgggctcaagcaatcctcctgcctcagcctccctagtagc

2701 tgggaCtttaagtgtacaccactgtgcctgctttgaatcctttacgaagagaaaaaaaaa

2761 attaaagaaagcctttagatttatccaatgtttactactgggattgcttaaagtgaggc

2821 cctccaacaccagggggttaattcctgtgattgtgaaaggggctacttccaaggcatctt

2881 catgcaggcagccccttgggagggcacctgagagctggtagagtctgaaattagggatgt

2941 gactggtatatagaattctccattttaactg

3001 gatgtgacgtaaggtcttcaatggtgggggg

00 3061 gcggtaaacaaatgattagggtagaggtggt

3121 agagccttcctgttgatatatagccttgttt

3181 tcggtggtggtatagtttttgtgcacaaaat

3241 agcgaacaatatccacttctgcgattcgatc

3301 ggcaggggccctctgtccacactgatcattg

3361 gcctgaagatctaagatcctaacatgtacattttatgtaaatatgtgcatatttgtacat

3421 aaaatgatattctgtttttaaataaacagacaaaacttgaaaaa

Figure 2C. The cDNA (SEQ ID. NO. 6) and amino acid sequence (SEQ ID. NO. 7) of 191 P4D12(b) The

C1start methionine is underlined. The open reading frame extends from nucleic acid 264-1796 including the stop codon.

00 00 1 ggccgtcgttgttggccacagcgtgggaagcagctctgggggagctcggagctcccgatc

61 acggcttcttgggggtagctacggctgggtgtgtagaacggggccggggctggggctggg

121 tcccctagtggagacccaagtgcgagaggcaagaactctgcagcttcctgccttctgggt

181 cagttccttattcaagtctgcagccggctcccagggagatctcggtggaacttcagaaac

1 M P L S L G A E M W G P E

241 gctgggcagtctgcctttcaaccATGCCCCTGTCCCTGGGAGCCGAGATGTGGGGGCCTG

14 A W L L L L L L L A S F T G R C P A G E

301 AGGCCTGGCTGCTGCTGCTGCTACTGCTGGCATCATTTACAGGCCGGTGCCCCGCGGGTG

34 L E T S D V V T V V L G Q D A K L P 1C F

361 AGCTGGAGACCTCAGACGTGGTAACTGTGGTGCTGGGCCAGGACGCAACTGCCCTGCT

54 Y R G D S G E Q V G Q V A W A R V D A G

421 TCTACCGAGGGGACTCCGGCGAGCAAGTGGGGCAAGTGGCATGGGCTCGGGTGGACGCGG

74 E G A Q E L A L L H S K Y G L H V S P A

481 GCAGCCCGACACCATCATCATCGCTAGGGCG

94 Y E G R V E Q P P PP R N P L D G S V L

541 CTTACGAGGGCCGCGTGGAGCAGCCGCCGCCCCCACGCAACCCCCTGGACGGCTCAGTGC

114 L R N A V Q A D E G E Y E C R V S T F P

601 TCCTGCGCAACGCAGTGOAGGCGGATGAGGGCGAGTACGAGTGCCGGGTCAGCACCTTCC

134 A G S F Q A R L R L R V L V P P L P S L

661 CCGCCGGCAGCTTCCAGGCGCGGCTGCGGCTCCGAGTGCTGGTGCTCCCCTGCCCTCAC

154 N P G P A L E E G Q G L T L A A S C T A

721 TGAATCCTGGTCCAGCACTAGAAGAGGGCCAGGGCCTGACCCTGGCAGCCTCCTGCACAG

174 E G S P A P S V T W D T E V K G T T S S

781 CTGAGGGCAGCCCAGCCCCCAGCGTGACCTGGGACACGGAGGTCAGGCACAACGTCCA

194 R S F K H S R S A A V T S E F H L V P S

841 GCCGTTCCTTCAAGCACTCCCGCTCTGCTGCCGTCACCTCAGAGTTCCACTTGGTGCCTA

214 R S M N G Q P L T C V V S H P G L L Q D

901 GCCGCAGCATGAATGGGCAGCCACTGACTTGTGTGGTGTCCCATCCTGGCCTGCTCCAGG

234 Q R I T H I L H V S F L A E A S V R G L

6/77

961 ACCAAAGGATCACCCACATCCTCCACGTGTCCTTCCTTGCTGAGGCCTCTGTGAGGGGCC

254 E D 0 N L W H I G R E G A M L K C L S E

00 1021 TTGAAGACCAAAATCTGTGGCACATTGGCAGAGAAGGAGCTATGCTCAAGTGCCTGAGTG

274 G Q P P P S Y NW TR LD G P L P S G V

CI1081 AAGGGCAGCCCCCTCCCTCATACAACTGGACACGGCTGGATGGGCCTCTGCCCAGTGGGG

294 R. V D G D T L G F P P L T T E H S G I Y

1141 TACGAGTGGATGGGGACACT'TTGGGCTTTCCCCCACTGACCACTGAGCAC.GCGGCATCT

314 V C H V S N E F S S R D S Q V T V D V L

1201 ACGTCTGCCATGTCAGCAATGAGTTCTCCTCAAGGGATTCTCAGGTCACTG-TGGATGTTC

334 D P 0 E D S G K Q V D L V S A S V V V V

1261 TTGACCCCCAGGAAGACTCTGGGAAGCAGGTGGACCTAGTGTCAGCCTCGC',TGGTGGTGG

cI354 G V I A AL L F C L L V VV V V I M S R

1321 TGGGTGTGATCGCCGCACTCTTGTTCTGCCTTCTGGTGGTGGTGGTGGTGC.TCATGTCCC

374 Y H R R K A Q Q M T Q K YE E E 1 T L T

*1381 GATACCATCGGCGCAAGGCCCAGCAGATGACCCAGAAATATGAGGAGGAGCTGACCCTGA

394 RE Nq S IR R. L H S H H T D P R SQ P E

1441 CCAGGGAGAACTCCATCCGGAGGCTGCATTCCCATCACACGGACCCCAGGA GCCAGCCGG

414 E S V G L R. A E G H P D S L K D 14 S S C

1501 AGGAGAGTGTAGGGCTGAGAGCCGAGGGCCACCCTGATAGTCTCAAGGACAACAGTAGCT

434 S V M S E E P E G R S Y S T L T T V R E

1561 GCTCTGTGATGAGTGAAGAGCCCGAGGGCCGCAGTTACTCCACGCTGACCAkCGGTGAGGG

454 1 E T Q T E L L S P G S G R A E E E E D

1621 AGATAGAAACACAGACTGAACTGCTGTCTCCAGGCTCTGGGCGGGCCGAGG1AGGAGGAAG

474 Q D E G I K Q A M N H F V Q E N G T L R.

1681 ATCAGGATGAAGGCATCAAACAGGCCATGAACCATTTTGTTCAGGAGAATGGGACCCTAC

494 A K P T G N G I Y I N~ G R G H L VI

1741 GGGCCAAGCCCACGGGCAATGGCATCTACATCAATGGGCGGGCACACCTGGTCTGAccca

1801 ggcctgcctcccttccctaggcctggctccttctgttgacatgggagattttagctcatc

1861 ttgggggcctccttaaacaccccatttcttgcggaagatgctCCCcatcccactgactg

1921 cttgacctttacctccaacccttctgttcatcgggagggctccaccaattgagtctctcc

1981 caccatgcatgcaggtcactgtgtgtgtgcatgtgtgcctgtgtgagtgttgactgactg

2041 tgtgtgtgtggaggggtgactgtccgtggaggggtgactgtgtccgtggtgtgtattatg

2101 ctgtcatatcagagtcaagtgaactgtggtgtatgtgccacgggatttgagtggttgcgt

2161 gggcaacactgtcagggtttggcttgtgtgtcatgtggctgtgtgtgacctctgcctgaa

2221 aaagcaggtattttctcag&ccccagagcagtattaatgatgcagaggtt.ggaggagaga

2281 ggtggagactgtggctcagacccaggtgtgcgggcatagctggagctggaatctgcctcc

2341 ggtgtgagggaacctgtctcctaccacttcggagccatgggggcaagtgtgaagcagcca

2401 gtccctgggtcagccagaggcttgaactgttacagaagccctctgccctctggtggcctc

2461 tgggcctgctgcatgtacatattttctgtaaatatacatgcgccgggagcttcttgcagg

2521 aatactgctccgaatcacttttaatttttttcttttttttttcttgccctttccattagt

2581 tgtattttttatttatttttatttttatttttttttagagatggagtctcactatgttgc

2641 tcaggctggccttgaactcctgggctcaagcaatcctcctgcctcagcctcctagtagc

00

2701 tgggactttaagtgtacaccactgtgcctgctttgaatcctttacgaagagaaaaaaaaa

2761 attaaagaaagcctttagatttatccaatgtttactactgggattgcttaaagtgaggcc

2821 cctccaacaccagggggttaattcctgtgattgtgaaaggggctacttccaaggcatctt

2881 catgcaggcagccccttgggagggcacctgagagctggtagagtctgaaattagggatgt

2941 gagcctcgtggttactgagtaaggtaaaattgcatccaccattgtttgtgataccttagg

3001 gaattgcttggacctggtgacaagggctcctgttcaatagtggtgttggggagagagaga

3061 gcagtgattatagaccgagagagtaggagttgaggtgaggtgaaggaggtgctgggggtg

3121 agaatgtcgcctttccccctgggttttggatcactaattcaaggctcttctggatgtttc

3181 tctgggttggggctggagttcaatgaggtttatttttagctggcccacccagatacactc

3241 agccagaatacctaaatttaatacccaaactcttctta-tct-aaatcf- ct atttct3301 ggcctaagggagaggctcccatccttcgttccccagccagcctaggacttcgaatgtgga

3361 gcctgaagatctaagatcctaacatgtacattttatgtaaatatgtgcatatttgtacat

3421 aaaatgatattctgtttttaaataaacagacaaaacttgaaaaa

00

Figure 2D. The cDNA (SEQ ID. NO. 8) and amino acid sequence (SEQ ID. NO. 9) of 191 P4DI 2(b) vA The

start methionine is underlined. The open reading frame extends from nucleic acid 264-1796 including the stop codon.

1 ggccgtcgttgttggccacagcgtgggaagcagctctgggggagctcggagctcccgatc

61 acggcttcttgggggtagctacggctgggtgtgtagaacggggccggggctggggctggg

121 tcccctagtggagacccaagtgcgagaggcaagaactctgcagcttcctgccttctgggt

181 cagttccttattcaagtctgcagccggctcccagggagatctcggtggaacttcagaaac

I M P L S L G A E M W G P E

241 gctgggcagtctgcctttcaaccATGCCCCTGTCCCTGGGAGCCGAGATGTGGGGGCCTG

14 A W L L L L L L L A S F T G R C P A G E

301 AGGCCTGGCTGCTGCTGCTGCTACTGCTGGCATCATTTACAGGCCGGTGCCCCGCGGGTG

j4 L E T S D V V T V V L G Q D A X L P C F

361 AGCTGGAGACCTCAGACGTGGTAACTGTGGTGCTGGGCCAGGACGCAAAACTGCCCTGCT

54 Y R G D S G E Q V G Q V A W A R V D A G

421 TCTACCGAGGGGACTCCGGCGAGCAAGTGGGGCAAGTGGCATGGGCTCGGGTGGACGCGG

74 E G A Q E L A L L H S K Y G L H V S P A

481 GCGAAGGCGCCCAGGAACTAGCGCTACTGCACTCCAAATACGGGCTTCATGTGAGCCCGG

94 Y E G R V E Q P P P P R N P L D G S V L

541 CTTACGAGGGCCGCGTGGAGCAGCCGCCGCCCCCACGCAACCCCCTGGACGGCTCAGTGC

114 L. R N A V Q A D E G E Y E C R V S T F P

601 TCCTGCGCAA CGCAGTGCAGGCGGATGAGGGCGAGTACGAGTGCCGGGTCAGCACCTTCC

134 A G S F Q A R L R L R V L V P P L P S L

661 CCGCCGGCAGCTTCCACGCGCGGCTGCGGCTCCGAGTGCTGGTGCCT6CCCTGCCCTCAC

154 N P G P A L E E G Q G L T L A A S C T A721 TGAATCCTGGTCCAGCACTAGAAGAGGGCCAGGGCCTGACCCTGGCAGCCTCCTGCACAG

174 E G S P A P S V T W D T E V K G T T S S781 CTGAGGGCAGCCCAGCCCCCAGCGTGACCTGGGACACGGAGGTCAAAGGCACAACGTCCA

194 R S F K H S R S A A V T S E F H L V P S

8/77

841 GCCGTTCCTTCAAGCACTCCCGCTCTGCTGCCGTCACCTCAGAGTTCCACTTGGTGCCTA

214 R S M N G Q P L T C V V S H P G L L Q D

00 901 GCCGCAGCATGAATGGGCAGCCACTGACTTGTGTGGTGTCCCATCCTGGCCTGCTCCAGG

234 Q R I T H I L H VS F L AEBAS V R GL

CI961 ACCAAAGGATCACCCACATCCTCCACGTGTCCTTCCTTGCTGAGGCCTCTGTGAGGGGCC

254 E D Q N L W H I G RE GCAM L K C L S E

S1021 TTGAAGACCAAAATCTGTGGCACATTGGCAGAGAAGGAGCTATGCTCAAGTGCCTGAGTG

274 G Q P P P S) Y N W T R L D G P L P S G V

C-I1081 AAGGGCAGCCCCCTCCCTCATACAACTGGACACGGCTGGATGGGCCTCTGCCCAGTGGGG

294 R V D G D T L G F P P L T T E H S G I Y

1141 TACGAGTGGATGGGGACACTTTGGCTTTCCCCCACTGACCACTGAGCACA..GCGGCATCT

314 V C H V S N E F S S R D S Q V T V D V L

1201 ACGTCTGCCATGTCAGCAATGAGTTCTCCTCAAGCGATTCTCAGGTCACTGTGGATGTTC

cI334 D P Q E D S G K Q VD L V S A S V V VV00

1261 TTGACCCCCAGGAAGACTCTGGGAAGCAGGTGGACCTAGTGTCAGCCTCGC;TGGTGGTGG

ci 354 G V I A A LL F C L L V V VV V liM S R

1321 TGGGTGTGATCGCCGCACTCTTGTTCTGCCTTCTGGTGGTGGTGGTGGTGC:TCATGTCCC

*374 Y H R R. K A Q Q M T Q K Y E E E Li T L T

*1381 GATACCATCGGCGCAAGGCCCAGCAGATGACCCAGAAATATGAGGAGGAG(.TGACCCTGA

394 R. E N S I R R. L H S H H T D P R S Q P E

1441 CCAGGGAGAA.CTCCATCCGGAGGCTGCATTCCCATCACACGGACCCCAGGAGCCAGCCGG

414 E S V G L R A E G H P D S L K D 11 S S C

1501 AGGAGAGTGTAGGGCTGAGAGCCGAGGGCCACCCTGATAGTCTCAAGGA CAACAGTAGCT

434 S V M S E E P E G P. S Y S T L T T V R E

1561 GCTCTGTGATGAGTGAAGAGCCCGAGGGCCGCAGTTACTCCACGCTGACCAkCGGTGAGGG

454 1 E T Q T E L' L S P G S G R. A E E E E D

1621 AGATAGAAACACAGACTGAACTGCTGTCTCCAGGCTCTGGGCGGGCCGAGGAGGAGGAAG

474 Q D E G I K QAM N HF V QE N GTLR

166 1 ATCAGGATGAAGGCATCAAACAGGCCATGAACCATTTTGTTCAGGAGAATGGGACCCTAC

494 A K P T G N4 G I Y I N G R. G H L *V

1741. GGGCCAAGCCCACGGGCAATGGCATCTACATCAATGGGCGGGACACCTGGTCTGAccca

1801 ggcctgcctcccttccctaggcctggctccttctgttgacatgggagattttagctcatc

1861 ttgggggcctccttaaacacccccatttcttgcggaagatgctccccatcccactgactg

1921 cttgacctttacctccaacccttctgttcatcgggagggctccaccaattgagtctctcc

1981 caccatgcatgcaggtcactgtgtgtgtgcatgtgtgcctgtgtgagtgttgactgactg

2041 tgtgtgtgtggaggggtgactgtccgtggaggggtgactgtgtccgtggtgtgtattatg

2101 ctgtcatatcagagtcaagtgaactgtggtgtatgtgccacgggatttgagtggttgcgt

2161 gggcaacactgtcagggtttggcgtgtgtgtcatgtggctgtgtgtgacctctgcctgaa

22 21 aaagcaggtattttctcagaccccagagcagtattaatgatgcagaggttggaggagaga

2281 ggtggagactgtggctcagacccaggtgtgcgggcatagctggagctgga.atctgcctcc

2341 agtgtgagggaacctgtctcctaccacttcggagccatgggggcaagtgtgaagcagcca

2401 gtccctgggtcagccagaggcttgaactgttacagaagccctctgccctctggtggcctc

9/77

2461 tgggcctgctgcatgtacatattttctgtaaatatacatgcgccgggagcttcttgcagg

2521 aatactgctccgaatcacttttaatttttttcttttttttttcttgccctttccattagt

00 2581 tgtattttttatttatttttatttttatttttttttagagatggagtctcactatgttgc

2641 tcaggctggccttgaactcctgggctcaagcaatcctcctgcctcagcctccctagtagc

2701 tgggactttaagtgtacaccactgtgcctgctttgaatcctttacgaagagaaaaaaaaa

Ct 2761 attaaagaaagcctttagatttatccaatgtttactactgggattgcttaaagtgaggcc

2821 cctccaacaccagggggttaattcctgtgattgtgaaaggggctacttccaaggcatctt

2881 catgcaggcagccccttgggagggcacctgagagctggtagagtctgaaattagggatgt

2941 gagcctcgtggttactgagtaaggtaaaattgcatccaccattgtttgtgataccttagg

3001 gaattgcttggacctggtgacaagggctcctgttcaatagtggtgttggggagagagaga

3061 gcagtgattatagaccgagagagtaggagttgaggtgaggtgaaggaggtgctgggggtg

3121 agaatgtcgcctttccccctgggttttggatcactaattcaaggctcttctggatgtttc

3181 tctgggttggggctggagttcaatgaggtttatttttagctggcccacccagatacactc

00 3241 agccagaatacctagatttagtacccaaactcttcttagtctgaaatctgctggatttct

3301 ggcctaagggagaggctcccatccttcgttccccagccagcctaggacttcgaatgtgga

3361 gcctgaagatctaagatcctaacatgtacattttatgtaaatatgtgcatatttgtacat

3421 aaaatgatattctgtttttaaataaacagacaaaacttgaaaaa

Figure 2E. The cDNA (SEQ ID. NO.: 10) and amino acid sequence (SEQ ID. NO. :Ii) of 191 P401 2(b) v.5. The

start methionine is underlined. The open reading frame extends from nudleic acid 264-1796 including the stop codon.

1 ggccgtcgttgttggccacagcgtgggaagcagctctgggggagctcggagctcccgatc

61 acggcttcttgggggtagctacggctgggtgtgtagaacggggccggggctggggctggg

121 tcccctagtggagacccaagtgcgagaggcaagaactctgcagcttcctgccttctgggt

181 cagttccttattcaagtctgcagccggctcccagggagatctcggtggaacttcagaaac

1 M P L S L G AE M W G P E

241 gctgggcagtctgcctttcaaccATGCCCCTGTCCCTGGGAGCCGAGATGTGGGGGCCTG

14 A W L L L L L L L A S F T G R C P A G E

301 AGGCCTGGCTGCTGCTGCTGCTACTGCTGGCATCATTTACAGGCCGGTGCCCCGCGGGTG

34 L E T S D V V T V V L G Q D A K L P C F

361 AGCTGGAGACCTCAGACGTGGTAACTGTGGTGCTGGGCCAGGACGCAAAACTGCCCTGCT

54 Y R G D S G E Q V G Q V A W A R V D A G

421 TCTACCGAGGGGACTCCGGCGAGCAAGTGGGGCAAGTGGCATGGGCTCGGGTGGACGCGG

74 E G A Q E L A L L H S K Y G L H V S P A

481 GCGAAGGCGCCCAGGAACTAGCGCTACTGCACTCCAAATACGGGCTTCATGTGAGCCCGG

94 Y E G R V E *Q P P P P R N P L D G S V L

541 CTTACGAGGGCCGCGTGGAGCAGCCGCCGCCCCCACGCAACCCCCTGGACGGCTCAGTGC

114 L R N A V Q A D E G E Y E C R V S T F P

601 TCCTGCGCAACGCAGTGCAGGCGGATGAGGGCGAGTACGAGTGCCGGGTCAGCACCTTCC

134 A G S F Q A R L R L R V L V P P L P S L

661 CCGCCGGC:AGCTTCCAGGCGCGGCTGCGGCTCCGAGTGCTGGTGCCTCCCCTGCCCTCAC

154 N P G P A L E E G Q G L T L A A S C T A

10/77

721 TGAATCCTGGTCCAGCACTAGAAGAGGGCCAGGGCCTGACCCTGGCAGCCITCCTGCACAG

174 E G S P A P S V T W D T E V K G T T S S

00 781 CTGAGGGCAGCCCAGCCCCCAGCGTGACCTGGGACACGGAGGTCAAAGGCACAACGTCCA

194 R S F K H S R S A A V T S E F H li V P S

214 RS MN G Q P L TC V VS H P G IL LQ0D

901 GCCGCAGCATGAATGGGCAGCCACTGACTTGTGTGGTGTCCCATCCTGGCC.TGCTCCAGG

234 Q R I T H I L H V S F L AE A S Vr RG L

961* ACCAAAGGATCACCCACATCCTCCACGTGTCCTTCCTTGCTGAGGCCTCTGITGAGGGGCC

254 E D Q N L W H I G R E G A M L K C L S E

1021 TTGAAGACCAAAATCTGTGGCACATTGGCAGAGAAGGAGCTATGCTCAAGTGCCTGAGTG

c-I274 G Q P P P S Y N W T R L D G P L I? S G V

1081 AAGGGCAGCCCCCTCCCTCATACAACTGGACACGGCTGGATGGGCCTCTGC CCAGTGGGG

00294 R VD G D T L G F P P L T T El H*1 G I Y

1141 TACGAGTGGATGGGGACACTTTGGGCTTTCCCCCACTGACCACTGAGCACAIGCGGCATCT

cI314 V C.l V S N E F S S R D S Q V T V D V L

1201 ACGTCTGCCATGTCAGCAATGAGTTCTCCTCAAGGGATTCTCAGGTCACTG'TGGATGTTC

334 D P Q E Dl S G K Q V D L V S A S V V V V

1261 TTGACCCCCAGGAAGACTCTGGGAAGCAGGTGGACCTAGTGTCAGCCTCGI3TGGTGGTGG

354 G V I A A L L F C L L V V V V V L~ M S R

1321 TGGGTGTGATCGCCGCACTCTTGTTCTGCCTTCTGGTGGTGGTGGTGGTGCTCATGTCCC

374 Y H R R K A Q Q M T Q K Y E E E L T L T

1381 GATACCATCGGCGCAAGGCCCAGCAGATGACCCAGAAATATGAGGAGGAGCTGACCCTGA

394 R E N S I R R L H S H H. T D P R S Q P E

1441 CCAGGGAGAACTCCATCCGGAGGCTGCATTCCCATCACACGGACCCCAGGAGCCAGCCGG

414 E S V G L R A E G H P D S L K D N S S C

1501. AGGAGAGTGTAGGGCTGAGAGCCGAGGGCCACCCTGATAGTCTCAAGGACAACAGTAGCT

434 S V M S E E P E G R S Y S T L T T V R E

1561 GCTCTGTGATGAGTGAAGAGCCCGAGGGCCGCAGTTACTCCACGCTGACCACGGTGAGGG

454 1 E T Q T E L L S P G S G R A E E E E D

1621 AGATAGAAACACAGACTGAACTGCTGTCTCCAGGCTCTGGGCGGGCCGAG-GAGGAGGAAG

474 Q D E G I K Q A M N H F V Q E N G T L R

1681 ATCAGGATGAAGGCATCAAACAGGCCATGAACCATTTTGTTCAGGAGAAT'GGGACCCTAC

494 A K P T G N G I Y I N G R G H L V

1741 GGGCCAAGCCCACGGGCAATGGCATCTACATCAATGGGCGGGGACACCTC;GTCTGAccca

1801 ggcctgcctcccttccctaggcctggctccttctgttgacatgggagattttagctcatc

1861 ttgggggcctccttaaacacccccatttcttgcggaagatgctccccatcccactgactg

1921 cttgacctttacctccaacccttctgttcatcgggagggctccaccaattgagtctctcc

1981 caccatgcatgcaggtcactgtgtgtgtgcatgtgtgcctgtgtgagtgttgactgactg

2041 tgtgtgtgtggaggggtgactgtccgtggaggggtgactgtgtccgtggtgtgtattatg

2101 ctgtcatatcagagtcaagtgaactgtggtgtatgtgccacgggatttgaxgtggttgcgt

2161 gggcaacactgtcagggtttggcgtgtgtgtcatgtggctgtgtgtgac(tctgcctgaa

11/77

2221 aaagcaggtaltttctcagaccccagagcagtattaatgatgcagaggttggaggagaga

2281 ggtggagactgtggctcagacccaggtgtgcgggcatagctggagctggaatctgcctcc

00 2341 ggtgtgagggaacctgtctcctaccacttcggagccatgggggcaagtgtgaagcagcca

2401 gtccctgggtcagccagaggcttgaactgttacagaagccctctgccctctggtggcctc

2461 tgggcctgctgcatgtacatattttctgtaaatatacatgcgccgggagcttcttgcagg

2521 aatactgctccgaatcacttttaatttttttcttttttttttcttgccctttccattagt

2581 tgtattttttatttatttttatttttatttttttttagagatggagtctcactatgttgc

2641 tcaggctggccttgaactcct~fggctcaagcaatcctcctgcctcagactccctagtagc

2701 tgggactttaagtgtacaccactgtgcctgctttgaatcctttacgaagagaaaaaaaaa

2761 attaaagaaagcctttagatttatccaatgtttactactgggattgcttaaagtgaggcc

__2821 cctccaacaccagggggttaattcctgtgattgtgaaaggggctacttccaaggcatctt

C12881 catgcaggcagccccttgggagggcacctgagagctggtagagtctgaaattagggatgt

2941 gagcctcgtggttactgagtaaggtaaaattgcatccaccattgtttgtgataccttagg

003001 gaattgcttggacctggtgacaagggctcctgttcaatagtggtgttggggagagagaga3061 gcagtgattatagaccgagagagtaggagttgaggtgaggtgaaggaggtgctgggggtg

rN2 3121 agaatgtcgcctttccccctgggttttggatcactaattcaaggctcttctggatgtttc

3181 tctgggttggggctggagttcaatgaggtttatttttagctggcccacccagatacactc

3241 agccagaatacctagatttagtacccaaactcttcttagtctgaaatctgctggatttct

3301 ggcctaagggagaggctcccatccttcgttccccagccagcctaggacttcgaatgtgga

3361 gcctgaagatctaagatcctaacatgtacattttatgtaaatatgtgcatatttgtacat

3421 aaaatgatattctgtttttaaataaacagacaaaacttgaaaaa

Figure 2F. The cDNA (SEQ ID. NO. 12) and amino acid sequence (SEQ ID. NO. :13) of 191 P4112(b) v.6. Thestart methionine is underlined. The open reading frame extends from nucleic acid 789-1676 including the stop codon.

1 ggccgtcgttgttggccacagcgtgggaagcagctctgggggagctcggagctcccgatc

61 acggcttcttgggggtagctacggctgggtgtgtagaacggggccggggctggggctggg

121 tcccctagtggagacccaagtgcgagaggcaagaactctgcagcttcctgccttctgggt

181 cagttccttattcaagtctgctactgctggcatcatttacaggccggtgccccgcgggtg

241 agctggagacctcagacgtggtaactgtggtgctgggccaggacgcaaaactgccctgct

301 tctaccgaggggactccggcgagcaagtggggcaagtggcatgggctcgggtggacgcgg

361 gcgaaggcgcccaggaactagcgctactgcactccaaatacgggcttcatgtgagcccgg

421 cttacgagggccgcgtggagcagccgccgcccccacgcaaccccctggacggctcagc

481 tctccagatcgcgtaggggagggcgtacctc

541 cccgcgtcagggcggctcatcgtctccgcta

601 tgactgcaccaagggcagctactgactcgaa

661 ctagcgcacccgggctggccggtaagaactc

721 gcgtctagatcgttcgcgcctaatcatgtct

1 M N G Q P L T C V V S H P G L L Q D781 gcgacTATGcGCCGCTGGGTTCACTGCGTCG

19 Q R I T H I L H V S F L A E A S V R G'L

841 ACC AAGGATCACCCACATCCTCCACGTGTCCTCCTTCTGAGGCCTCTGTGAGGGGCC

12/77

39 E D Q N L W H I G R E G A M L K C L S R

901 TTGAAGACCAAAATCTGTGGCACATTGGCAGAGAAGGAGCTATGCTCAAGTGCCTGAGTG

00 59 G Q P P P S Y N W T R L D G P L P S G V

961 AAGGGCAGCCCCCTCCCTCATACAACTGGACACGGCTGGATGGGCCTCTGCCCAGTGGG

79 R V D G D T L G F P P L T T E H S G I Y

1021 TACGAGTGGATGGGGACACTTTGGGCTTTCCCCCACTGACCACTGAGCACAGCGGCATCT

99 V C H V S N 'E F S S R D S Q V T V D V L

1081 ACGTCTGCCATGTCAGCAATGAGTTCTCCTCAAGGGATTCTCAGGTCACTGTGGATGTTC

119 D P Q E D S G K Q V D L V S A S V V VV

1141 TTGACCCCCAGGAAGACTCTGGGAAGCAGGTGGACCTAGTGTCAGCCTCGGTGGTGGTGG

139 G V I A A L L F C L L V V V V V L M S R

1201 TGGGTGTGATCGCCGCACTCTTGTTCTGCCTTCTGGTGGTGGTGGTGGT4CTCATGTCCC

Cl159 Y H R R K AQ Q M T Q K Y E EE L T L T

1261 GATACCATCGGCGCAAGGCCCAGCAGATGACCCAGAAATATGAGGAGGACICTGACCCTGA

00 179 R E N S I R R L H S H H T D P R S Q P E

1321 CCAGGGAGAACTCCATCCGGAGGCTGCATTCCCATCACACGGACCCCAGG3AGCCAGCCGG

199 E S V G L R A E G H P D S L K D N S S C-

1381 AGGAGAGTGTAGGGCTGAGAGCCGAGGGCCACCCTGATAGTCTCAAGGA(:AACAGTAGCT

219 S V M S E E P E G R S Y S T L T T V R E

1441 GCTCTGTGATGAGTGAAGAGCCCGAGGGCCGCAGTTACTCCACGCTGACCACGGTGAGGG

239 1 E T Q T E L L S P G S G R A E E E E D

1501 AGATAGAAACACAGACTGAACTGCTGTCTCCAGGCTCTGGGCGGGCCGAG"GAGGAGGAAG

259 Q D E G I K Q A M N H F V Q E N G T L R

1561 ATCAGGATGAAGGCATCAAACAGGCCATGAACCATTTTGTTCAGGAGAATGGGACCCTAC

279 A K P T G N G I Y I X G R G H L V

1621 GGGCCAAGCCCACGGGCAATGGCATCTACATCAATGGGCGGGGACACCTGGTCTGACCCa

1681 ggcctgcctcccttccctaggcctggctccttctgttgacatgggagattttagctcatc

1741 ttgggggcctccttaaacacccccatttcttgcggaagatgctccccatcccactgactg

1801 cttgacctttacctccaacccttctgttcatcgggagggctccaccaattgagtctctcc

1861 caccatgcatgcaggtcactgtgtgtgtgcatgtgtgcctgtgtgagtgttgactgactg

1921 tgtgtgtgtggaggggtgactgtccgtggaggggtgactgtgtccgtggtgtgtattatg

1981 ctgtcatatcagagtcaagtgaactgtggtgtatgtgccacgggatttcIagtggttgcgt

2041 gggcaacactgtcagggtttggcgtgtgtgtcatgtggctgtgtgtgacctctgcctgaa

2101 aaagcaggtattttctcagaccccagagcagtattaatgatgcagaggtxtggaggagaga

2161 ggtggagactgtggctcagacccaggtgtgcgggcatagctggagctggaatctgcctcc

2221 ggtgtgagggaacctgtctcctaccacttcggagccatgggggcaagtqltgaagcagcca

2281 gtccctgggtcagccagaggcttgaactgttacagaagccctctgcccl:ctggtggcctc

2341 tgggcctgctgcatgtacatattttctgtaaatatacatgcgccgggagcttcttgcagg,

2401 aatactgctccgaatcacttttaatttttttcttttttttttcttgccctttccattagt

2461 tgtattttttatttatttttatttttatttttttttagagatggagtctcactatgttgc

2521 tcaggctggccttgaactcctgggctcaagcaatcctcctgcctcagcctccctagtagc

2581 tgggactttaagtgtacaccactgtgcctgctttgaatcctttacgaagagaaaaaaaaa

13/77

2641 attaaagaaagcctttagatttatccaatgtttactactgggattgcttaaagtgaggcc

2701 cctccaacaccagggggttaattcctgtgattgtgaaaggggctacttccaaggcatctt

00 2761 catgcaggcagccccttgggagggcacctgagagctggtagagtctgaaattagggatgt

2821 gagcctcgtggttactgagtaaggtaaaattgcatccaccattgtttgtgataccttagg

2881 gaattgcttggacctggtgacaagggctcctgttcaatagtggtgttggggagagagaga

2941 gcagtgattatagaccgagagagtaggagttgaggtgaggtgaaggaggtgctgggggtg

3001 agaatgtcgcctttccccctgggttttggatcactaattcaaggctcttctggatgtttc

3061 tctgggttggggctggayttcaatgaggtttatttttagctggcccacccagatacactc

3121 agccagaatacctagatttagtacccaaactcttcttagtctgaaatctgctggatttct

3181 ggcctaagggagaggctcccatccttcgttccccagccagcctaggacttcgaatgtgga

__3241 gcctgaagatctaagatcctaacatgtacattttatgtaaatatgtgcatatttgtacat

3301 aaaatgatattctgtttttaaataaacagacaaaacttgaaaaa

00 Figure 2G. The cDNA (SEQ ID. NO.: 14) and amino acid sequence (SEQ ID. NO.: 15) of 191P4D12(b) v.7. Thestart methionine is underlined. The open reading frame extends from nucleic acid 264-1721 Including the stop codon.

1 ggccgtcgttgttggccacagcgtgggaagcagctctgggggagctcggagctcccgatc

61 acggcttcttgggggtagctacggctgggtgtgtagaacggggccggggctggggctggg

121 tcccctagtggagacccaagtgcgagaggcaagaactctgcagcttcctgccttctgggt

181 cagttccttattcaagtctgcagccggctcccagggagatctcggtggaacttcagaaac

1 M P L S L G A E M W G P E

241 gctgggcagtctgcctttaATGCCCCTGTCCCTGGGAGCCGAGATGTGGGGGCCTG

14 A W L L L L L L L A S F T G R C P A G E

301 AGGCCTGGCTGCTGCTGCTGCTACTGCTGGCATCATTTACAGGCCGGTGCCCCGCGGGTG

34 L E T S -D V V T V V L G Q D A K L P C F

361 AGCTGGAGACCTCAGACGTGGTAACTGTGGTGCTGGGCCAGGACGCAAAACTGCCCTGCT

54 Y R G D S G E Q V G Q V A W A R V D A G

421 TCACAGGCCGCACATGGCATGAGGTGGGAGG

74 E G A Q E L A L L H S K Y G L H V S P A

481 GCGAAGGCGCCCAGGAACTAGCGCTACTGCACTCCAAATACGGGCTTCATGTGAGCCCGG

94 Y E G R V E Q P P P P R N P L D G S V L

541 CTTACGAGGGCCGCGTGGAGCAGCCGCCGCCCCCACGCAACCCCCTGGACGGCTCAGTGC

114 L R N A V Q A D E G E Y E C R V S T F P

601 TCCTGCGCAACGCAGTGCAGGCGGATGAGGGCGAGTACGAGTGCCGGGTCAGCACCTTCC

134 A G S F Q A R L R L R V L V P P L P S L

661 CCGCCGGCAGCTTCCAGGCGCGGCTGCGGCTCCGAGTGCGGTGCCTCCCCTGCCCTCAC

154 N P G P A L E E G Q G L T L A A S C T A

721 TGAATCCTGGTCCAGCACTAGAAGAGGGCCAGGGCCTGACCCTGGCAGCCTCCTGCACAG

174 E G S PA P S V TW D T E V K G T T S S

781 CTGAGGGCAGCCCAGCCCCCAGCGTGACCTGGGACACGGAGGTCAAAGGC-ACAACGTCCA

194 R S F K H S R S A A V T S E F H L VP S

841 GCCGTTCCTTCAAGCACTCCCGCTCTGCTGCCGTCACCTCAGAGTTCCACTTGGTGCCTA

14/77

214 R S M N G Q P L T C V V S H P G L L Q D

901 GCCGCAGCATGAATGGGCAGCCACTGACTTGTGTGGTGTCCCATCCTGGCCTGCTCCAGG

234 Q R I T H I L H V S F L A E A S V R G L00

961 ACCAAAGGATCACCCACATCCTCCACGTGTCCTTCCTTGCTGAGGCCTCTGTGAGGGGCC

254 E D Q N L W H I G R E G A M L K C L S E

1021 TTGAAGACCAAAATCTGTGGCACATTGGCAGAGAAGGAGCTATGCTCAAGTGCCTGAGTG

274 G Q p P P S Y N W T R L D G P L P S G V

1081 AAGGGCAGCCCCCTCCCTCATACAACTGGACACGGCTGGATGGGCCTCTGCCCAGTGGGG

c-i294 R V D G D T L G F P P L T T E H S G I Y

1141 TACGAGTGGATGGGGACACTTTGGGCTTTCCCCCACTGACCACTGAGCACAGCGGCATCT

314 V C H V S N E F S S R D S Q V T V D V L

c-i1201 ACGtCTGCCATGTCAGCAATGAGTTCTCCTCAAGGGATTCTCAGGTCACTGTGGATGTTCc-i334 D P Q E D S G K Q V D L V S A S V V V V

1261 TTGACCCCCAGGAAGACTCTGGGAAGCAGGTGGACCTAGTGTCAGCCTCGGTGGTGGTGG

00 354 G V I AA L L F C L L V VV V VL M S R

1321 TGGGTGTGATCGCCGCACTCTTGTTCTGCCTTCTGGTGGTGGTGGTGGT'GCTCATGTCCC

374 Y H R R K A Q Q M T Q K Y E E E L T L T

1381 GATACCATCGGCGCAAGGCCCAGCAGATGACCCAGAAATATGAGGAGGA-GCTGACCCTGA

394 R E N S I R R L H S H H T D P R S Q S E

1441 CCAGGGAGAACTCCATCCGGAGGCTGCATTCCCATCACACGGACCCCACGAGCCAGAGTG

414 E P E G R S Y S T L T T V R E I E T Q T

1501 AAGAGCCCGAGGGCCGCAGTTACTCCACGCTGACCACGGTGAGGGAGAT'AGAAACACAGA

434 E L L S P G S G R A E E E E D Q D E G I

1561 CTGAACTGCTGTCTCCAGGCTCTGGGCGGGCCGAGGAGGAGGAAGATCAGGATGAAGGCA

454 K Q A M.N H F V Q E N G T L R A K P T G

1621 TCAAACAGGCCATGAACCATTTTGTTCAGGAGAATGGGACCCTACGGGCCAAGCCCACGG

474 N G I Y I N G R G H L V

1681 GCAATGGCATCTACATCAATGGGCGGGGACACCTGGTCTGAcccaggcctgcctcccttc

1741 cctaggcctggctccttctgttgacatgggagattttagctcatcttggfgggcctcctta

1801 aacacccccatttcttgcggaagatgctccccatcccactgactgcttgacctttacctc

1861 caacccttctgttcatcgggagggctccaccaattgagtctctcccacc!atgcatgcagg

1921 tcactgtgtgtgtgcatgtgtgcctgtgtgagtgttgactgactgtgtgltgtgtggaggg

1981. gtgactgtccgtggaggggtgactgtgtccgtggtgtgtattatgctgt.catatcagagt

2 041 caagtgaactgtggtgtatgtgccacgggatttgagtggttgcgtgggcaacactgtcag

2101 ggtttggcgtgtgtgtcatgtggctgtgtgtgacctctgcctgaaaaaylcaggtattttc

2161 tcagaccccagagcagtattaatgatgcagaggttggaggagagaggtcggagactgtggc

2221 tcagacccaggtgtgcgggcatagctggagctggaatctgcctccggtqjtgagggaacct

2281 gtctcctaccacttcggagccatgggggcaagtgtgaagcagccagtccctgggtcagcc

2341 agaggcttgaactgttacagaagccctctgccctctggtggcctctggqcctgctgcatg

2401 tacatattttctgtaaatatacatgcgccgggagcttcttgcaggaatatctgctccgaat

2461 cacttttaatttttttcttttttttttcttgccctttccattagttgtattttttattta

2521 tttttatttttatttttttttagagatggagtctcactatgttgctcaggctggccttga

15/77

2581 actcctgggctcaagcaatcctcctgcctcagcctccctagtagctgggactttaagtgt

2641 acaccactgtgcctgctttgaatcctttacgaagagaaaaaaaaaattaaagaaagcctt

00 2701 tagatttatccaatgtttactactgggattgcttaaagtgaggcccctccaacaccaggg

2761 ggttaattcctgtgattgtgaaaggggctacttccaaggcatcttcatgcaggagcccc

2821 ttgggagggcacctgagagctggtagagtctgaaattagggatgtgagcct'cgtggttac

2881 tgagtaaggtaaaattgcatccaccattgtttgtgataccttagggaattgcttggacct

2941 ggtgacaagggctcctgttcaatagtggtgttggggagagagagagcagtgattatagac

3001 cgagagagtaggagttgaggtgaggtgaaggaggtgctgggggtgagaatgtcgcctttc

3061 cccctgggttttggatcactaattcaaggctcttctggatgtttctctgggttggggctg

3121 gagttcaatgaggtttatttttagctggcccacccagatacactcagccagaatacctag

__3181 atttagtacccaaactcttcttagtctgaaatctgctggatttctggcctaagggagagg

3241 ctcccatccttcgttccccagccagcctaggacttcgaatgtggagcctgaagatctaag

3301 atcctaacatgtacattttatgtaaatatgtgcatatttgtacataaaatgatattctgt

003361 ttttaaataaacagacaaaacttgaaaaa

cK1Figure 2H. The cDNA (SEQ ID. NO. :16) and amino acid sequence (SEQ ID. NO. :17) of 191 P401 2(b) v.8. Thestart methionine is underlined. The open reading frame extends from nucleic acid 264-1796 including the stop codon.

1 ggccgtcgttgttggccacagcgtgggaagcagctctgggggagctcggagctcccgatc

61 acggcttcttgggggtagctacggctgggtgtgtagaacggggccggggctggggctggg

121 teccctagtggagacccaagtgcgagaggcaagaactctgcagcttcctgccttctgggt

181 cagttccttattcaagtctcagccggctcccagggagatctcggtggaacttcagaaac

1 M P L S L G A E M W G P E

241 gcggattcttacAGCCTTCTGACGGTTGGCT

14 A W L L L L L L L A S F T G R C P A G E

301 AGGCCTGGCTGCTGCTGCTGCTACTGCTGGCATCATTTACAGGCCGGTGCCCCGCGGGTG

34 L E T S D V V T V V L G Q D A K L P C F

361 AGCTGGAGACCTCAGACGTGTAACTGTGGTGCTGGCCAGGACGCAACTGCCCTGCT

54 Y R G D S G E Q V G Q V A W A R V D A G

421 TCTACCGAGGGGACTCCGGCGAGCAAGTGGGGAGTGGCATGGGCTCGGGTGGACGCGG

.74 E G, A Q E L A LL H SK Y G L H V S P A

481 GCAGCCCGACACCATCATCATCGCTAGGGCG

94 Y E G R V E Q P P P P R N P L D G S V L

541 CTAGGGCCTGGACGCCCCAGACCCGAGCCGG

114 L R N A V Q A D E G E Y E C R V S T F P

601 TCCTGCGCAACGCAGTGCAGGCGGATGAGGGCGAGTACGAGTGCCGGGTCAGCACCTTCC

134 A G S F 0 A R L R L R V L V P P L P S L

661 CCGCCGGCAGCTTCCAGGCGCGGCTGCGGCTCCGAGGCTGGTGCCTCCCCTGCCCTCAC

154 N P G P A L E E G Q G L T L A A S C T A

721 TGACTGCACCAAGGGCGGCGCCGCGCCTCrA

174 E G S P A P S V T W D T E V K G T T S S

781 CTGAGGGCAGCCCAGCCCCCAGCGTGACCTGGGACAGGTCGGCAACGTCCA

16/ 77

194 R S F K H S R S A A V T S E F H Ii V P S

841 GCCGTTCCTTCAAGCACTCCCGCTCTGCTGCCGTCACCTCAGAGTTCCACI'TGGTGCCTA

00 214 R S M N G Q P L T C V V S H P G li L Q D

01GCCGCAGCATGAATGGGCAGCCACTGACTTGTGTGGTGTCCCATCCTGGCCTGCTCCAGG

C-]234 Q R I TH I L H V S F L AE A S V R G L

961 ACCAAAGGATCACCCACATCCTCCACGTGTCCTTCCTTGCTGAGGCCTCTC1TGAGGGGCC

254 E D Q N L W H I G RE GA M L K C L S E

1021 TTGAAGACCAAAATCTGTGGCACATTGGCAGAGAGGAGCTATGCTCAG'GCCTGAGTG

C-I274 G3 Q P P P S Y N W T R L D G3 P L P S G V

1081 AAGGGCAGCCCCCTCCCTCA-TACAACTGGACACGGCTGGATGGGCCTCTG.:CCAGTGGGG

294 R V D G D T L G F P P L T T E H .3 G I Y

C-I 1141 TACGAGTGGATGGGGACACTTTGGGCTTTCCCCCACTGACCACTGAGCACAGCGGCATCT

C-]314 V C H VS N E F S S R D S Q V T V D V L

CI 1201 ACTTCAGCGATATCCTCAGATTAGCCGGAGT00

334 D PQ E D S G K Q V D LV S A S V V VV

1261 TTGACCCCCAGGAAGACTCTGGGAAGCAGGTGGACCTAGTGTCAGCCTCGGTGGTGGTGG

354 G3 V I A A L L F C L L V V V V V L M S R

1321 TGGGTGTGATCGCCGCACTCTTGTTCTCCCTTCTGGTGGTGGTGGTGGTC.CTCATGTCCC

374 HERR KA Q Q M T Q K Y E E EL T L T

1381 GATACCATCGGCGCAAGGCCCAGCAGATGACCCAGAAATATGAGGAGGAGCTGACCCTGA

394 R E N S I R R L H S H H T D P R S Q P E

1441 CCAGGGAGAACTCCATCCGGAGGCTGCATTCCCATCACACGGACCCCAGCIAGCCAGCCGG

414 E S V G3 L R A E G3 H P D S L K D N S S C

1501 AGGAGAGTGTAGGGCTGAGAGCCGAGGGCCACCCTGATAGTCTCAAGGA(:AACAGTAGCT

434 S V M S B E P E G3 R S Y S T L T T V R E

1561 GCTCTGTGATGAGTGAAGAGCCCGAGGGCCGCAGTTACTCCACGCTGAC(2ACGGTGAGGG

454 I E T Q T E L L S P G S G R A E E E E D

1621 AGATAGAAACACAGACTGAACTGCTGTCTCCAGGCTCTGGGCGGGCCGA(3GAGGAGGAAG

474 Q D E G I K Q A M N H F V Q E N G T L R

1681 ATCAGGATGAAGGCATCAAACAGGCCATGAACCATTTTGTTCAGGAGAATGGGACCCTAC

494 A K P T G N G I Y I N G R G H L V

1741 GGGCCAAGCCCACGGGCAATGGCATCTACATCAATGGGCGGGGACACCTGGTCTGAccca

1801 ggcctgcctcccttccctaggcctggctccttctgttgacatgggagattttagctcatc

1861 ttgggggcctccttaaacacccccatttcttgcggaagatgctccccatcccactgactg

1921 cttgacctttacctccaacccttctgttctcgggagggctccaccaattgagtctctcc

1981 caccatgcatgcaggtcactgtgtgtgtgcatgtgtgcctgtgtgagtcttgactgactg

2041 tgtgtgtgtggaggggtgactgtccgtggaggggtgactgtgtCcgtggtgtgtattatg

2101 ctgtcatatcagagtcaagtgaactgtggtgtatgtgccacgggatttgagtggttgcgt

2161 gggcaacactgtcagggtttggcgtgtgtgtcatgtggctgtgtgtgac~ctctgcctgaa

2221 aaagcaggtattttctcagaccccagagcagtattaatgatgcagaggt.tggaggagaga

2281 ggtggagactgtggctcagacccaggtgtgcgggcatagctggagctggaatctgcctcc

2341 ggtgtgagggaacctgtctcctaccacttcggagccatgggggcaagtgtgaagcagcca

17/77

2401 gtccctgggtcagccagaggcttgaactgttacagaagccctctgccctctggtggcctc

2461 tgggcctgctgcatgtacatattttctgtaaatatacatgcgccgggagcttcttgcagg

00 25.21 aatactgctccgaatcacttttaatttttttcttttttttttcttgccctttccattagt

2581 tgtattttttatttatttttatttttatttttttttagagatggagtctcactatgttgc

2641 tcaggctggccttgaactcctgggctcaagcaatcctcctgcctcagcctccctagtagc

Ct 2701 tgggactttaagtgtacaccactgtgcctgctttgaatcctttacgaagagaaaaaaaaa

2761 attaaagaaagcctttagatttatccaatgtttactactgggattgcttaaagtgaggcc

2821 cctccaacaccagggggttaattcctgtgattgtgaaaggggctacttccaaggcatctt

2881 catgcaggcagccccttgggagggcacctgagagctggtagagtctgaaattagggatgt

2941 gagcctcgtgctggtgacaagggctcctgttcaatagtggtgttggggagagagagagca

3001 gtgattatagaccgagagagtaggagttgaggtgaggtgaaggaggtgctgggggtgaga

3061 atgtcgcctttccccctgggttttggatcactaattcaaggctcttctggatgtttctct

3121 gggttggggctggagttcaatgaggtttatttttagctggcccacccagatacactcagc

00 3181 cagaatacctagatttagtacccaaactcttcttagtctgaaatctgctggatttctggc3241 ctaagggagaggctcccatccttcgttccccagccagcctaggacttcgaatgtggagcc

C13301 tgaagatctaagatcctaacatgtacattttatgtaaatatgtgcatatttgtacataaa

3361 atgatattctgtttttaaataaacagacaaaacttgaaaaa

Figure 21. The cDNA (SEQ ID. NO. :18) and amino acid sequence (SEQ ID. NO. 19) of 191 P4D1 2(b) v.9 cloneBCPI. The start methlonine is underlined. The open reading frame extends from nucleic acid 708-1121 including the stop codon.

1 gtctgacccaggcctgcctcccttccctaggcctggctccttctgttgacatgggagatt

61 ttagctcatcttgggggcctccttaaacacccccatttcttgcggaagatgctccccatc

121 ccactgactgcttgacctttacctccaacccttctgttcatcgggagggctccaccaatt

181 gagtctctcccaccatgcatgcaggtcactgtgtgtgtgcatgtgtgcctgtgtgagtgt

241 tgactgactgtgtgtgtgtggaggggtgactgtccgtggaggggtgactgtgtccgtggt

301 gtgtattatgctgtcatatcagagtcaagtgaactgtggtgtatgtgccacgggatttga

361 gtggttgcgtgggcaacactgtcagggtttggcgtgtgtgtcatgtggctgtgtgtgacc

421 tctgcctgaaaaagcaggtattttctcagaccccagagcagtattaatgatgcagaggtt

481 ggaggagagaggtggagactgtggctcagacccaggtgtgcgggcatagctggagctgga

541 atctgcctccggtgtgagggaacctgtctcctaccacttcggagccatgggggcaagtgt

601 gaagcagccagtccctgggtcagccagaggcttgaactgttacagaagccctctgccctc

1 M R R E L

661 tggtggcctctgggcctgctgcatgtacatattttctgtaaatatacATGCGCCGGAGC

6 L AG I LL R I T F N F F L F F F L P F

721 TTCTTGCAGGAATACTGCTCCGAATCACTTTTAATTTTTTTCTTTTTTTTTTCTTGCCCT

26 P L V V F F I Y F Y F Y F F L E M E S 1I

781 TTCCATTAGTTGTATTTTTTATTTATTTTTATTTTTATTTTTTTTTAGAGATGGAGTCTC

46 Y V A Q A G L E L L G S S N P P A S A S

841 ACTATGTTGCTCAGGCTGGCCTTGAACTCCTGGGCTCAAGCAATCCTCCTGCCTCAGCCT

66 L V A G T L S V H H C A C F E S F T K R

901 CCCTAGTAGCTGGGACTTTAAGTGTACACCACTGTGCCTTGCGTCCTTACGAAGA

18/77

86 K K K L K K A F R F I Q C L L L G L L K

961 GAAAAAATTAAAGAAAGCCTTTAGATTTATCCAATGTTTACTACTG3GATTGCTTA

00 106 V R PLOQ H Q G VN SC D C E R '3 Y F Q

1021 AAGTGAGGCCCCTCCAACACCAGGGGGTTAATTCCTGTGATTGTGAAAGGGGCTACTTCC

CI126 G I F M Q A AP W E G T

1081 AAGACTAGAGACCTGGAGCCT~acgtggcga

1141 ttagggatgtgagcctcgtggttactgagtaaggtaaaattgcatccaccattgtttgtg

1201 ataccttagggaattgcttggacctggtgacaagggctcctgttcaatagtggtgttggg

c-I 1261 gagagagagagcagtgattatagaccgagagagtaggagttgaggtgaggtgaaggaggt

1321 gctgggggtgagaatgtcgcctttccccctgggttttggatcactaattcaaggctcttc

1381 tggatgtttctctgggttggggctggagttcaatgaggtttatttttagctggcccaccc

1441 agatacactcagccagaatacctagatttagtaccaaactcttcttagtctgaaatctg

1501 ctggatttctggcctaagggagaggctcccatccttcgttccccagccagcctaggactt

1561 cgaatgtggagcctgaagatctaagatcctaacatgtacattttatgtaaatatgtgcat00

1621 atttgtacataaaatgatattctgtttttaaataaacagaeaaaacttg

Figure 2J. The cDNA (SEQ ID. NO.: 20) and amino acid sequence (SEQ ID. NO.: 21) of 191 P4D12(b) v.10. The

start methionine is underlined. The open reading frame extends from nucleic acid 264-1796 including the stop codon.

1 ggccgtcgttgttggccacagcgtgggaagcagctctgggggagctcggzLgctcccgatc

61. acggcttcttgggggtagctacggctgggtgtgtagaacggggccggggctggggctggg

121 tcccctagtggagacccaagtgcgagaggcaagaactctgcagcttcctcgccttctgggt

181 cagttccttattcaagtctgcagccggctcccagggagatctcggtggadtcttcagaaac

1 M P L S L G-A E M W O P E

241 gctgggcagtctgcctttcaaccATGCCCCTGTCCCTGGGAGCCGAGAT(TGGGGGCCTG

14 A W L L L L L L L A S F T G R C P A G E

301 AGGCCTGGCTGCTGCTGCTGCTACTGCTGGCATCATTTACAGGCCGGTGC CCCGCGGGTG

34 LOGT S D V V T VV L G QD A KL P C F

361 AGCTGGGGACCTCAGACGTGGTAACTGTGTGCTGGCCAGACGCAACTGCCCTGCT

54 Y R G D S G E Q V G Q V A W A R V D A G.

421 TCTACCGAGGGGACTCCGGCGAGCAAGTGGGGCAAGTGGCATGGGCTCGIGTGGACGCG

74 E G A Q E L A L L H S K Y G L H V S P A

481 GCGAAGGCGCCCAG0AACTAGCGCTACTOCACTCCAAATACGGGCTTCATGTGAGCCCGG

94 -Y E G R V E Q P P P P R N P L D G S V L

541 CTTACGAGGGCCGCGTGGAGCAGCCGCCGCCCCCACGCAACCCCCTGGACGGCTCAGTGC

114 L R N A V Q A D E G E Y E C R V S T F P

601 TCCTGCGCAACGCAGTGCAGGCGGATGAGGGCGAGTACGAGTGCCGGGTCAGCACCTTCC

134 A G S F Q A R L R L R V L V P P L P S L

661 CCGCCGGCAGCTTCCAGGCGCGGCTGCGGCTCCGAGTGCTGGTGCCTCCCCTGCCCTCAC

154 N P G P A L E E G Q G L T L A A S C T A

721 TGAATCCTGGTCCAGCACTAGAAGAGGGCCAGGGCCTGACCCTGGCAGCCTCCTGCACAG

174 E 0 S P A P S V T W D T E V K G T T S S

19/77

781 CTGAGGGCAGCCCAGCCCCCAGCGTGACCTGGGACACGGAGGTCAAAGGCACAA-CGTCCA

194 R S F K H S R S A A V T S E F H L V P S

00 842. GCCGTTCCTTCAAGCACTCCCGCTCTGCTGCCGTCACCTCAGAGTTCCACTTGGTGCCTA

214 R S M N G Q P L TC V VS H P G L LQD

901 GCCGCAGCATGAATGGGCAGCCACTGACTTGTGTGGTGTCCCATCCTGGCCTGCTCCAGG

ct 234 Q R I t H I L H V S F L A E A S V R G L

961. ACCAAAGGATCACCCACATCCTCCACGTGTCCTTCCTTGCTGAGGCCTCTGTGAGGGGCC

254 E D Q N L W H I G RE G A M L K C L S E

11021 TTGAAGACCAAAATCTGTGGCACATTGGCAGAGAAGGAGCTATGCTCAAGTGCCTGAGTG

274 G Q P P P S Y N W T R L D G P L P S G V

1081 AAGGGCAGCCCCCTCCCTCATACAACTGGACACGGCTGGATGGGCCTCTGCCCAGTGGGG

294 R V D G D*T L G F P*P L T T E H S G I Y

1141 TACGAGTGGATGGGGACACTTTGGGCTTTCCCCCACTGACCACTGAGCACAGCGGCATCT

00 314 V C H V S N E F S S R D S Q V T V D V L

1201 ACGTCTGCCATGTCAGCAATGAGTTCTCCTCAAGGGATTCTCAGGTCACTGTGGATGTTC

Cl334 D P Q E D S G K Q V DL V S A S V V VV

1261 TTGACCCCCAGGAAGACTCTGGGAAGCAGGTGGACCTAGTGTCAGCCTCGGTGGTGGTGG

354 G V I A A L L F C L L V V V V V L M S R

1321 TGGGTGTGATCGCCGCACTCTTGTTCTGCCTTCTGGTGGTGGTGGTGGTGCTCATGTCCC

374 Y H R R K A Q Q M T Q K Y E E E L T L T

1381 GATACCATCGGCGCAAGGCCCAGCAGATGACCCAGAAATATGAGGAGGAGCTGACCCTGA

394 R E N SI R R L H S HRH T D P R S Q P E

1441 CCAGGGAGAACTCCATCCGGAGGCTGCATTCCCATCACACGGACCCCAGGAGCCAGCCGG

414 E S V G L R A E G H P D S L K D N S S C

1501 AGGAGAGTGTAGGGCTGAGAGCCGAGGGCCACCCTGATAGTCTCAAGGACAACAGTAGCT

434 S V M S E E P E G R S Y S T L T T V R E

1561 GCTCTGTGATGAGTGAAGAGCCCGAGGGCCGCAGTTACTCCACGCTGACCACGGTGAGGG

454 I E T Q T E L L S P G S G R A E E E E D

1621 AGATAGAAACACAGACTGAACTGCTGTCTCCAGGCTCTGGGCGGGCCGAGGAGGAGGAAG

474 0 D E G I K Q A M N H F V Q E N G T L R

1681 ATCAGGATGAAOGCATCAAACAGCCATGAACCATTTTGTTCAGGAGAATGGGACCCTAC

494 A K P T G N G I Y I N G R G H L V*

1741 GGGCCAAGCCCACGGGCAATGGCATCTACATCAATGGGCGGGGACACCTGGTCTGAccca

1801 ggcctgcctcccttccctaggcctggctccttctgttgacatgggagattttagctcatc

1861 ttgggggcctccttaaacacccccatttcttgcggaagatgctccccatcccactgactg

1921 cttgacctttacctccaacccttctgttcatcgggagggctccaccaattgagtctctcc

1981 caccatgcatgcaggtcactgtgtgtgtgcatgtgtgcctgtgtgagtgttgactgactg

2041 tgtgtgtgtggaggggtgactgtccgtggaggggtgactgtgtccgtggtgtgtattatg

2101 ctgtcatatcagagtcaagtgaactgtggtgtatgtgccacgggatttgagtggttgcgt

2161 gggcaacactgtcagggtttggcgtgtgtgtcatgtggctgtgtgtgacctctgcctgaa

2221 aaagcaggtattttctcagaccccagagcagtattaatgatgcagaggttggaggagaga

2281 ggtggagactgtggctcagacccaggtgtgcgggcatagctggagctggaatctgcctc

20/77

2341. ggtgtgagggaacctgtctcctaccacttcggagccatgggggcaagtgtgaagcagcca

2401 gtccctgggtcagccagaggcttgaactgttacagaagccctctgccctctggtggcctc

00 2461 tgggcctgctgcatgtacatattttctgtaaatatacatgcgccgggagcttcttgcagg

2521 aatactgctccgaatcacttttaatttttttcttttttttttcttgccctttccattagt

2581 tgtattttttatttatttttatttttatttttttttagagatggagtctcactatgttgc

2641 tcaggctggccttgaactcctgggctcaagcaatcctcctgcctcagcctccctagtagc

2701 tgggactttaagtgtacaccactgtgcctgctttgaatcctttacgaagagaaaaaaaaa

2761 attaaagaaagcctttagatttatccaatgtttactactgggattgcttaaagtgaggcc

2821 cctccaacaccagggggttaattcctgtgattgtgaaaggggctacttcca.aggcatctt

2881 catgcaggcagccccttgggagggcacctgagagctggtagagtctgaaattagggatgt

2941 gagcctcgtggttactgagtaaggtaaaattgcatccaccattgtttgtgataccttagg

3001 gaattgcttggacctggtgacaagggctcctgttcaatagtggtgttggggagagagaga

C1 3061 gcagtgattatagaccgagagagtaggagttgaggtgaggtgaaggaggjtgctgggggtg.

3121 agaatgtcgcctttcccctgggttttggatcactaattcaaggctcttctggatgtttc00

3181 tctgggttggggctggagttcaatgaggtttatttttagctggcccacccatgatacactc

3241 agccagaatacctagatttagtacccaaactcttcttagtctgaaatctg(:tggatttct

3301 ggcctaagggagaggctcccatccttcgttccccagccagcctaggactt( gaatgtgga

3361 gcctgaagatctaagatcctaacatgtacattttatgtaaatatgtgcataitttgtacat

3421 aaaatgatattctgtttttaaataaa~agacaaaacttgaaaaa

Figure 2K. The cDNA (SEQ ID. NO. 22) and amino acid sequence (SEQ ID. NO. 23) of 191 P4ID12(b) v.1 1. The

start methionine is underlined. The open reading frame extends from nucleic acid 264-1796 including the stop codon.

1 ggccgtcgttgttggccacagcgtgggaagcagctctgggggagctcggagctcccgatc

61 acggcttcttgggggtagctacggctgggtgtgtagaacgggccggggctggggctggg

121 tcccctagtggagacccaagtgcgagaggcaagaactctgcagcttcctgccttctgggt

181 cagttccttattcaagtctgcagccggctcccagggagatctcggtggaacttcagaaac

1 M F L S L G AE MW G F E

241 gctgggcagtctgcctttc ccATGCCCCTGTCCCTGGGAGCCGAGATGTGGGGGCCTG

14 A W L L L L L L L A S F T G R C P A G E

301 AGGCCTGGCTGCTGCTGCTGCTACTGCTGGCATCATTTACAGGCCGGTGC.ICCCGCGGGTG

34 L E T S D V V T V V L G Q D A K L P C F

361 AGCTGGAGACCTCAGACGTGGTAACTGTGGTGCTGGGCCAGGACGCAICTGCCCTGCT

54 Y R G D S G E Q V G Q V A W A R V D A G

421 TCTACCGAGGGGACTCCGGCGAGCAAGTGGGGCAAG3TGGCATGGGCTCG(3GTGGACGCGG

74 E G A Q E L A L L H S K Y G L H V S P A

481 GCGAAGGCGCCCAGGAACTAGCGCTACTGCACTCCAAATACGGGCTTC~rGTGAGCCCGG

94 Y E G R V E Q P P F F R N P L D G S V L

541 OTTACGAGGGCCGCGTGGAGCAGCCGCCGCCCCCACGCAACCCCCTGGAI:GGCTCAGTGC

114 L R NA V Q A D E GE Y E C R V S T F P

601 TCCTGCGCAACGCAGTGCAGGCGGATGAGGGCGAGTACGAGTGCCGGGTCAGCACCTTCC

134 A G S F Q A R L R L R V M V P P L P S L

21/77

661 CCGCCGGCAGCTTCCAGGCGCGGCTGCGGCTCCGAGTGATGGTGCCTCCCCTGCCCTCAC

154 N P G P A L E E G Q G L T L A A S C T A

00 721 TGAATCCTGGTCCAGCACTAGAAGAGGGCCAGGGCCTGACCCTGGCAGCCTCCTGCACAG

174 E G S PA P S V T W D T E V K G T T S S

c-I781 CTGAGGGCAGCCCAGCCCCCAGCGTGACCTGGGACACGGAGGTCAAAGGCACAACGTCCA194 R S F K HS R S AA V T S E P H L V P S

841 GCCGTTCCTTCAAGCACTCCCGCTCTGCTGCCGTCACCTCAGAGTTCCACTTGGTGCCTA

214 R S M NG Q P L T C V V S H P G L L Q D

901 GCCGCAGCATGAATGGGCAGCCACTGACTTGTGTGGTGTCCCATCCTGGCCTGCTCCAGG

234 Q R I T H I L H V S F L A E A S V R G L

__961 ACCAAAGGATCACCCACATCCTCCACGTGTCCTTCCTTGCTGAGGCCTCTGTGAGGGGCC

cI254 E D Q N L W H I G RE G A M L K C L S E

1021. TTGAAGACCAAAATCTGTGGCACATTGGCAGAGAAGGAGCTATGCTCAAGTGCCTGAGTG

00 274 G Q P P P S Y N W T R L D G P L P S G V

1081 AAGGGCAGCCCCCTCCCTCATACAACTGGACACGGCTGGATGGGCCTCTGCCCAGTGGGG

cI294 R V D G DT L G F P P L T T E H S G I Y

1141 TACGAGTGGATGGGGACACTTTGGGCTTTCCCCCACTGACCACTGAGCACAGCGGCATCT

314 V C H V S N E F S S R D S Q V T V D V L

1201 ACGTCTGCCATGTCAGCAATGAGTTCTCCTCAAGGGATTCTCAGGTCACTGTGGATGTTC

334 D P Q E D S G K Q V D L V. S A S V V V V

1261 TTGACCCCCAGGAAGACTCTGGGAAGCAGGTGGACCTAGTGTCAGCCTCGGTGGTGGTGG

354 G V I A A L L F C L L V V V V V L M S R

1321 TGGGTGTGATCGCCGCACTCTTGTTCTGCCTTCTGGTGGTGGTGGTGGTGCTCATGTCCC

374 Y H R R K A Q Q M T Q K Y E E E L T L T

1381 GATACCATCGGCGCAAGGCCCAGCAGATGACCCAGAAATATGAGGAGGAGCTGACCCTGA

394 R E N S I R R L H S H H T D P R S Q P E

1441 CCAGGGAGAACTCCATCCGGAGGCTGCATTCCCATCACACGGACCCCAGGAGCCAGCCGG

414 E S V G L R A E G H P D S L K D N S S C

1501 AGGAGAGGTAGGGCTGAGAGCCGAGGCCACCCTGATAGTCTCAAGGACAACAGTAGCT

434 S V M S E E P E G R S Y S T L T T V R E

1561 GCCGGTATAGGCGGGCGATATCCCGCAGTAG

454 I E T Q T E L L S P G S G R A E E E E D

1621 AGATAGAAACACAGACTGAACTGCTGTCTCCAGGCTCTGGGCGGGCCGAGGAGGAGGAAG

474 Q D E G I K Q A M N H F V Q E N G T L R

1681 ATCAGGATGAAGGCATCAAACAGGCCATGAACCATTTTGTTCAGGAGAATGGGACCCTAC

494 A K P T G N G I Y I N G R G H L V*

1741 GGGCCAAGCCCACGGGCAATGGCATCTACATCAATGGGCGGGGACACCTGGTCTGAccca

1801 ggcctgcctcccttccctaggcctggctccttctgttgacatgggagattttagctcatc

1861 ttgggggcctccttaaacacccccatttcttgcggaagatgctccccatcccactgactg

1921 cttgacctttacctccaacccttctgttcatcgggagggctccaccaattgagtctctcc

1981 caccatgcatgcaggtcactgtgtgtgtgcatgtgtgcctgtgtgagtgttgactgactg

2041 tgtgtgtgtggaggggtgactgtccgtggaggggtgactgtgtccgtggtgtgtattatg

22/77

2101 ctgtcatatcagagtcaagtgaactgtggtgtatgtgccacgggatttgagtggttgcgt

2161 gggcaacactgtcagggtttggcgtgtgtgtcatgtggctgtgtgtga~c(tctgcctgaa

00 2221 aaagcaggtattttctcagacccagagcagtattaatgatgcagaggttggaggagaga2281 ggtggagactgtggctcagacccaggtgtgcgggcata~gctggagctgg.atctgcctcc

2341 ggtgtgagggaacctgtctcctaccacttcggagccatgggggcaagtggaagcagcca

2401 gtccctgggtcagccagaggcttgaactgttacagaagccctctgccct(tggtggcctc

2461 tgggcctgctgcatgtacatattttctgtaaatatacatgcgccgggagcttcttgcagg

2521 aatactgctccgaatcacttttaatttttttcttttttttttcttg~cctttccattagt

C12581 tgtattttttatttatttttatttttatttttttttagagatggagtct4actatgttgc

2641 tcaggctggccttgaactcctgggctcaagcaatcctcctgcctcagcctccctagtagc

2701 tgggactttaagtgtacaccactgtgcctgctttgaatcctttacgaagagaaaaaaaaa

2761 attaaagaaagcctttagatttatccaatgtttactactgggattgcttaaagtgaggcc

2821 cctccaacaccagggggttaattcctgtgattgtgaaaggggctacttccaaggcatctt

2881 catgcaggcagccccttgggagggcacctgagagctggtagagtctgaaattagggatgt00

2941 gagcctcgtggttactgagtaaggtaaaattgcatccaccattgtttgtgataccttagg

3001 gaattgcttggacctggtgacaagggctcctgttcaatagtggtgttggggagagagaga

3061 gcagtgattatagaccgagagagtaggagttgaggtgaggtgaaggaggtgctgggggtg

3121 agaatgtcgcctttccccctgggttttggatcactaattcaaggctcttctggatgtttc

3181 tctgggttggggctggagttcaatgaggtttatttttagtggcccacccagatacactc

3241 agccagaatacctagatttagtacccaaactcttcttagtctgaaatctgctggatttct

3301 ggcctaagggagaggctcccatccttcgttcccagccagcctaggacttcgaatgtgga

3361 gcctgaagatctaagatcctaacatgtacattttatgtaaatatgtgcatatttgtacat

3421 aaaatgatattctgtttttaaataaacagacaaaacttgaaaaa

Figure 2L. The cDNA (SEQ ID. NO. 24) and amino acid sequence (SEQ ID. NO. 25) of 191 P4D1 2(b) v.1 2. The

start metthionine is underlined. The open reading frame extends from nucleic acid 264-1796 including the stop codon.

1 ggccgtcgttgttggccacagcgtgggaagcagc tctgggggagc tcggagctcccgatc

61 acggcttcttgggggtagctacggctgggtgtgtagaacgggccggg-ctggggctggg

121 tcccctagtggagacccaagtgcgagaggcaagaactctgcagcttcct.gccttctgggt

181 cagttccttattcaagtctgcagccggct~ccagggagatctcggtggaacttcagaaac

1 M P L S L G A E M W G P E

241 gctgggcagtctgcctttcaaccATGCCCCTGTCCCTGGGAGCCGAGAGTGGGGGCCTG

14 A W L L L L L L L A S F T G R. C P A G E

301 AGGCCTGGCTGCTG CTGCTGCTACTGCTGGCATCATTTACAGGCCGGTCQCCCCGCGGGTG

34 L E T S D V V T V V L G Q D A K L P C F

361 AGCTGGAGACCTCAGACGTGGTAACTGTGGTGCTGGGCCAGGACGCAA~aCTGCCCTGCT

54 Y R. G D S G E Q V G Q V A W A R V D A G

421 TCTACCGAGGGGACTCCGGCGAGCAAGTGGGGCAAGTGGCATGGGCTCG;GGTG3GACGCGG

74 E G 'A Q E L A L L H S K Y G L H V S P A

481 GCGAAGGCGCCCAGGAACTAGCGCTACTGCACTCCAAATACGGGCTTCATGTGAGCCCGG

94 Y E G R V E Q P P P P R N P L D G S V L

23/ 77

541 CTTACGAGGGCCGCGTGGAGCAGCCGCCGCCCCCACGCAACCCCCTGGACGGCTCAGTGC

114 L R N A V Q A D E G E Y E C R V S T F P

00 601 TCCTGCGCAACGCAGTGCAGGCGGATGAGGGCGAGTACGAGTGCCGGGTCAGCACCTTCC

134 A G S F Q A R L R L R V L V P P L P S L

C-I661 CCGCCGGCAGCTTCCAGGCGCGGCTGCGGCTCCGAGTGCTGGTGCCTCCCCTGCCCTCAC

154 N P G P A L E E G Q G L T L A A S C T A

721 TGAATCCTGGTCCAGCACTAGAAGAGGGCCAGGGCCTGACCCTGGCAGCCTCCTGCACAG

174 E G S PA P S VT W D T E V K G T T S S

781 CTGAGGGCAGCCCAGCCCCCAGCGTGACCTGGGACACGGAGGTCAAAGGCACAACGTCCA

194 R S F K H S R S. A A V T S E F H L V P S

__841 GCCGTTCCTTCAAGCACTCCCGCTCTGCTGCCGTCACCTCAGAGTTCCACTTGGTGCCTA

c-I214 R S M N G Q P L T C V V S R P G L L Q D

901 GCCGCAGCATGAATGGGCAGCCACTGACTTGTGTGGTGTCCCATCCTGGCCTGCTCCAGG

00234 Q R I T H I L H V S F L A E A S V R G L

961 ACCAAAGGATCACCCACATCCTCCACGTGTCCTTCCTTGCTGAGGCCTCTGTGAGGGGCC

c-I254 E D Q N L W H I G R E G A M L K C L S E

1021 TTGAAGACCAAAATCTGTGGCACATTGGCAGAGAAGGAGCTATGCTCAAGTGCCTGAGTG

274 G Q P P P S Y N W T R L D G P L P S G V

1081 AAGGGCAGCCCCCTCCCTCATACAACTGGACACGGCTGGATGGGCCTCTGCCCAGTGGGG

294 R V D G D T L G F P P L T T E H S G I Y

1141 TACGAGTGGATGGGGACACTTTGGGCTTTCCCCCACTGACACTGAGCAAGCGGCATCT

314 V C H.V S N E F S S R D S Q V T V D V L

1201 ACGTCTGCCATGTCAGCAATGAGTTCTCCTCAAGGGATTCTCAGGTCACTGTGGATGTTC

334 D P Q E D S G K Q V D L V S A S V V V -V

1261 TTGACCCCCAGGAAGACTCTGGGAAGCAGGTGGACCTAGTGTCAGCCTCGGTGGTGGTrGG

354 G V I A A L L F C L L V V V V V L M S R

1321 TGGGTGTGATCGCCGCACTCTTGTTCTGCCTTCTGGTGGTGGTGGTGGTGCTCATGTCCC

374 Y H R R K A Q Q M T Q K Y E E E L T L T

1381 GATACCATCGGCGCAAGGCCCAGCAGATGACCCAGAAATATGAGGAGGAGCTGACCCTGA

394 R E N S I R R L H S H H T D P R S Q P E

1441 CCAGGGAGAACTCCATCCGGAGGCTGCATTCCCATCACACGGACCCCAGGAGCCAGCCGG

414 E S V G L R A E G H P D S L K D N S S C

1501 AGGAGAGTGTAGGGCTGAGAGCCGAGGGCCACCCTGATAGTCTCAAGGACAACAGTAGCT

434 S V M S E E P E G C S Y S T L T T V R E

1561 GCTCTGTGATGAGTGAAGAGCCCGAGGGCTGCAGTTACTCCACGCTGACCACGGTGAGGG

454 1 E T Q T E L L S P G S G R A E E E E D

1621 AGATAGAAACACAGACTGAACTGCTGTCTCCAGGCTCTGGGCGGGCCGAGGAGG;AGGAG

474 Q D E G I K Q A M N H F V Q E N G T L R

1681 ATCAGGATGAAGGCATCAACAGGCCATGAACCATTTTGTTCAGGAGATGGGACCCTAC

494 A K P T G N G I Y I N G R G H L V

1741 GGGCCAAGCCCACGGGCAATGGCATCTACATCAATGGGCGGGGACACCTGTCTGAccca

1801 ggcctgcctcccttccctaggcctggctccttctgttgacatgggagattttagctcatc

24/77

1861 ttgggggcctccttaaaca~ccccatttcttgcggaagatgctccccatcccactgactg

1921 cttgacctttacctccaacccttctgttcatcgggagggctccaccaattgagtctctcc

00 1981 caccatgcatgcaggtcacttgttgtgtgcatgtgtgcctgtgtgagtgttgactgactg

2041 tgtgtgtgtggaggggtgactgtc Cgtggagggtgacttgttccgtggttgtattatg

C1 2101 ctgtcatatcagagtcaagtgaactgtggtgtatgtgccacgggatttgagtggttgcgt

2161 gggcaacactgtcagggtttggcgtgtgtgtcatgtggctgtgtgtgacct ctgcctgaa

2221 aaagcaggtattttctcagaccccagagcagtattaatgatgcagaggttggaggagaga

2281 ggtggagactgtggct~cagacccagg tgtgcgggcatagctggagctggaatctgcctcc

2341 ggtgtgagggaacctgtctcctaccacttcggagccatgggggcaagtgtclaagcagcca

2401 gtccctgggtcagccagaggcttgaactgttacagaagccctctgccctct:ggtggcctc

2461 tgggcctgctgcatgtacatattttctgtaaatatacatgcgccgggagcttcttgcagg

(712641 tcaggctggccttgaactcctgggctcaagcaatcctcctgcctcagcctc:cctagtagc00

2701 tgggactttaagtgtacaccactgtgcctgctttgaatcctttacgaaac3aaaaaaaaa

2761 attaaagaaagcctttagatttatccaatgtttactactgggattgcttaiatgaggcc

2821 cccaccaggtatcttattaaggtctcagctt

2881 catgcaggcagccccttgggagggcacctgaggctggtagagtctgaaattagggatgt

2941 gagcctcgtggttactgagtaaggtaaaattgcatccaccattgtttgtgataccttagg

3001 gaattgcttggacctggtgacaagggctcctgttcaatagtggtgttggggagagagaga

3061 gcagtgattatagaccgagagagtaggagttgaggtgaggtgaaggaggtgctgggggtg

3121 agaatgtcgcctttccccctgggttttggatcactaattcaaggctcttctggatgtttc

3181 tctgggttggggctggagttcaatgaggtttatttttagctggcccacccagatacactc

3241 agccagaatacctagatttagtacccaaactcttcttagtctgaaatctgctggatttct

3301 ggcctaagggagaggctcccatccttcgttccccagccagcctaggacttcgaatgtgga

3361 gcctgaagatctaagatcctaacatgtacattttatgtaaatatgtgcatatttgtacat

3421 aaaatgatattctgtttttaaataaacagacaaaacttgaaaaa

Figure 2M. The cDNA (SEQ ID. NO. 26) and amino acid sequence (SEQ ID. NO. 27) of 191 P4D12(b) v.1 3. The

start methionine is underlined. The open reading frame extends from nucleic acid 264-1799 inclu ding the stop codon.

1 ggccgtcgttgttggccacagcgtgggaagcagctctgggggagctcggagctcccgatc

61 acggcttcttgggggtagctacggctgggtgtgtagaacggggccgggctggggctggg

121 tcccctagtggagacccaagtgcgagaggcaagaactctgcagcttcctgccttctgggt

181 cagttccttattcaagtctgcagccggctcccagggagatctcggtggaacttcagaaac

1 M P L S L G A E M WOG P E

241 gctgggcagtctgcctttcaCC ATGCCCCTGTCCCTGGGAGCCGAGAT3GGGGCCTG

14 A W L L L L L L L A S F T G R C P A G E

301 AGCCTGGCTGCTGCTGCTGCTACTGCTGGCATCATTTACAGCCGGTGCCCCGCGGGTG

34 L E T S D V V T V V L G Q D A K L P C F

361 AGCTGGAGACCTCAGACGTGGTAACTGTGGTGCTGGGCCAGGACGCAAACTGCCCTGCT

54 Y R G -D S G E Q V G Q V A W A R V D A G

25/77

421 TCTACCGAGGGGACTCCGGCGAGCAAGTGGGGCAAGTGGCATGGGCTCGGGTGGACGCGG

74 E G A Q E L A L L H S K Y G L H V S P A

00 481 GCGAAGGCGCCCAGGAACTAGCGCTACTGCACTCCAAATACGGGCTTCATGTGAGCCCGG

94 Y E G R V E Q P P P P R N P L D G S V L

541 CTTACGAGGGCCGCGTGGAGCAGCCGCCGCCCCCACGCAACCCCCTGGACGGCTCAGTGC

114 L R N A V Q A D E G E Y E C R V S T F P

601 TCCTGCGCAACGCAGTGCAGGCGGATGAGGGCGAGTACGAGTGCCGGGTCAGCACCTTCC

134 A G S F QA R L R LRV LV P P L P S L

661 CCGCCGGCAGCTTCCAGGCGCGGCTGCGGCTCCGAGTGCTGGTGCCTCCCCTGCCCTCAC

154 N P G P A L E E G Q G L T L A A S C T A

__721 TGAATCCTGGTCCAGCACTAGAAGAGGGCCAGGGCCTGACCCTGGCAGCCTCCTGCACAG

CI174 E G S PA P S V T W D T E VK G T T

781 CTGAGGGCAGCCCAGCCCCCAGCGTGACCTGGGACACGGAGGTCAAAGGCACAACGTCCA

00194 R S F KEH S R S A A VT S E F H L V P S

841 GCCGTTCCTTCAAGCACTCCCGCTCTGCTGCCGTCACCTCAGAGTTCCACTTGGTGCCTA

214 R S MN G Q P L T C V V S H P G L L Q D

901 GCCGCAGCATGAATGGGCAGCCACTGACTTGTGTGGTGTCCCATCCTGGCCTGCTCCAGG

234 Q R I T H I L H V S F L A E A S V R G L

961 ACCAAAGGATCACCCACATCCTCCACGTGTCCTTCCTTGCTGAGGCCTCTGTGAGGGGCC

254 E D Q N L W H I G R E G A M L K C L S E

1021 TTGAAGACCAAAATCTGTGGCACATTGGCAGAGAAGGAGCTATGCTCAAGTGCCTGAGTG

274 0 Q P P P S Y N W T R L D G P L P S G V

1081 AAGGGCAGCCCCCTCCCTCATACAACTGGACACGGCTGGATGGGCCTCTGCCCAGTGGGG

294 R V DG D T L G F P P L T T E H S GI Y

1141 TACGAGTGGATGGGGACACTTTGGGCTTTCCCCCACTGACCACTGAGCACAGCGGCATCT

314 V C H V S N E F S S R D S Q V T V D V L

1201 ACGTCTGCCATGTCAGCAATGAGTTCTCCTCAAGGGATTCTCAGGTCACTGTGGATGTTC

334 A D P Q E D S G K Q V D L V S A S V V V

1261 TTGCAGACCCCCAGGAAGACTCTGGGAAGCAGGTGGACCTAGTGTCAGCCTCGGTGGTGG

354 V G V I A A L L.F C L L V V V V V L M S

1321 TGGTGGGTGTGATCGCCGCACTCTTGTTCTGCCTTCTGTGGTGTGTGGTGCTCATGT

374 R Y H R R K A Q Q M T Q K Y E E E L T L

1381 CCCGATACCATCGGCGCAGGCCCAGCAGATGACCCAGATATGAGGAGGAGCTGACCC

394 T R E N S I R R L H S H H T D P R S Q P

1441 TGACCAGGGAGAACTCCATCCGGAGGCTGCATCCCATCCGACCCCAGGAGCCAGC

414 E E S V G L R A E G H P D S L K D N S S

1501- CGGAGGAGAGTGTAGGGCTGAGAGCCGAGGGCCACCCTGATAGTCTCAAGGACAACAGTA

434 C S V M S E E P E G R S Y S T L T T V R

1561 GCTGCTCTGTGATGAGTGAAGAGCCCGAGGGCCGCAGTTACTCCACGCTGACCACGGTGA

454 E I E T Q T E L L S P G S G R A E E E E

1621 GGGAGATAGAAACACAGACTGAACTGCTGTCTCCAGGCTCTGGGCGGGCCGAGGAGGAGG

474 D Q D E G I K Q A M N H F V Q E N G T L

26/77

1681 AAGATCAGGATGAAGGCATCAAACAGGCCATGAACCATTTTGTTC-AGGAG)aTGGGACCC

494 R A K P T G N G I Y I N G R G H L V

00 1741 TACGGGCCAAGCCCACGGGCAATGGCATCTACATCAATGGGCGGGGAAC( TGGTCTGAc

1801 ccaggcctgcctcccttccctaggcctggctccttctgttgacatgggagattttagctc

1861 atcttgggggcctccttaaacacccccatttcttgcggaagatgctccccaitcccactga

1921 ctgcttgacctttacctccaacccttctgttcatcgggagggctccaccaattgagtctc

1981 tcccaccatgcatgcaggtcactgtgtgtgtgcatgtgtgcctgtgtgagtgttg actga

2041 ctgtgtgtgtgtggaggggtgactgtccgtggaggggtgactgtgtccgtggtgtgtatt

2101 atgctgtcatatcagagtcaagtgaactgtggtgtatgtgccacgggatttgagtggttg

2161 cgtgggcaacactgtcagggtttggcgtgtgtgtcatgtggctgtgtgtgacctctgcct

2221 gaaaaagcaggtattttctcagaccccagagcagtattaatgatgcagaggttggaggag

2281 agaggtggagactgtggctcagacccaggtgtgcgggcatagctggagct~ggaatctgcc

2341 tccggtgtgagggaacctgtctcctaccacttcggagccatgggggcaagtgtgaagcag

(71 2401 ccagtccctgggtcagccagaggcttgaactgttacagaagccctctgccctctggtggc00

2461 ctctgggcctgctgcatgtacatattttctgtaaatatacatgcgccgggagcttcttgc

2521 aggaatactgctccgaatcacttttaatttttttcttttttttttcttgccctttccatt

2641 tgctcaggctggccttgaactcctgggctcaagcaatcctcctgcctcagcctccctagt

2701 agctgggactttaagtgtacaccactgtgcctgctttgaatcctttacgaagagaaaaaa

2761 aaaattaaagaaagcctttagatttatccaatgtttactactgggattgcttaaagtgag

2821 gcccctccaacaccagggggttaattcctgtgattgtgaaaggggctacttccaaggcat

2881 cttcatgcaggcagccccttgggagggcacctgagagctggtagagtctgaaattaggga

2941 tgtgagcctcgtggttactgagtaaggtaaaattgcatccaccattgtttgtgatacctt

3001 agggaattgcttggacctggtgacaagggctcctgttcaatagtggtgttggggagagag

3061 agagcagtgattatagaccgagagagtaggagttgaggtgaggtgaaggaggtgctgggg

3121 gtgagaatgtcgcctttccccctgggttttggatcactaattcaaggctC'ttctggatgt

3181 ttctctgggttggggctggagttcaatgaggtttatttttagctggccca.ccagataca

3241 ctcagccagaatacctagatttagtacccaaactcttcttagtctgaaat.ctgctggatt

3301 tctggcctaagggagaggctcccatccttcgttccccagccagcctaggacttcgaatgt

3361 ggagcctgaagatctaagatcctaacatgtacattttatgtaaatatgtgCcatatttgta

3421 cataaaatgatattctgtttttaaataaacagacaaaacttgaaaaa

Figure 2N. The cDNA (SEQ ID. NO.: 28) and amino acid sequence (SEQ ID. INO.: 29) of 191 P4DI2(b) v.14. The

start methionine is underlined. The open reading frame extends from nucleic acid 708-1121 including the stop codon.

1 gtctgacccaggcctgcctcccttccctaggcctggctccttctgttgac.atgggagatt

61 ttagctcatcttgggggcctccttaaacacccccatttcttgcggaagatgctccccatc

121 ccactgactgcttgacctttacctccaacccttctgttcatcgggaggg(.tccaccaatt

181 gagtctctcccaccatgcatgcaggtcactgtgtgtgtgcatgtgtgcctgtgtgagftgt

241 tgactgactgtgtgtgtgtggaggggtgactgtccgtggaggggtgactgtgtccgtggt

301 gtgtattatgctgtcatatcagagtcaagtgaactgtggtgtatgtgccaicgggatttga

361 gtggttgcgtgggcaacactgtcagggtttggcgtgtgtgtcatgtggctgtgtgtgacc

27/77

421 tctgcctgaaaaagcaggtattttctcagaccccagagcagtattaatgatgcagaggtt

481 ggaggagagaggtggagactgtggctcagacccaggtgtgcgggcatagctggagctgga

00 541 atctgcctccggtgtgagggaacctgtctcctaccacttcggagccatgggggcaagtgt

601 gaagcagccagtccctgggtcagccagaggcttgaactgttacagaagccctctgccctc

1 M R RE L

661 tggtggcctctgggcctgctgcatgtacatattttctgtaaatatacATGCGCCGGGAGC

6 L AG I LL R I T F N F F L F F F L P F

721 TTCTTGCAGGAATACTGCTCCGAATCACTTTTAATTTTTTTCTTTTTTTTTTCTTGCCCT

26 P L V V F F I Y F Y F Y F F L E M E S H

781 TTCCATTAGTTGTATTTTTTATTTATTTTTATTTTTATTTTTTTTTAGAGATGGAGTCTC

46 Y V A Q A G L E L L G S S N P P A S D S

841 ACTATGTTGCTCAGGCTGGCCTTGAACTCCTGGGCTCAAGCAATCCTCCTGCCTCAGACT

66 L VA G T L S V H H C A C F E S F T KR

00 901 CCCTAGTAGCTGGGACTTTAAGTGTACACCACTGTGCCTGCTTTGAATCCTTTACGAAGA

86 K K K L K K AF R F I Q C L L L G L L K

CI961 GAAAAAATTAAAGAAAGCCTTTAGATTTATCCAATGTTTACTACTGGGATTGCTTA

106 V R P L Q H Q G V N S C D C E R G Y F Q

1021 AAGTGAGGCCCCTCCAACACCAGGGGGTTAATTCCTGTGATTGTGAAAGGGGCTACTTCC

126 G I F M Q A A P W E G T

1081 AAGGCATCTTCATGCAGGCAGCCCCTTGGGAGGGCACCTGAgagctggtagagtctgaaa

1141 ttagggatgtgagcctcgtggttactgagtaaggtaaaattgcatccaccattgtttgtg

1201 ataccttagggaattgcttggacctggtgacaagggctcctgttcaatagtggtgttggg

1261 gagagagagagcagtgattatagaccgagagagtaggagttgaggtgaggtgaaggaggt

1321 gctgggggtgagaatgtcgcctttccccctgggttttggatcactaattcaaggctcttc

1381 tggatgtttctctgggttggggctggagttcaatgaggtttatttttagctggcccaccc

1441 agatacactcagccagaatacctagatttagtacccaaactcttcttagtctgaaatctg

1501 ctggatttctggcctaagggagaggctcccatccttcgttccccagccagcctaggactt

1561 cgaatgtggagcctgaagatctaagatcctaacatgtacattttatgtaaatatgtgcat

1621 atttgtacataaaatgatattctgtttttaaataaacagacaaaacttg

28/77

Figure 3:

Figure 3A. Amino acid sequence of 191P4D12(b) v.1 (SEQ ID. NO.: 30). The 191P4DI2(b) 0. clone W~ protein has 510 amino

acids.

1 MPLSLGAEMW GPEAWLLLLL LLLASFTGRCP AGELETSDVV TVVLGQDAKL PCFYRGDSGE

00

61

121

181

241.

QVGQVAWARV

DEGEYECRVS

VTWDTEVKGT

HVSFLAEASV

DAGEGAQELA~

TFPAGSFQAR

LLHSKYGLHV S PAYEGRVEQ

LRLRVLVPPL

TSSRSFKIISR SAAVTSEFHL

301 GFPPLTTEHS

361 PCLLVVVVVL

421 EGHPDSLKDN

RGLEDQNLWH

GIYVCHVSNE

MSRYHRRKAQ

SSCSVMSEEP

IGREGAMLKC

FS SRDSQVTV

QMTQKYEEEL

EGRSYSTLTT

PSLNPGPALE

VPSRSMNGQP

LSEGQPPPSY

DVLDPQEDSG

TLTRENS IRR

VRE IETQTEL

PPPPRNPLDG

EGQGLTLAAS

LTCVVSHPGL

NWTRLDGPLP

KQVDLVSASV

LHSHHTDPRS

LSPGSGRAEE

SVLLRNAVQA

CTAEGS PAPS

LQDQRITHIL

SGVRVDGDTL

VVVGVIAALL

QPEESVGLRA

EEDQDEGIKQ

481 AMNHFVQEMG TLRAKPTGNG IYINGRGHLV

Figure 3B. Amino acid sequence of 191 P4D1 2(b) v.2 (SEQ ID. NO. The 191 P4D1 2(b) v.2 protein has 5 10 amino acids.

1

61

121

181

241

301

361

421

MPLSLGAEMW

QVGQVAWARV

DEGEYECRVS

VTWDTEVKGT

HVSFLAEASV

GFPPLTTEHS

FCLLVVVVVL

EGHPDSLKDN

GPEAWLLLLL

DAGEGAQELA

TFPAGS FQAR

TSSRSFKHSR

RCLEDQbNLWH

GIYVCI4VSNE

MSRYHRRKAQ

SSCSVMSEEP

LLASFTGRCP AGELETSDVV

LLHSKYGLHV

LRLRVLVPPL

SAAVTSEFHL

IGREGAMLKC

FS SRD SQVT V

QMTQKYEEEL

EGRSYSTLTT

SPAYEGRVEQ

P SLNPG PALE

VPSRSMNGQP

LSEGQPPPSY

DVLDPQEDSG

TLTREWS IRR

VRE IETQTEL

TVVLGQDAKL

PPPPRNPLDG

EGQGLTLAAS

LTC'VVSHPGL

NWTRLDGPLP

KQVIDLVSASV

LHSHHTDPRS

LS PGSGRAEE

PCLYRGDSGE

SVLLRNAVQA

CTAEGSPAPS

LQDQRITHIL

SGVRVDGDTL

VVVGVIAALL

QPEESVGLRA

EEDQDEGI KQ

481 AMvNHFVQENG TLRAKPTGNG IYINGRGHLV

Figure 3C. Amino acid sequence of 191 P4D12(b) v.6 (SEQ ID. NO. 32). The 191P4D12(b) v.6 protein has 295 amino acids.

1 MNGQPLTCWV SHPGLLQDQR ITHILHVSFL AEASVRGLED QNLWHIGREG AMLKCLSEGQ

61 PPPSYNWTRL DGPLPSGVRV DGDTLGFPPL TTEHSGIYVC I{VSNEFSSRD SQVTVDVLDP

121 QEDSGKQVDL VSASVVVVGV IAALLFCLLV VVVVLMSRYH RRICAQQMTQK YEEELTLTRE

181 NSIRRLHSHH TDPRSQPEES VGLRAEGEPD SLKDNSSCSV MSEEPEGRSY STLTTVREIE

241 TQTELLSPGS GRAEEEEDQD EGIKQAMNHF VQENGTLRAK PTGNqGIYING RGHLV

Figure 31). Amino acid sequence of 191 P4D12(b) v.7 (SEQ ID. NO. The 191 P4D1 2(b) v.7 protein has 485 amino acids.

1 MPLSLGAEMW GPEAWLLLLL LLASFTGRCP AGELETSDVV TVVLGQDAKL PCFYRGDSGE

61 QVGQVAW.ARV DAGEGAQELA LLHSKYGLHV SPAYEGRVEQ PPPPRINPLDG SVLLR.NAVQA

121 DEGEYECRVS TFPAGSFQA. LRLRVLVPPL PSLNPGPALE EGQGLTLAAS CTAEGSPAPS

29177

00

181 V'TWDTEVKGT TSSRSFKHSR SAAVTSEFHL VPSRSMNGQP LTCVVSHPGL

241 HVSFLAEASV RGLEDQNLWH IGREGAMLKC LSEGQPPPSY NWTRLDGPLP

301 GFPPLTTEHS GIYVCH-VSNE FSSRDSQVTV DVLDPQEDSG KQVDLVSASV

361 FCLLVVVVVL MSRYHRRKAQ QMTQKYEEEL TLTREUSIRR LHSH-TDPRS

421 STLTTVREIE TQTELLSPGS GRAEEEEDQD EGIKQANNHF VQENGTLRAK

481 RGHLV

LQDQRITHIL

SGVRVDGDTL

VVVGVIAALL

QSEEPEGRSY

PTGNGIYING

Figure 3E. Amino acid sequence of 191130D12(b) v.10 (SEQ ID. NO.: 34). The 191P4D12(b) 0.0 protein has 510 amino acids.

61

121

1181

241

301

361

421

481

MPLSLGAEMW

QVGQVAWARV

DEGEYECRVS

VTWDTEVKGT

HYS FJAEASV

GFPPLTTEHS

FCLLVVXTVVL

EGHPDSLKDN

AMVNHFVQENG

GPEAWLLLLL

DAGEGAQELA

TFPAGSFQAR

TSSRSFKHSR

RGLEDQNLWH

GIYVCHVSNE

MSRYHRRKAQ

SSCSVMSEEP

TLR-AKPTGNG

LLASFTGRCP

LLHSKYGLHV

LRLRVLVPPL

SAAVTSEFHL

IGREGAMLKC

FS SRDSQVTV

QMTQKYEEEL

EGRSYSTLTT

TYTNGRGHLjV

AGELGTSDVV

S PAYEGRVEQ

PSLNPGPALE

VPSRSMNGQP

LSEGQPPPSY

DVLDPQEDSG

TLTRENS IRR

VREIETQTEL

TVVLGQDAKL

PPPPRNPLDG

EGQGLTLAAS

LTCVVSHPGL

NWTRLDGPLP

KQVDLVSASV

LHSHHTDPRS

LSPGSGRAEE

PCFYRGDSGE

SVLLRNAVQA

CTAEGS PAPS

LQDQRITHIL

SGVRVDGDTL

VVVGVIAALL

QPEESVGLRA

EEDQDEGIKQ

Figure 3F. Amino acid sequence of 191P4Dl2(b) v.11 (SEQ ID. NO.: 35). The 191P4D12(b) v.11 protein has 510 amino acids.

1 MPLSLGAEMW GPEAWLLLLL LLASFTGRCP AGELETSDVV TVVLGQDAKL PCFYRGDSGE

*61

121

181

241

301

361

421

481

QVGQVAWARV

DEGEYECRVS

VTWDTEVKGT

HVSFLAEASV

GFPPLTTEHS

FCLLVVVVVL

EGHPDSLKDN

AMNHFVQENG

DAGEGAQELA

TFPAGSFQAR

TSSRSFKHSR

RGLEDQNLWH

GIYVCHVSNE

MSRYHRRKAQ

SSCSVMSEEP

TLRAKPTGNG

LLHSKYGLIV

LRLRVMVPPL

SAAVTSEFHL

IGREGAMLKC

FS SRDSQVTV

QMTQKYEEEL

EGRSYSTLTT

IYINGRGHLV

S PAYEGRVEQ

PSLNPGPALE

VPSRSMNGQP

LSEGQPPPSY

DVLDPQEDSG

TLTRENS IRR

VREIETQTEL

PPPPRNPLDG

EGQGLTLAAS

LTCVVSHPGL

NWTRLDGPLP

KQVDLVSASV

LHSHHTDPRS

LS PGSGRAEE

SVLLRNAVQA

CTAEGS PAPS

LQDQRITHIL

SGVRVDGDTL

VVVGVIAAL 2

QPEESVGLRA

EEDQDEGI KQ

Figure 3G. Amino acid sequence of 1911341)12(b) v.12 (SEQ ID. NO. 36). The 191P4D12(b) v.12 protein has 510 amino acids.

1

61

121

181

241

301

MPLSLGAEMW

QVGQVAWARV

DEGEYECRVS

VTWDTEVKGT

HVS FLAEASV

GFPPLTTEHS

GPEAWLLLLL

DAGEGAQELA

TFPAGSFQAR

TSSRSFKHSR

RGLEDQNLWH

GIYVCHVSNE

LLAS FTGRCP

LLHS KYGLHV

LRLRVLVPPL

SAAVTSEFH-L

IGIZEGAMLKC

FSSRDSQVTV

AGELETSDVV

S PAYEGRVEQ

PSLNPGPALE

VP SRSMNGQ P

LSEGQPPPSY

DVLDPQEDSG

TVVLGQDAKL

PPPPRNPLDG

EGQGLTLAAS

LTCVVSHPGL

NWTRLDGPLP

KQVDLVSASV

PCFYRGDSGE

SVLLRNAVQA

CTAEGS PAPS

LQDQRITHIL

SGVRVDGDTL

VVVGVIAALL

30/77

361 FCLLVVVVVL MSRYHRRKAQ QMTQKYEEEL TLTRENSIRR LHSHHTDPRS QPEESVGLRA

421 EGHPDSLKDN SSCSVMSEEP EGCSYSTLTT VREIETQTEL LSPGSGRAEE EEDQDEGIKQ

481 AMVNHFVQENG TLRAIKPTGNG IYINGRGHLV

Figure 3H. Amino acid sequence of 191P412(b) v.13 clone 9C (SEQ ID. NO.: 37). The 191P4D12(b) 0.3 protein has 511

amino acids.

00

6

12

18

24

36

1 MPLSLGAEMW

1 QVGQVAWARV

:1 DEGEYECRVS

1 VTWDTEVKGT

:1 HVSFLAEASV

~1 GFPPLTTEHS

I LFCLLVVVVV

~1 AEGHPDSLKD

GPEAWLLLLL

DAGEGAQELA

TFPAGSFQAR

TSSRSFKHSR

RGLEDQNLWH

GIYVCHVSNE

LMSRYHRP.KA

NSSCSVMSEE

LLASFTGRCP

LLHSKYGLHV

LRLRVLVPPL

SAAVTSEFHL

IGREGAMLKC

FS SRDSQVTV

QQMTQKYEEE

PEGRSYSTLT

AGELETSDVV

S PAYEGRVEQ

PSLNPGPALE

VPSRSMNGQP

LSEGQPPPSY

DVLADPQEDS

LTLTRENSI R

TV\/LGQDAKL

PPEPPRNPLDG

EGQGLTLAAS

LTCVVSHPGL

NWTIRLDGPLP

GKQVDLVSAS

RLI{SHH-TDPR

PCFYRGDSGE

SVLLRNAVQA

CTAEGS PAPS

LQDQRITHIL

SGVRVDGDTL

VVVVGVIAAL

SQPEESVGLR

EEEDQDEGIKMVREIETQTE LLSPGSGRAE

481 QAMNHFVQEN GTLRAKPTGN~ GIYINGRGHL V

Figure 31. Amino acid sequence of 19112012(b) v.9 clone BCPI (SEQ ID. NO.: 38). The 191P4D12(b) v.9 protein has 137

amino acids.

1 MRRELLAGIL LRITFNFFLF FFLPFPLVVF FIYFYFYFFL EMESHYVAQA GLELLGSSNP

61 PASASLVAGT LSVHHCACFE SFTKRKKKLK KAFRFIQCLL LGLLKVRPLQ HQGVNSCDCE

121 RGYFQGIFMQ AAPWEGT

Figure UJ Amino acid sequence of 191P4D12(b) v.14 (SEQ ID. NO. 39). The 191P4D12(b) v.14 protein has 137 amino acids.

1 MRRELLAGIL LRITFNFFLF FFLPFPLVVF FIYFYFYFFL EMESHYVAQA GLELLGSSNP

61 PASDSLVAGT LSVKHCACFE SFTKRKKKLK KAFRFIQCLL LGLLKVRPLQ HQGVNSCDCE

121 RGYFQGIFMQ AAPWEGT

31/77

Figure 4: Alignment of 191M412(b) witfi known homologs.

A) Alignment of 191 P401 2(b) (SEQ ID NO: 40) with human Ig superfamily receptor LNIR (gi 14714574) (SEQ ID NO: 41)00 Score 927 bits (2397), Expect 0.0

Identities 510/51.0 (100%) Positives 510/510 (100%)

Query: 1 MPLSLGAEMWGPEAWLLLLLLiASFTGRCPAGELETSDVVTVVGQDAKjPCFYRGDSGE MPLSLGAEMWGPEAWLLLLLLLASFTGRCPAGELETSDVVTVVLjGQDAKLPCFYRGDSGE

SSbj ct: 1 MPLSLGAEMWGPEAWLLLLLLLASFTGRCPAGELETSDVVTVVLGQDAKLPCFYRGDSGE

S Query: 61 QVGQVAWARVDAGEGAQELALLHSKYGLHVSPAYEGRVEQPPPPRNPLjDGSVLLRNAVQA 120QVGQVAWARVDAGEGAQELALLHSKYGLHVSPAYEGRVEQPPPPRNPLDGSVLLRNAVQA

S Sbj ct: 61 QVGQVAWARVDAGEGAQELAJLHSKYGLHV8PAYEGRVEQPPP PRNPLDGSVLLRNAVQA 120

Query: 121 DEGEYECRVSTFPAGSFQAFJJRLRVLVPPLPSLNPGPALEEGQGLTLAASCTAEGSPAPS 180DEGEYECRVSTFPAGSFQARLRLRVLVPPLPSLNPGPAJEEGQGLTLAASCTAEGSPAPS

Sbj ct: 121 DEGEYECRVSTFPAGSFQARLRLRVLVPPLPSLNPGPAJEEGQGLTLAASCTAEGSPAPS 180

S Query: 181 VTWDTEVKGTTSSRSFKHSRSAVTSEFHLVPSRSMNGQPLTCVVSHPGLLQDQRITHIL 240VTWDTEVKGTTSSRSFKHSRSAAVTSEFHLVPSRSMNGQPLTCVVSHPGLLQDQRITHIL

S Sbjct: 181 VTWDTEVKGTTSSRSFKHSRSAAVTSEFHLVPSRSMNGQPLTCVVSHPGLLQDQRITHIL 240

OC) Query: 241 HVSFLAEASVRGLEDQNLWHIGRE3AMLKCLSEGQPPPSYNWTRLDGPLPSGVRVDGDTL 300HVS FLAEASVRGLEDQNLWHIGREGAMLKCLSEGQPPPSYNWTRLDGPLPSGVRVDGDTL

S Sbj ct: 241 HVS FLAEASVRGbEDQNLWHIGREGAMLjKCLSEGQPPPSYNWTRLDGPLPSGVRVDGDTL 300

Query: 301 GFPPLTTEHSGIYVCHVSNEFSSRDSQVTVDVLDPQEDSGKQVDLVSASVVVVGVIAALL 360GFPPLTTEHSGIYVCHVSNEFSSRDSQVTVDVLJ)PQEDSGKQVDLVSASVVVVGVIAALL

Sbjct: 301 GFPPLTTEHSGIYVCHVSNEFSSRDSQVTVDVLDPQEDSGKQVDLVSASVVVVGVIAAJL 360

Query: 361 FCLLVVVVVLMSRYHRRKAQQMTQKYEEELTLTRENSIRRLHSHIITDPRsQPEESVGLRA 420FCLLVVVVVLMSRYHRRKAQQMTQKYEEELTLTRENSIRRLHSHHTDPRSQPEESVGLRA

sbj Ct: 361 FCLLW /VVLMSRYHRRKAQQMTQKYEEELTLTRENSIRRLHSHHTDPRSQPEESVGLRA 420

Query: 421 EGHPDSLKDNSSCSVMSEEPEGRSYSTLTTVREIETQTELLSPGSGRAEEEEDQDEGIKQ 480EGHPDSLKDNSSCSVMSEEPEGRSYSTLTTVREIETQTELLSPGSGRAEEEEDQDEGIKQ

Sbjct: 421 EGHPDSLKDNSSCSVMSEEPEGRSYSTLTTVREIETQTELLSPGSGRAEEEEDQDEGIKQ 480

Query: 481 AMNHFVQENJGTLRAKPTGNGIYINGRGHIJV 510AMNHFVQENGTLRAKPTGNGIYINGRGHLV

Sbjct: 481 AMNHFVQEN'GTLRA1CPTGNGIYINGRGHLjV 510

B) Alignment of 191 P4D1 2(b) (SEQ ID NO: 42) with mouse nectin 4 (gi 18874521) (SEQ ID NO: 43).Score 893 bits (2308), Expect 0.0Identities 470/510 Positives =485/510 Gaps 2/510

Query: 1 MPLSLGAEMWGPEAWLLLLLLASFTGRCPAGEL'rSDVVTVVLGQDAKLIPCFYRGDSGE MPLSLGAEMWGPEAW L LL LASFTG+ AGELETSDVVTVVLGQDAKLPCFYRGD E

Sbj ct: 1 MPLSLGAEMWGPEAW-LRLLFLASFTGQYSAGELETSDVVTVVLGQDAKZPCFYRGDPDE 59

Query: 61 QVGQVAWARVDAGEGAQELALLHiSKYGLHVSPAYEGRVEQPPPPRNPLDGSVLLNAVQA 120QVGQVAWARVD EG +ELALLHSKYGIJHV+PAYE RVEQPPPPR+PLDGSVLLRNAVQA

Sbj Ct: 60 QVGQVAWARVDPNEGIRELALLHSKYGLHVN1PAYEDRVEQPPPPRDPLDGSVLL.NAVQA 119

Query: 121 DEGEYECRVSTFPAGSFQARIIRIRVLVPPLPSLNPGPALEEGQGLTLAASCTAEGSPAPS 180DEGEYECRVSTFPAGSFQAR+RLRVLVPPLPSLNPGP LEEGQGLTLA1ASCTAEGSPAPS

Sbj Ct: 120 DEGEYECRVSTFPAGSFQARMRIRVLVPPLPSIMPGPPLEEGQGLTLA CTAEGSPAPS 179

Query: 181 VTWDTEVKGTTSSRSFKHSRSAAVTSEFHLVPSRSMNGQPLTCVVSHPGLLQDQRITHIL 240VTWDTEVKGT SSRSF H RSAAV'2SEFHLVPSRSMNGQPLTCVVSHPGLLQD+RITH L

Sbj ct: 180 VTWDTEVKGTQSSRSFTHPRSAAVTSEFHLVPSRSMNGQPLTCVVSHPGLJQDRRITHTL 239

Query: 241 HVSFLAEASVRGLEDQNLWHIGREGAMLKCLSEGQPPPSYNWTRLDGPLPSGVRVDGDTL 300V+FLAEASVRGLEDQNLW +GREGA LKCLSEGQPPP YNWTRLDGPLPSGVRV GDTL

Sbj ct: 240 QVAFLAEASVRGLEDQNLWQVGREGATLKCLSEGQPPPKYNWTRLDGPLPSGVRVKGDTh 299

Query: 301 GFPPLTTEHSGIYVCHVSNEFSSRDSQVTVDVLDPQEDSGKQVDLVSASVVVGVIAALL 360GFPPLTTEHSG+.YVCHVSNE SSRDSQVTV+VLDP ED GKQVDLVSASV++VGVIAAILL

Sbjct: 300 GFPPIJTTEHSGVYVCHVSNELSSRDSQVTVEVLDP-ED)PGKVDLVSASVIIVG;VIAALL 358

32/77

Query: 361 FCLLWVVVVLMSRYHRRKAQQMTQKYEEELTLTRENSIRRLHSHHTDPRSQPEESVGLRA 420FCLLVVVVVLMSRYHRRKAOQMTQKYEEELTLTRENS IRRL1HSHI{+DPRSQPEESVGLRA

Sbjct: 359 FCLLVVVVVLMSRYHRRKAQOMTQKYEEELTLTRENSIRRLHSH{SDPRSQPEESVGLRA 418

Query:

sbj ct:

421 EGHPDSLKDNSSCSVMSEEPEGRSYSTLTTVREIETQTELLSPGSGRAEEEEDQDEGIKQ 480EGHPDSLKDNSSCSVMSEEPEGRSYSTLTTVREIETQTELLSPGSGR EE++DQDEGIKQ

419 EGMPDSLKDNSSCSVMSEEPEGRSYSTLTTVREIETQTELLSPGSGRTEEDDDQDEGIKQ 478

Query: 481

Sbjct: 479

AMNHFVQENGTLRAKPTGNGIYINGRG3HLV 510AMNHI*VQENGTLRAKPTGNGIYINGRGHLVAMNHFVQENGTLRAKPTGNGIYINGRGHLV 508

33/77

00 ~Figure 5a: 191 P4D1 2B variant 1 Hydrophilicity profile(Hopp Woods 1981. Proc.

Nati. Acad. Sci. U.S.A. 78:3824-3828)

0.9 ________ProtScale output for user sequence

c-I phob. M pp 8~Wood

0.7

0.6

0.5

0.4

0.3

8.20 100 200 300 400 500

Position

34/77

00 Figure 5b: 191 P4DI2B variant 7 Hydrophilicity profile(Hopp Woods 1981. Proc.Nati. Acad. Sci. U.S.A. 78:3824-3828)

ProtScale output for user sequence0.9

Hphok. 'Hopp Wood-

c01 .8 00

0.7

0.6

0

0.

0.4

0.3

0.2

188 159 200 250 380 359 0 4 Position

35/77

Figure 5c: 191 P4D1 2B variant 9 Hydrophilicity profile(Hopp Woods 1981. Proc.Nati. Acad. Sci. U.S.A. 78:3824-3828)

00

ProtSoale output for user sequence

Hphob Hopp cods-

Posit ion

36/77

00Figure 6a: 191 P4DI 2B variant 1 Hydropathicity Profile

(Kyte Doolittle 1982. J. Mol. Biol. 157:105-132)

ProtScale output for user sequence

Hphob. /Kyte Doolittle

Position

37/77

00

Figure 6b: 191 P4DI 2B variant 7 Hydropathicity Profile(Kyte Doolittle 1982. J. Mol. Biol. 157:105-1 32)

ProtSoale output f or user sequence

Nphob. /Kyte Uoolittle-

100 150 200 250Position

300 350 400 450

38/77

Figure 6c: 191 P4DI 2B variant 9 Hydropathicity Profile(Kyte Doolittle 1982. J. Mol. Biol. 157:105-132)

ProtSoale output for user sequenoe

Hphob. e Doolittle-

0.700

0.6

0.4

0.3

8.2-

0.1 40 68 80 100 120

Position

39/77

Figure 7a: 191 P4D1 2B variant 1 Accessible Residues Profile(Janin 1979. Nature 277:491-492)

00

0.

0.7

0.65

0.6

0.55

0.45

0.4

0.35

0.3

ProtScale output for user sequence

accessikle r sidues

Position

40/77

00

Figure 7b: 191 P4DI 2B variant 7 Accessible Residues Profile(Janin 1979. Nature 277:491-492)

0.75

0.7

0.65

0.55

ProtSoale 6utput for user sequence

accessible residues-

Ir

0.35

8.3100 158 288 258

Position300 358 400 450

41/77

00

Figure 7c: 191 P41DI12B variant 9 Accessible Residues Profile(Janin 1979. Nature 277:49.1-492)

ProtSoale output for user sequence

accessible residues-

Position

42/77

00 Figure 8a: 191 P4D1 2B variant 1Average Flexibility Profile

(Bhaskaran Ponnuswamy 1988.Int. J. Pept. Protein Res. 32:242-255)

Pr'otScale output for user sequenoe

Average flexibility

0.7

0.6

0.3

0.20 108 200 300. 406 Soo

Position

43/77

00 Figure 8b: 191 P4DI12B variant 7Average Flexibility Profile

(Bhaskaran Ponnuswamy 1988.Int. J. Pept. Protein Res.- 32:242-255)

ProtSoale output f or user sequenoe

0 15eIS 200 250 300 350 400 450Position

44/77

00 Figure 8c: 191 P4DI 2B variant 9Average Flexibility Profile

(Bhaskaran Ponnuswamy 1988.Int. J. Pept. Protein Res. 32:242-255)

ProtScale output for user sequence

Ave age fle

00

0.6

0

0.4

0.3A

0.2

40 60 80 tooPosition

45/77

Figure 9a: 191 P4D1 2B variant 1Beta-turn Profile

(Deleage, Roux B. 1987. Protein Engineering 1:289-294)

ProtSoale output for user sequence

beia-turn .'De eage Roux

Posit ion

46/77

00

Figure 9b: 191 P4DI 2B variant 7Beta-turn Profile

(Deleage, Roux B. 1987. Protein Engineering 1:289-294)

ProtSoale output for user sequence

so 100 150 200 250 300, 350 400 450Position

47/77

Figure 9c: 191 P4DI 2B variant 9Beta-turn Profile

(Deleage, Roux B. 1987. Protein Engineering 1:289-294)

0.7

0.65

0.6

0.55

0.45

0.4

0.35

0.3

8.25

ProtScale ou-tput for user sequence

beta-turn Deleage &Roux

Position

48/77

00

Figure

367 420 699A T C

1590C

2184 2341G G

2688C191 P4 1 2B v. 1

3464 bp1 3464

420C191 P4D1 2B v.2 1

3464 bpI

191P4D12B v031

3464 bp

3464

2184

T 3464

2341

191P4D12B v.43464 bp

1 3464

2688A 3464

191P4D12B v3464 bp

a

367

191P4Dl2B vM13464 bp

1 3464

49/77

Figure 10 (con'd)

699A 3464191 P4D1 2B v. 111

3464 bp

1590

191P4D12B v.12 1 3464

3464 bp

1263-1265

3467 bpI

191 P4DI2B v.14

3467

1669898A

(1791) (3459:

Figure 10. Schematic alignment of SNP variants of 191 P4DI2B.

50/77

00

Figure 11

5I91P4D12B v.1 1 E F

510 aa

146L

443R 510

191 P4D1 2B v.2510 aa

191 P4DI 2B v.6295 aa

531 L 510

295

(216) (510)

191 P4D 12B v.7485 aa

191 P401 2B v.1 0510 aa

19 1P4D12B v.1 1510 aa

1 411 412 485

1)(411) (437) (510)

IG 5

146511

51/77

00 Figure 11 (con'd)

443

191 P4D12B v.12510 aa

1 510

334

191 P4D12B v.13511 aa

641 A 137191P4D12B v.9

137 aa

191P4D12B.v.14137 aa DZZZ

Figure 11. Schematic alignment of protein variants of 191 P4DI 2B.

52/77

2008202217 20 May 2008

Figure 12

191P4D12B v.13459 bp

191P4D12B v.63339 bp

191P4D12B v.73384 bp

1 342 702

1 197 2 2

(17) (318)

1 342 702

m

993

873

1114 1263 1420 1496 1571

94 13 13 00 13 76 51-Im I

3459

3339

1114 1263 1420 146 3384

Em

(1496) (1572)

1263 1420 1496 1571191P4D12B v.83396 bp

342 702 993 1114

m J m

2950 3396

(290) (3014)

1669

191P4D12B v.91669 bp (141)

191P4D12BPotential exons 3 B-D E E3 B A,

2008202217 20 May 2008Fig: 13A Secondary structure. prediction of 191 P4DI 2B variant 1

20 30 40 50 60

MPLSLGAEMWGPEAWLLLLLLLASFTGRCPAGELETSDVVTVVLGQDAKLPCFYRGDSGEQVGQVAWARV

ccccccccccchhhhhhhhhhhhhhcccccccceccceeeeeeecccccceeeecccccchhhhhhhhhc

DAGEGAQELALLHSKYGLHVSPAYEGRVEQPPPPRNPLDGSVLLRNAVQADEGEYECRVSTFPAGS FQAR

ccccchhhhhhhhhhcccceccccccccccccccccccccceehhhhhccccccceeeeecccccchhhh

LRLRVLVPPLPSLNPGPALEEGQGLTLAASCTAEGSPAPSVTWDTEVKGTTS SRS FKHSRSAAVTSEFHL

heeeeecccccccccccccccccceeeeeecccccccccccccccccccccccccccccccceeecceee

VPSRSMI'GQPLTCVVSHPGLLQDQRITHILHVS FLAEASVRGLEDQNLWHIGREGAMLKCLSEGQPPPSY

cccccccccceeeeeeccccccchhhhhhehhhhhhhhhhcccccccheehhccchehehhccccccccc

NWTRLDGPLPSGVRVDGDTLGFPPLTTEHSGIYVCHVSNEFSSRlSQVTVDVLDPQEDSGKQVDLVSASV

cccccccccccccccccccccccccccccceeeeeeeccccccccceeeeeecccccccccceeeeeeeh

VVVGVIAALLFCTJLVVVVVLMSRYHRRKAQQMTQKYEEELTLTREN IRRLHSHH=DPRSQPEESVGLRA

hhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhcccchhhhhhhcccccccccccc ccecc

EGHPDSLKDNSSCSVMSEEPEGRSYSTLITVRB IETQTELLSPGSGRAEEEEDQDEGIKQAMNHFVQENG

ccccccccccccceeeccccccccceeeeeeeeeeccceeccccccccccccchhhhhhhhhhheeeccc

TLRAKPTGNGIYINGRGHLV

ceeeccccceeeeecccccc

Alpha helix 24.90%Extended strand 18.63%Random coil 56.47%

2008202217 20 May 2008

138 Secondary structure prediction of 191 P4DI 2B variant 6

20 30 40 50 60

1 *I I I I I I

cccccccccccccccCCCCCC CCeeeeeeeccccccccceeeeeecccccccccceeeehhh

IAALLFCLLVVVVVLMSRYRRKAQQMTQKEELTLES IRRLHSHHTDPRSQPEESVGLRAEGHPD

hhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhcccchhhcccccccccccccceccccccc

SLKDNSSCSVNSEEPEGRSYSTLTTVREIETQTELLS PGSGRAEEEEDQDEGIKAHVQGTLRAK

ccccccceeeccccccccceeeeeeeeeeccceeccccccccccccchhhh~eeccec

PTGNGIYINGRGHLV

cccceeeeecccccc

Alpha helix 28.47%Extended Strand 19.32%Random coil :52.20%

2008202217 20 May 2008

13C Secondary structure prediction of 191 P4DI-2B variant 720 30 40 so 60

1 1 1 1 1 1 IMPLSLGAEMWGPEAWLLLLLLLAS FTGRCPAGELETSDVVTVVLGQDAKLPCFYRGDSGEQVGQVAWARV

ccccccccccchhhhhhhhhhhhhhcccccccceccceeeeeeecccccceeeecccccchhhhhhhhhc

DAGEGAQELAILLHSKYGLEVSPAYEGRVEQPPPPRNPLDGSVLLRNAVQAflEGEYECRVSTFPAGSFQAR

ccccchhhhhhhhhhcccceccccccccccccccccccccceehhhhhccc~ccceeeeecccccchblhh

LRLRVLVPPLPSLNPGPAJEEGQGLThAASCTAEGS PAPSVTWDTEVKGTTS SRS FKHSRSAAVTSEFHL

heeeeecccccccccccccccccceeeeeeccccccccccccccccccccccccccccccceeecceee

VPSRSMNGQPLTCVVSHPGLLQDQRITHILIVSFLAEASVRGLEDQNLWHIGREGAMLKCLSEGQPPPSY

cccccccccceeeeeeccccccchhhhhhehhhhhhhhhhcccccccheehhccchehehhccccccccc

Zi NWTRILDGPLPSGVRVDGDTIGFPPLTTEHSGIYVCHVSNBFS SRDSQVTVDVLDPQEDSGKQVDLVSASV

cccccccccccccccccccccccccccccceeeeeeeccccccccceeeeeecccccccccceeeeeeeh

VVVGVIAA.LLFCLLVVVVVIJMSRYKPRKAQQMTQKYEEELTLTRENS IRRLHSHHTDPRSQSEEPEGRSY

hhhhhh -hhh~~hhhhhhhhhhhhhhhhhhhhhcccchhhhhhhccccccccccccccccc

STLTTREIETQTELLSPGSGRAEEEEDQDEGIKQAMN{FVQENGTLRAKPTGNGIYINGRGHLV

eeeeeeeeeeccceeccccccccccccchhhhhhhhhheeecccceeeccccceeeeecccccc

Alpha helix 26.19%Extended strand 18.76%Random coil :55.05%

2008202217 20 May 2008

13D Secondary structure prediction of 191 P4DI2B variant 9

20 30 40 50 60

1 1 1 1 1 1IMRELLAGILLRITFNFFLFFFLPFPLVVFFIYFYFYFFLEMESFIVAQAGLELLGSSNPPASASLVAGT

chhhhhhhhhhhhhll~hChblhchhhhhhhhhhhhhhhhlI11cchhhccccccccccheeccc

ceeccchehhhhhhhhhhhhhhhhhhhhhhhheeeccccccccccccccccchhheeeeccccccc

Alpha helix 56.20%Extended strand 8.76%Random coil 35.04%

2008202217 20 May 2008Transmembrane preuiction TorFi v Ir~u-i A varint i13E

rMpr- r dfkfl-f

1 transmembrane domairpredicted

020

3000

0000

1 000

1000

-2000

-3000

-5000

-0000.

TMHMM posterior probabilities for Sequenoe

13F

1 transmembrane domainpredicted

a102030 400 500

Predicted to reside inside

Transmembrane domain

2008202217 20 May 2008

Transmembrane prediction for 191 P4DI 2B variant 6VHW_.

13G

1 transmembrane dcpredicted

)mainC CCC

1 C C C

1 0CC

C CCC

-SC CC

C CCC

C CC ICC ICCe C CBC C

0 ftme me.

Transmembrane domain

TM HMM posterior probabilities for Sequence

13H

1 transmembrane domain predicted

100

Predicted to reside outside

150 200 250

STransmembrane domain

2008202217 20 May 2008Transmembrane preaiction Tor iui r'iuuis variant 131

1 transmembrane, d=mpredicted

in

Y~pr-ed r--pt~ -ke .dll...

-too:

30000

L OGo

Transmembrane domain

13J

1 transmembrane domepredicted

TMAHMM posterior probabilities for Sequence

100 150 200 250 300 350 400 450

Predicted to reside outside Predicted to reside insideTransmembrane domain

13K

2 transmembrane domairpredicted

13L

I transmembrane domairpredicted

2008202217 20 May 2008

rransmembrane prediction for 191 P4DI 2B- variant 9T"P_0 MUrtpWtV r- -k-w"f~f

3000

IM000

L 0 0 6

Transmembrane domains

TMHMM posterior probabilities for Sequence

4 0 60 80 100 120

Predicted to reside outside Peitdt eieisd

Transmembrane domain

2008202217 20 May 2008

Figure 14A 191 P4D12 Expression by RT-PCR

M1 234 56789

1. Vital Pool 1

2. Vital Pool 2 26X

3. Normal kidney4. Prostate Cancer Pool

Bladder cancer pool

6. Colon Cancer Pool7. Lung Cancer Pool I8. Breast Cancer Pool

9. Metastasis Cancer Pool

2008202217 20 May 2008

Figure 14B

1 2 3 4 5 6 7 8 9 10 11

191P4D12

B-Actin

Prostate cancer pool

Bladder cancer pool

Kidney cancer pool

Colon cancer pool

Lung cancer pool

Ovary cancer pool

26X

Ovary cancer pool

Breast cancer pool

Metastasis pool

Pancreas cancer pool

LAPC prostate cancer xenografts

2008202217 20 May 2008

Figure 15 191P4D12 Expression in Normal Tissues

kb 12 3 4 5 6 7 8 kb 12 3 4 5 6 7 8

4.4- 4.4-

2.4-2.4-

1.4- 1.4-

0.24-0.24-

1. Heart2. Brain3. Placenta4. Lung

Liver6. Skeletal Muscle7. Kidney8. Pancreas

1. Spleen2. Thymus3. Prostate4. Testis5. Uterus6. Small Intestine7. Colon8. Leukocytes

2008202217 20 May 2008

Figure 16 Expression of 191P4D12 in Bladder Cancer Patient

Specimens and in-Normal Tissues

kb BCP NP NB NK NC NL NBr NO NPa

BCP Bladder cancer pool: Pool of 3 differentbladder cancer specimens

4.4- NP normal prostateNB normal bladderNK normal kidney

1.4- pNC normal colonNL normal lungNBr normal breast

NO normal ovaryNPa normal pancreas

2008202217 20 May 2008

Fiqure 17 Expression of-191P4D12 in Bladder CancerPatient Specimens

kb CL CL CL CL N T1 T2 T3 T4

Ti Invasive transitional papillary, grade 2

4.4- T2 Transitional papillary, grade 2

T3 Transitional, grade 3

2. T4 Poorly diff. Transitional

1.4 T5 Mod. to poorly diff. Squamous cell

CL Cell lines (from left to right): HT1197, UM-U3, TCCSUP, J82

N Normal BladderT Tumor

2008202217 20 May 2008

Figure 18 191P4D12 Expression inProstate Cancer Xenografts

kb 1 2 3 4

1 Normal Prostate

2.4 2. LAPC-4AD3. LAPC-4AI

1.4 LAPC-9ADLAPC-9AI

0.24-

2008202217 20 May 2008

Figure 19 191P4D12 Expression in Cervical CancerPatient Specimens

kb

4.4-

2.4-

1.4-

1 2 3 4

Normal CervixHela Cell LineCervix Tumor #1Cervix Tumor #2Cervix Tumor #3

2008202217 20 May 2008

Figure 20 191P4D12 Expression in Lung Cancer PatientSpecimens

kb CL CL CL CL N Nat T1 T2 T3 T4 T5 T6 T7 T8 T9 CL Cell lines (in order from left to right):

A427, NCI H146, NCI H82, SKLU1N Normal lungNat Normal adjacent to tumorT Tumor

4.4-

T1 Adeno I B

2.4- T2 Adeno I B

T3 Adeno I B

1.4- T4 Squamous stage IB

Squamous stage IIB

T6 Squamouse stage IIIA

T7 Squamous stage IIIA

T8 Large cell stage IlIA

T9 Large cell stage IB

Figure 21A 191P4D12 Expression in Lung Cancer.

00 ExpressionPathology Grade Level

1 Bronchioalveolar IA2 Squamous3 Adeno Mod Diff4 Adeno Mod Diff

Non-small cell6 Adeno 37 Squamous8 Adeno IB9 Squamous

Small Cell IC 11 Small Cell I

12 Small Cell IS 13 Large Cell' IV

00 14 Squamous 1130 15 Squamous IB

16 Squamous IIIA17 Papillary IV18 Papillary IB19 Adeno IIIA

Adeno IIlA21 Squamous IIB22 Squamous IB23 Adeno IB24 Large Cell IIIA

Small Cell IIB26 Squamous IB27 Squamous IIIA28 Papillary29 Adeno I

Large Cell 11B31 Large Cell I.rc ht~g oiie~'

70/77

Figure 21B 191P4D12 Expression in Bladder Cancer

00

00

I

ExpressinGrade :LevelI,Pathology

Normal1-

234

6789

111213

TransitionalTransitionalTransitionalSquamousPapillaryTransitionalTransitionalTransitionalTransitionalPapillaryTransitional

14 Transitional 2PapIllary 3

16 Transitional17 Squamous

Not18 determined 319 1Transitional 3

71/77

Figure 21C 191P4D12 Expression in Prostate Cancer.

0 1 Expression-.

4 5 j4 t 4

7

00] 17 7

19 9 y1lt

.1 not determined21 LAPC-4AD W 4"'t22 LAPC-4A123 LAPC-9AD24 LAPC-9A1

PeircQ in osiv V A

72/77

Fi-gure 21D 191P4D12 Expression in Colon Cancer.

00:Sta e Expression

o Patlent# :Sag Level

16II

73/7 7

Figure 21E 191P4D12 Expression in Uterus Cancer.

00 i0oi Expression

0 -patient Grade LevelI AdenoCA G

2 AdenoCA G3 AdenoCA G4 AdenoCA G

AdenoCA G6 AdenoCA G27 AdenoCA G28 AdenoCA G29 AdenoCA G3A

AdenoCA Well diff.11 Carclnosarcoma G312 Stromal sarcoma HI h qrade

00 A i~e 7 00' 6

74/77

Figure 21F 191P4D12 Expression in Cervical Cancer.

00o Patent#reveio

ci2

03ci4

01ci1

00 10 140 fPyeae;Y~. 74

=i nm' a t 00

75/7 7

2008202217 20 May 2008

Fiqure 22 Transient Expression of 1.91 P4D12 in Transfected 293T Cells

1 2 3 4

1. 293T-191P4D12.pTag5 supemnatant2. 293T-191P4D12.pTag5 lysate

363. 293T-191 P4DI 2.pcDNA3.1/MycHis lysate4. 293T-pcDNA3.1I/MycHis negative control

2008202217 20 May 2008

Figure 23, Expression of 191 P4D1 2 in Transdluced Cells Following RetroviralGen e Transfer

4.4-

2.4-

1.4-

1. LAPC-4AD2. 3T33. 3T3.191P4DI2.pSRa

Al

00 SEQUENCE LISTING

<110> Agensys, Inc.Raitano, Arthur B.Challita-Eid, Pia M.Jakobovits, AyaFaris, MaryGe, Wangmao

<120> Nucleic Acids and Corresponding ProteinsEntitled 191P4D12(b) Useful in Treatment and Detection ofCancer

<130> 51158-20082.40

<140><141>

Not Yet Assigned

<150> US60/404,306<151> 2002-08-16

<150> US60/423,290

<151> 2002-11-01

<160> 130

<170> FastSEQ for Windows Version

<210> 1<211> 223<212> DNA<213> Homo sapiens

<400> 1gatcactaattttatttttaactcttcttattccccagcc

tcaaggctctgctggcccacgtctgaaatcagcctaggac

tctggatgtt tctctgggtt ggggctggag ttcaatgagg ccagatacac tcagccagaa tacctagatt tagtacccaa 120tgctggattt ctggcctaag ggagaggctc ccatccttcg 180ttcgaatgtg gagcctgaag atc 223

<210> 2<211> 3464<212> DNA<213> Homo sapiens

<220><221> CDS<222> (264) (1796)

<400> 2ggccgtcgttacggcttctttcccctagtgcagttccttagctgggcagt

gt tggccacagggggtagctgagacccaagttcaagtctgctgcctttca

gcgtgggaag cagctctggg ggagctcgga gctcccgatcacggctgggt gtgtagaacg gggccggggc tggggctgggtgcgagaggc aagaactctg cagcttcctg ccttctgggtcagccggctc ccagggagat ctcggtggaa cttcagaaacacc atg ccc ctg tcc ctg gga gcc gag atg tgg

Met Pro Leu Sen Leu Gly Ala Glu Met Trp

ggg cct gag gcc tgg ctg ctg ctg ctg cta ctg ctg gca tca ttt acaGly Pro Glu Ala Trp Leu Leu Leu Leu Leu Leu Leu Ala Ser Phe Thr

1/105

ggc cgg tgcGly Arg Cys

gtg ctg ggcVal. Leu Gly

gcg ggt gag ctgAla Gly Giu Leu

gagGlu

acc tca gac gtg gta act gtgThr Ser Asp Val Val Thr Val.

cag gac gca aaa ctg ccc tgc ttcGin Asp Ala Lys Leu Pro Cys Phe

tac cgaTyr Arg

ggg gac tccGly Asp Ser

ggc gag caa gtg ggg caaGly Glu Gin Val Gly Gin

gca tgg gct cggAla Trp Ala Arg

gac gcg ggc gaaAsp Ala Gly 0Th

00

ggcGly

gcc cag gaa ctaAla Gin Giu Leu

cta ctg cac tccLeu Leu His Ser

tac ggg ctt catTyr Gly Leu His

389

437

485

533

581.

629

677

agc ccg gct tacSer Pro Ala Tyr

ggc cgc gtg gagGly Arg Val Giu

cagGin1.00

ccg ccg ccc ccaPro Pro Pro Pro

cgc aacArg Asn105

ccc ctg gacPro Leu Asp

ggc gag tacGly Giu Tyr

125

tca gtg ctc ctgSer Val Leu Leu

cgcArg1.15

aac gca gtg cagAsn Ala Val Gin

gcg gat gagAla Asp Glu120

agc ttc cagSer Phe Gin

gag tgc cgg gtcGiu Cys Arg Val.

agcSer130

acc ttc ccc gccThr Phe Pro Ala

gcg cggAla Arg

140

ctg cgg ctc cgaLeu Arg Leu Arg

gtgVal145

ctg gtg cct cccLeu Val Pro Pro

ccc tca ctg aatPro Ser Leu Asn

ggt cca gca ctaGly Pro Ala Leu

gaaGlu160

gag ggc cag ggcGiu Gly Gin Gly

acc ctg gca gccThr Leu Ala Ala

tccSer170

725

773

821tgc aca gctCys Thr Ala

gtc aaa ggcVal Lys Gly

gcc gtc accAla Val Thr

205

gag ggcGlu Gly

175

aca acgThr Thr190

agc cca gcc cccSer Pro Ala Pro

gtg acc tgg gacVal Thr Trp, Asp

acg gagThr Glu185

tcc agc cgtSer Ser Arg

tccSer195

ttc aag cac tccPhe Lys His Ser

cgc tct. gctArg Ser Ala200

atg aat gggMet Asn Gly

tca gag ttc cacSer Glu Phe His

gtg cct agc cgcVal Pro Ser Arg

agcSer215

cag cca ctg act tyt gtgGin Pro Leu Thr Cys Val

220

tcc cat cct. ggc ctg ctc cag gac caaSer His Pro Gly Leu Leu Gin Asp Gin

230

aggArg235

atc acc cac atcIle Thr His Ilie

cac gtg tcc ttcHis Val Ser Phe

cttLeu245

gct gag gcc tctAla Giu Aia Ser

1013

1061agg ggc ctt gaa gacArg Gly Leu Glu Asp

caa aat ctgGin Asfl Leu

tgg cac att ggc aga gaa gga gctTrp His Ile Gly Arg Giu Gly Ala

2/105

255 26025 26S

atg ctc aagMet Leu Lys

aca cgg ctgThr Ary Leu

285

ctg agt gaa gggLeu Ser Glu Gly

ccc cct ccc tcaPro Pro Pro Ser

tac aac tggTyr Asn Trp,280

gat ggg gacAsp Gly Asp

1109

1157gat ggg cct ctgAsp Gly Pro Leu

cccPro290

agt ggg gta cgaSer Gly Val Arg

gtgVal295

act ttgThr Leu

300

ggc ttt ccc ccaGly Phe Pro Pro

acc act gag cacThr Thr Giu His

agcSer310

ggc atc tac gtcGly Ile Tyr Val

1205

1253tgcCys315

cat gtc agc aatHis Val Ser Asn

gagGiu320

ttc tcc tca aggPhe Ser Ser Arg

tct cag gtc actSer Gin Val Thr

gtgVal330

gat gtt ctt gac ccc cay gaa gac tct ggg aag cag gtg gacAsp Val Leu Asp Pro Gin Glu Asp Ser Gly Lys Gin Val Asp

cta gtgLeu Val345

1301

tca gcc tcgSer Ala Ser

ctt ctg gtgLeu Leu Val

365

gtg gtg gtg ggtVal Val Val Gly

gtgVal355

atc gcc gca ctcIle Ala Ala Leu

ttg ttc tgcLeu Phe Cys360

cgg cgc aagArg Arg Lys

1349

1397gtg gtg gtg gtgVal Val Val Val

atg tcc cga tacMet Ser Arg Tyr

gcc cagAla Gin

380

cay atg acc cayGin Met Thr Gin

aaaLys385

tat gag gag gagTyr Giu Giu Glu

acc ctg acc aggThr Leu Thr Arg

gagGlu39S

aac tcc atc cggAsn Ser Ile Arg

ctg cat tcc catLeu His Ser His

cacHis405

acg gac ccc aggThr Asp Pro Arg

1445

1493

1541cay ccg gag gagGin Pro Giu Glu

ag tSer415

gta gyg ctg agaVal Gly Leu Arg

gccAla420

gag ggc cac cctGlu Gly His Pro

gat agtAsp Ser425

ctc aag gacLeu Lys Asp

cyc agt tacArg Ser Tyr

445

aacAsn430

agt agc tgc tctSer Ser Cys Ser

atg agt gaa gagMet Ser Giu Giu

ccc gag ggcPro Glu Gly440

1589

too acg ctg accSer Thr Leu Thr

acgThr450

gtg agg gag ata gaa aca cag actVal Ary Giu Ile Giu Thr Gin Thr

455

1637

gaa ctgGiu Leu

460

ctg tct cca gycLeu Ser Pro Gly

tctSer465

ggg cgg gcc gagGly Arg Ala Giu

gagGiu470

gag gaa gat cagGiu Giu Asp Gin

1685

1733gatAsp475

gaa ggc atc aaaGiu Gly Ile Lys

cayGin480

gcc atg aac catAla Met Asn His

tttPhe485

gtt cag gag aatVal Gin Giu Asn

gggGly490

acc cta cgg gcc aag ccc acg ggc aat ggc atc tac atc aat ggg cggThr Leu Arg Ala Lys Pro Thr Gly Asn Gly Ile Tyr Ile Asn Giy Arg

1781

3/105

495 50050 505

gga cac ctg gtc tga cccaggcctg cctcccttcc ctaggcctgg ctccttctgt 1836Gly His Leu Val

tgacatgggaagatgctcccgggctccaccgcctgtgtgaac tgtgt ccggccacgggatggctgtgtgtatgatgcagatagctggagcatgggggcaaagccctctgccatgcgccggttttttcttgagagatggagtcctgcctcaatcc tt ta cgactgggattgaaggggctacggtagagtctcaccattgttatagtggtgtgaggtgaaggattcaaggcttagctggccctagtctgaaaccagcctagggtaaatatgtttgaaaaa

gattttagctcatcccactgaattgagtctgtgttgactgtggtgtgtatttgagtggttgacctctgccggttggaggatggaatctgcgtgtgaagcacctctggtgggagcttcttgccctttccattctcactatggc c tccc tagaagagaaaaacttaaagtgattccaaggcagaaattagggtgtgataccttggggagagaaggtgctgggcttctggatgacccagatactctgctggatacttcgaatggcatatttgt

catcttggggactgcttgacctcccaccatactgtgtgtgtatgctgtcagcgtgggcaatgaaaaagcagagaggtggactccggtgtggccagtccctcctctgggcccaggaatacttagttgtattttgctcaggctagctgggacaaaaattaaaggcccctccatcttcatgcaatgtgagccttagggaattggagagcagtgggtgagaatgtttctctgggact cag cc agttctggcctatggagcctgaacataaaatg

gcctccttaactttacctccgcatgcaggttgtggaggggtatcagagtccactgtcaggggtattttctgactgtggctagggaacctggggtcagccatgctgcatgtgctccgaatcttttatttattggccttgaat t taagtgt agaaagcctttacaccaggggggcagcccctcgtggttactcttggacctgattatagacctcgcctttccttggggctggaatacctagaagggagaggcagatctaagaatattctgtt

acacccccataacccttctgcactgtgtgttgactgtccgaagtgaactggtttggcgtgcagaccccagcagacccaggtctcctaccagaggc ttgaaacatattttcacttttaattttttatttttctcctgggctcaccactgtgagatttatccgttaattccttgggagggcagagtaaggtagtgacaaggggagagagtagccctgggtttagttcaatgatttagtaccctcccatcctttcctaacatgtttaaataaa

t tc ttgcggattcatcgggagtgcatgtgttggaggggtgtggtgtatgttgtgtcatgtagcagtattatgtgcgggcacttcggagccctgttacagatgtaaatatatttttcttttatttttttttcaagcaatcccctgctttgaaatgt ttac tgtgattgtgacctgagagctaaattgcatcctcctgttcagagttgaggttggatcactaggtttattttaaactcttctcg tt ccc cagtacattttatcagacaaaac

1896195620162076213621962256231623762436249625562616267627362796285629162976303630963156321632763336339634563464

<210> 3<211> 510<212> PRT<213> Homo sapiens

<400> 3Met Pro Leu Ser Leu

1 5Leu Leu Leu Leu Leu

Gly Ala Glu Met Trp10Thr

Gly Pro Glu Ala Trp, Leu

Leu Ala Ser

Thr

Phe25Thr

Gly Arg Cys

Glu Leu Glu

Lys Leu Pro

Ser Asp Val Val40Gly

Val Val Leu Gly

Gin

Pro Ala Gly

Gin Asp Ala

Val Gly GinCys Phe Tyr

Val Ala

Arg

Asp

Asp Ser Gly

Trp Ala Arg

Leu

Val

Tyr

Ala Gly Glu Gin Glu Leu

Leu His Ser Lys

Pro

Gly Leu His Pro Ala Tyr Glu Gly

Arg Val Glu

Leu Leu Arg115

Val Ser Thr

Gin100Asn

Pro Pro Pro Pro Leu Asp

Ala Val Gin Ala120Ser

Glu Gly Glu Tyr125Leu

Gly Ser Val110Glu Cys Arg

Arg Leu ArgPhe Pro Ala130

Val Leu Val Pro Pro Leu

Gly135Pro

Phe Gln Ala Arg140GlySer Leu Asn Pro Pro Ala Leu Glu

4/105

145 150 155 160Glu Gly Gin Gly Leu Thr Leu Ala Ala Ser Cys Thr Ala Glu Gly Ser

00165 170 175Pro Ala Pro Ser Val Thr Trp Asp Thr Giu Val Lys Gly Thr Thr Ser

180 185 190Ser Arg Ser Phe Lys His Ser Arg Ser Ala Ala Val Thr Ser Glu Phe

195 200 205His Leu Val Pro Ser Arg Ser Met Asn Gly Gin Pro Leu Thr Cys Val

210 215 220Val Ser His Pro Gly Leu Leu Gin Asp Gin Arg Ile Thr His Ile Leu225 230 235 240His Val Ser Phe Leu Ala Glu Ala Ser Val Ary Gly Leu Glu Asp Gin

245 250 255Asn Leu Trp His Ile Gly Arg Glu Gly Ala Met Leu Lys Cys Leu Ser

260 265 270C] Glu Gly Gin Pro Pro Pro Ser Tyr Asn Trp Thr Arg Leu Asp Gly ProC1275 280 285

Leu Pro Ser Gly Val Arg Val Asp Gly Asp Thr Leu Gly Phe Pro Pro00290 295 30000 Leu Thr Thr Glu His Ser Gly Ile Tyr Val Cys His Val Ser Asn Giu

305 310 315 320Phe Ser Ser Arg Asp Ser Gin Val Thr Val Asp Val Leu Asp Pro Gin

325 30335Giu Asp Ser Gly Lys Gin Val Asp Leu Val Ser Ala Ser Val Val Val

340 345 350Val Gly Val Ile Ala Ala Leu Leu Phe Cys Leu Leu Val Val Val Val

355 360 365Val Leu Met Ser Arg Tyr His Arg Arg Lys Ala Gin Gin Met Thr Gin

370 375 380Lys Tyr Giu Giu Glu Leu Thr Leu Thr Arg Glu Asn Ser Ile Arg Arg385 390 395 400Leu His Ser His His Thr Asp Pro Arg Ser Gin Pro Giu Giu Ser Val

405 410 415Gly Leu Arg Ala Glu Gly His Pro Asp Ser Leu Lys Asp Asn Ser Ser

420 425 430Cys Ser Val Met Ser Giu Giu Pro Giu Giy Arg Ser Tyr Ser Thr Leu

435 440 445Thr Thr Val Arg Giu Ile Giu Thr Gin Thr Giu Leu Leu Ser Pro Gly

450 455 460Ser Gly Arg Ala Glu Giu Glu Giu Asp Gin Asp Glu Gly Ile Lys Gin465 470 475 480Ala Met Asn His Phe Vai Gin Glu Asn Gly Thr Leu Arg Ala Lys Pro

485 490 495Thr Gly Asn Gly Ile Tyr Ile Asn Gly Arg Gly His Leu Val

500 505 510

<210> 4<211> 3464<212> DNA<213> Homo sapiens

<220><221> CDS

*<222> (264) (1796)

<400> 4ggccgtcgtt gttggccaca gcgtgggaag cagctctggg ggagctcgga gctcccgatc acggcttctt gggggtagct acggctgggt gtgtagaacg gggccggggc tggggctggg 120tcccctagtg gagacccaag tgcgagaggc aagaactctg cagcttcctg ccttctgggt 180

5/105

cagttectta ttcaagtctg cagccggctc ecagggagat ctcggtggaa cttcagaaac 240

gctgggcagt ctgcctttea ace atg ccc ctg tcc ctg gga gCC gag atg tgg 293Met Pro Leu Ser Leu Gly Ala Glu Met Trp00

00

ggg cct gag gee tgg ctg etg ctg ctgGly Pro Glu Ala Trp Leu Leu Leu Leu

ctg ctg gca teaLeu Leu Ala Ser

ttt acaPhe Thr

ggc cgg tgcGly Arg Cys

gtg ctg ggcVal Leu Gly

ecPro

geg ggt gag etgAla Gly Glu Leu

ace tea gacThr Ser Asp

cag gac gca aaaGin Asp Ala Lys

ccc tgc ctc tacPro Cys Leu Tyr

gtg gta act gtgVal Val Thr Val

ega ggg gac tcArg Gly Asp Ser

gac gcg ggc gaaAsp Ala Gly Glu

3421

389

437

485

533

581

ggc gagGly Glu

caa gtg ggg eaaGin Val Gly Gin

gea tgg get eggAla Trp Ala Arg

ggcGly

gee eag gaa etaAla Gin Glu Leu

eta ctg eac teeLeu Leu His Ser

tae ggg ctt catTyr Gly Leu His

age ceg get tacSer Pro Ala Ty

gagGlu

gge ege gtg gagGly Arg Val Glu

ceg ceg ccc ecaPro Pro Pro Pro

cgc aaeArg Asn105

eec ctg gaePro Leu Asp

g9c gag tacGly Glu Tyr

125

ggeGly110

tea gtg etc ctgSer Val Leu Leu

aac gea gtg eagAsn Ala Val Gin

geg gat gagAla Asp Glu120

age ttc cagSer Phe Gin

gag tgc egg gteGlu Cys Arg Val

ace ttc eec geeThr Phe Pro Ala

geg eggAl a Arg

140

etg egg etc egaLeu Arg Leu Arg

etg gtg cet. eec etg ccc tea etg aatLeu Val Pro Pro Leu Pro Ser Leu Asn

150

ectPro155

ggt eea gca etaGly Pro Ala Leu

gag gge cag ggeGlu Gly Gin Gly

ctgLeu165

ace etg gca geeThr Leu Ala Ala

teeSer170

tge aca get. gagCys Thr Ala Glu

ggeGly175

age eca gee cccSer Pro Ala Pro

ageSer180

gtg ace tgg gacVal Thr Trp Asp

aeg gagThr Giu185

gte aaa ggeVal Lys Gly

gee gte aceAla Val Thr

205

eag eca ctgGin Pro Leu

220

acaThr190

aeg tee age cgtThr Ser Ser Arg

tte aag eaePhe Lys His

tee ege tet getSer Arg Ser Ala

200

tea gag ttc cacSer Glu Phe His

t tgLeu210

gtg cet age egeVal Pro Ser Arg

ageSer215

atg aat gggmet Asn Gly

869

917

965act tgt gtgThr Cys Val

gtgVal225

tee cat cet ggcSer His Pro Gly

etc cag gac caaLeu Gin Asp Gln

6/105

aggArg235

atc acc cac: atcIle Thr His Ile

cac gtg tcc ttcHis Val Ser Phe

cttLeu245

gct gag gcc tctAla Giu Ala Ser

gtgVal250

1013

1061agg ggc ctt gaaArg Gly Leu Giu

gacAsp255

caa aat ctg tggGin Asn Leu Trp

att ggc aga gaaIle Gly Arg Giu

gga gctGly Aia265

atg ctc aagMet Leu Lys

aca cgg ctgThr Arg Leu

285

ctg agt gaa gggLeu Ser Giu Giy

cagGin275

CCC cct ccc tcaPro Pro Pro Ser

tac aac: tggTyr Asn Trp280

gat ggg gacAsp Gly Asp

00

gat ggg cct ctgAsp Giy Pro Leu

cccPro290

agt ggg gta cgaSer Gly Val Arg

act ttgThr Leu

300

ggc ttt ccc ccaGiy Phe Pro Pro

acc: act gag cacThr Thr Giu His

ggc atc tac gtcGly Ile Tyr Val

1109

1157

1205

1253

1301

cat gtc agc aatHis Val Ser Asn

ttc tcc tca aggPhe Ser Ser Arg

gatAsp325

tct cag gtc actSer.Gin Val Thr

gat gtt ctt gacAsp Val Leu Asp

cag gaa gac tctGin Giu Asp Ser

gggGly340

aag cag gtg gacLys Gin Val Asp

cta gtgLeu Val345

tca gcc tcgSer Ala Ser

ctt ctg gtgLeu Leu Val

365

gtgVal1350

gtg gtg gtg ggtVal Val Val Gly

gtgVal355

atc gcc gca ctcIle Ala Ala Leu

ttg ttc: tgcLeu Phe Cys360

cgg cgc aagArg Arg Lys

1349

1397gtg gtg gtg gtgVal Val Val Val

ctcLeu370

atg tcc oga tacMet Ser Arg Tyr

gcc cagAla Gin

380

cag atg acc: cagGin Met Thr Gin

tat gag gag gagTyr Glu Glu Giu

acc ctg acc aggThr Leu Thr Arg

1445

gagGiu395

aac tcc atc cgg agg ctg cat tcc cat cac acg gac ccc aggAsn Ser Ile Arg Arg Leu His Ser His His Thr Asp Pro Arg

1493

cag ccg gag gagGin Pro Giu Giu

agtSer415

gta ggg ctg agaVal Gly Leu Axg

gccAl a420

gag ggc cac cctGlu Gly His Pro

gat agtAsp Ser425

1541

1589ctc aag gacLeu Lys Asp

cgc agt tacArg Ser Tyr

445

agt agc tgc tctSer Ser Cys Ser

gtgVal1435

atg agt gaa gag ccc gag ggcMet Ser Glu Giu Pro Glu Gly

440

tcc acg ctg accSer Thr Leu Thr

gtg agg gag ataVal Arg Giu Ile

gaaGlu455

aca cag actThr Gin Thr

1637

gaa ctgGiu Leu

460

ctg tct cca ggcLeu Ser Pro Gly

ggg cgg gcc gag gag gag gaa gat cagGly Arg Ala Giu Glu Glu Giu Asp Gin

470

1685

7/105

00gatAsp475

gaa ggc atc aaa cag gcc atg aac cat ttt gtt cag gag aat gggGiu Gly Ile Lys Gin Ala Met Asn His Phe Val Gin Giu Asn Gly

480 485 490

1733

acc cta cgg 9CC aag ccc acg ggc aat ggc atc tac atc aat ggg cgg 1781

Thr Leu Arg Ala Lys Pro Thr Gly Asn Gly Ile Tyr Ile Asn Gly Arg495 500 505

gga cac ctg gtc tga. cccaggcctg cctcccttcc ctaggcctgg ctccttctgt 1836

Gly His Leu Val*510

tgacatggga gattttagct catcttgggg gcctccttaa acacccccat.agatgctcccgggctccaccgcctgtgtgaactgtgtccggccacgggatggctgtgtgt.atgatgcagatagctggagcatgggggcaaagccctctgccatgcgccggttttttcttgagagatggagtcctgcctcaatcctttacgactgggattgaaggggctacggtagagtctcaccattgttatagtggtgtgaggtgaaggattcaaggcttagctggccctagtctgaaaccagcctagggtaaatatgt,ttgaaaaa.

catcccactgaattgagtctgtgttgactgtggtgtgtatttgagtggttgacctctgCCggttggaggatggaatctgcgtgtgaagcacctctggtgggagcttcttgccctttccat.tctcactatggcctccctagaagagaaaaacttaaagtgattccaaggcagaaattagggtgtgataccttggggagaga.aggtgctgggcttctggatgacccagatactctgctggatacttcgaatggcatatttgt

actgcttgacctcccaccatactgtgtgtgtatgctgtcagcgtgggcaatgaaaaagcagagaggtggactccggtgtggccagtccctcctctgggcccaggaatacttagttgtattttgctcaggctagctgggacaaaaattaaaggcccctccatcttcatgcaatgtgagccttagggaattggagagcagtgggtgagaatgtttctctgggactcagccagttctggcctatggagcctgaacataaaatg

ctttacctccgcatgcaggttgtggaggggtatcagagtccactgtcaggggtattttctgactgtggctagggaacctggggtcagccatgctgcatgt.gctccgaatcttttatttattggccttgaatttaagtgtagaaagcctttacaccaggggggcagcccct.cgtggt tact.cttggacctgattatagactcgcctttccttggggctggaatacctagaagggagaggcagatctaagaatattctgtt

aacccttctgcactgtgtgttgactgtccgaagtgaactggtttggcgtgcagaccccagcagacccaggtctcctaccagaggcttgaaacatattttcacttttaattttttatttttctcctgggct.caccactgtgagatttatccgttaattccttgggagggcagagtaaggtagtgacaaggggagagagtagccctgggttt.agttcaatgatttagtaccctcccatcctttcctaacatgtttaaataaa

ttcttgcgga 1896ttcatcggga 1956gtgcatgtgt 2016tggaggggtg 2076tggtgtatgt 2136tgtgtcatgt 2196agcagtatta 2256tgtgcgggca 2316cttcggagcc 2376ctgttacaga 2436tgtaaatata 2496tttttctttt. 2556attttttttt, 2616caagcaatcc 2676cctgctttga 2736aatgtttact 2796gtgattgtga 2856cctgagagct 2916aaattgcatc 2976ctcctgttca 3036gagttgaggt 3096tggatcacta 3156ggtttatttt 3216aaactcttct 3276cgttccccag 3336tacattttat. 3396cagacaaaac 3456

3464

<210> <211> 510<212> PRT<213> Homo sapiens

<400> Met Pro Leu Ser Leu Giy Ala Glu Met Trp Gly

1 5 10Leu Leu Leu Leu Leu Leu Ala Ser Phe Thr Gly

25

Giu Leu Glu Thr Ser Asp Val Val Thr Val Val40

Lys Leu Pro Cys Leu Tyr Arg Gly Asp Ser Gly

Val Ala Trp Ala Arg Val Asp Ala Gly Glu Gly70

Leu Leu His Ser Lys Tyr Gly Leu His Val Ser

Pro Glu Ala Trp Leu

Arg Cys Pro Ala Gly

Leu Gly Gin Asp Ala

Glu Gin Val Gly Gin

Gin Glu Leu

Pro Ala Tyr

8/105

Arg Val Glu Gin Pro Pro Pro Pro Arg Asn Pro Leu Asp Gly Ser Val100 105 110

00

00

Leu

Val

Val145Glu

Pro

Ser

His

Val225His

Asn

Glu

Leu

Leu305Phe

Glu

Val

Val

Lys385Leu

Gly

Cys

Thr

Ser465Ala

Thr

Leu Arg115

Ser Thr130Leu Val

Gly Gin

Ala Pro

Arg Ser195

Leu Val210Ser His

Val Ser

Leu Trp

Gly Gin275

Pro Ser290Thr Thr

Ser Ser

Asp Ser

Gly Val355

Leu Met370Tyr Giu

His Ser

Leu Arg

Ser Val435

Thr Val450Gly Arg

Met Asn

Gly Asn

Asn

Phe

Pro

Gly

Ser180Phe

Pro

Pro

Phe

His260Pro

Gly

Glu

Arg

Gly340Ile

Ser

Giu

His

Ala420Met

Arg

Al a

His

Gly500

Ala

Pro

Pro

Leu165Val1

Lys

Ser

Gly

Leu245Ile

Pro

Val

His

Asp325Lys

Ala

Arg

Glu

His405Giu

Ser

Giu

Glu

Phe485Ile

Val

Ala

Leu150Thr

Thr

His

Arg

Leu230Ala

Gly

Pro

Arg

Ser310Ser

Gin

Al a

Tyr

Leu390Thr

Giy

Glu

Ile

Glu470Val

Tyr

Gin

Gly135Pro

Leu

Trp

Ser

Ser215Leu

Giu

Arg

Ser

Val295Giy

Gin

Val1

Leu

His375Thr

Asp

His

Glu

Glu455Giu

Gin

Ile

Al a120Ser

Ser

Ala

Asp

Arg200Met

Gin

Ala

Giu

Tyr280Asp

Ile

Val

Asp

Leu360Arg

Leu

Pro

Pro

Pro440Thr

Giu

Glu

Asn

Asp

Phe

Leu

Al a

Tht185Ser

Asn

Asp

Ser

Gly265Asn

Gly

Tyr

Thr

Leu345Phe

Arg

Thr

Arg

Asp425Glu

Gin

Asp

Asn

Gly505

Glu

Gin

Asn

Ser170Giu

Ala

Gly

Gin

Val250Al a

Trp

Asp

Val

Val330Val

Cys

Lys

Arg

Ser410Ser

Gly

Thr

Gin

Gly490Arg

Gly

Ala

Pro.155Cys

Val

Ala

Gin

Arg235Arg

Met

Thr

Thr

Cys315Asp

Ser

Leu

Ala

Glu395Gin

Leu

Arg

Giu

Asp475Thr

Gly

Giu

Arg140Gly

Thr

Lys

Val

Pro220Ile

Gly

Leu

Arg

Leu300His

Val

Ala

Leu

Gin380Asn

Pro

Lys

Ser

Leu460Glu

Leu

His

Tyr125Leu

Pro

Ala

Gly

Thr205Leu

Thr

Leu

Lys

Leu285Gly

Val

Leu

Ser

Val365Gin

Ser

Glu

Asp

Tyr445Leu

Gly

Arg

Leu

Giu

Arg

Al a

Glu

Thr190Ser

Thr

His

Giu

Cys270Asp

Phe

Ser

Asp

Val1350Val1

Met

Ile

Glu

Asn430Ser

Ser

Ile

Ala

Val510

Cys

Leu

Leu

Gly175Thr

Giu

Cys

Ile

Asp255Leu

Gly

Pro

Asn

Pro335Val

Val

Thr

Arg

Ser415Ser

Thr

Pro

Lys

Lys495

<210> 6<211> 3464<212> DNA<213> Homo sapiens

<220>

9/105

<221> CDS<222> (264) (1796)

00c400> 6ggccgtcgttacggcttctttc ccc tagtgcagttccttagctgggcagt

gttggccacagggggtagctgagacccaagttcaagtctgctgcctttca

gcgtacggtgcgc ag cacc

.gggaag cagctctggg ggagctcggajctgggt gtgtagaacg gggccggggcragaggc aagaactctg cagcttcctg:cggctc ccagggagat ctcggtggaaatg ccc ctg tcc ctg gga 9CCmet Pro Leu Ser Leu Gly Ala

1

gctcccgatctggggctgggccttctgggtcttcagaaacgag atg tgG1u Met Trp

ggg cct gag gccGly Pro Giu Ala

tggTrp

ctg ctg ctg ctg cta ctg ctg gca tca ttt acaLeu Leu Leu Leu Leu Leu Leu Ala Ser Phe Thr

ggc cgg tgcGly Arg Cys

gtg ctg ggcVal Leu Gly

cccPro

gcg ggt gag ctg gag acc tca gac gtg gta act gtg

Ala Gly Glu Leu Glu Thr Ser Asp Val Val Thr Val

341

389

437cag gac gca aaaGin Asp Ala Lys

ccc tgc ttc tacPro Cys Phe Tyr

ggg gac tccGly Asp Ser

ggc gagGly Glu

caa gtg ggg caaGin Val Gly Gin

gca tyg gct cggAla Trp Ala Arg

gac gqg ggc gaaAsp Ala Gly Glu

ggcGly

gcc cag gaa cta gcg cta ctg cac tccAla Gin Glu Leu Ala Leu Leu His Ser

tac gyg ctt catTyr Gly Leu His

agc ccg gct tacSer Pro Ala Tyr

gyc cgc gtg gagGly Arg Val Glu

ccg ccg ccc ccaPro Pro Pro Pro

cgc aacArg Asn105

ccc ctg gacPro Leu Asp

ggc gag tacGly Glu Tyr

125

tca gtg ctc ctgSer Val Leu Leu

cgcArg115

aac gca gtg cagAsn Ala Val Gin

gcg gat gagAla Asp Glu120

agc ttc caySer Phe Gin

gag tgc cgg gtcGlu Cys Arg Val

agcSer130

acc ttc ccc gccThr Phe Pro Ala

ggcGly135

gcg cggAl a Arg

140

ctg cgg ctc cgaLeu Arg Leu Arg

gtgVal145

ctg gtg cct ccc ctg ccc tca ctg aatLeu Val Pro Pro Leu Pro Ser Leu Asn

150

cctPro155

ggt cca gca ctaGly Pro Ala Leu

gaaGlu160

gag ggc cag ggcGlu Gly Gin Gly

ctgLeu165

acc ctg gca 9ccThr Leu Ala Ala

tgc aca gctCys Thr Ala

gag ggc agc cca gcc ccc agcGlu Gly Ser Pro Ala Pro Ser

175 180

gtg acc tgg gacVal Thr Trp Asp

acg gagThr Glu185

gtc aaa ggc aca acg tcc agc cgt. tcc ttc aag cac tcc

Val Lys Gly Thr Thr Ser Ser Arg Ser Phe Lys His Sercgc tct gctArg Ser Ala200

869

10/105

gcc gtc accAla Val. Thr

205

tca gag ttc cac ttg gtg cct agc cgcSer Giu Phe His Leu Val Pro Ser Arg

atg aat gggMet Asn Giy00

0

cag cca ctg act tgt gtg gtg tccGin Pro Leu Thr Cys Val Val Ser

220 225

cat cct ggcHis Pro Gly

ctgLen230

ctc cag gac caaLeu Gin Asp Gin

aggArg235

atc acc cac atcIle Thr His Ile

ctc cac gtg tcc ttc cttLeu His Vai Ser Phe Leu240 245

gct gag gcc tctAla Glu Ala Ser

agg ggc ctt gaaArg Giy Leu Giu

caa aat ctg tggGin Asn Leu Trp

att ggc aga gaaIle Giy Arg Giu

gga gctGly Ala265

965

1013

1063.

1109

1157

atg ctc aagMet Leu Lys

aca cgg ctgThr Arg Leu

285

ctg agt gaa gggLeu Ser Giu Gly

ccc cct ccc tca tac aac tggPro Pro Pro Ser Tyr Asn Trp

gat ggg cct ctgAsp Giy Pro Len

cccPro290

agt ggg gta cgaSer Gly Val Arg

gtgVal295

gat ggg gacAsp Gly Asp

act ttgThr Leu

300

ggc ttt ccc ccaGly Phe Pro Pro

ctgLeu305

acc act gag cacThr Thr Gin His

agcSer310

ggc atc tac gtcGly Ile Tyr Val

tgcCys315

cat gtc agc aatHis Val Ser Asn

ttc tcc tca aggPhe Ser Ser Arg

tct cag gtc actSer Gin Val Thr

gtgVal330

1205

1253

1301gat gtt ctt gacAsp Val Leu Asp

cccPro335

cag gaa gac tctGin Gin Asp Ser

aag cag gtg gacLys Gin Val Asp

cta gtgLeu Val345

tca gcc tcgSer Ala Ser

ctt ctg gtgLeu Leu Val

365

gtgVal1350

gtg gtg gtg ggtVal. Val Var- Gly

gtgVal355

atc gcc gca ctcIle Ala Ala Leu

ttg ttc tgcLeu Phe Cys360

cgg cgc aagArg Arg Lys

1349

1397gtg gtg gtg gtgVal Val Val Val

ctcLeu370

atg tcc cga tacMet Ser Arg Tyr

gcc cagAla Gin

380

cag atg acc cagGin Met Thr Gin

tat gag gag gagTyr Gin Gin Gin

acc ctg acc aggThr Len Thr Arg

1445

gagGiu395

aac tcc atc cggAsn Ser Ie Arg

aggArg400

ctg cat tcc cat cac acg gac ccc aggLen His Ser His His Thr Asp Pro Arg

405

agcSer410

1493

cag ccg gag gagGin Pro Gin Glu

agtSer415

gta ggg ctg agaVal Gly Leu Arg

gccAl a420

gag ggc cac cctGiu Gly His Pro

gat agtAsp Ser425

1541

ctc aag gacLen Lys Asp

agt agc tgc tct gtg atg agt gaa gag ccc gag ggcSer Ser Cys Ser Val Met Ser Giu Giu Pro Gin Gly

1589

11/105

cgc agt tac tccArg Ser Tyr Ser

445

acg ctg acc acg gtg agg gag ata gaa aca cag act

Thr Leu Thr Thr Vai Arg Giu Ile Giu Thr Gin Thr450 45500

00

gaa ctgGiu Leu

460

ctg tct cca ggcLeu Ser Pro Gly

tctSer465

ggg cgg gcc gagGly Arg Aia Giu

gagGiu470

gag gaa gat cagGiu Giu Asp Gin

gatAsp475

gaa ggc atc aaaGiu Giy Ile Lys

cagGin480

gcc atg aac catAla Met Asn His

t ttPhe485

gtt cag gag aatVal Gin Glu Asn

gggGly490

1637

1685

1733

1781

1836

acc cta cgg gccThr Leu Arg Ala

aagLys495

ccc acg gycPro Thr Gly

aat ggcAsn Gly

500

atc tac atc aatIle Tyr Ile Asn

ggg cggGly Arg505

gga cac ctgGly His Leu

tga cccaggcctg cctcccttcc ctaggcctgg ctccttctgt

tgacatggga gattttagct catcttgggg gcctccttaa acacccccat ttcttgcgga 1896

agatgctcccgggctccaccgcctgtgtgaactgtgtccggccacgggatggctgtgtgtatgatgcagatagctggagcatgggggcaaagccctctgccatgcgccggttttttcttgagagatggagtcctgcctcaatcctttacgactgggat tgaaggggctacggtagagtctcaccattgttatagtggtgtgaggtgaaggattcaaggcttagctggccctagtctgaaaccagcctagggtaaatatgtttgaaaaa

catcccactgaattgagtctgtgttgactgtggtgtgtatttgagtggttgacctctgccggttggaggatggaatctgcgtgtgaagcacctctggtgggagcttcttgccctttccattctcactatggcctccctagaagagaaaaacttaaagtgattccaaggcagaaat tagggtgtgataccttggggagagaaggtgctgggcttctggatga ccc agatactctgctggatacttcgaatggcatatttgt

actgcttgacctcccaccatac tgtgtgtgtatgctgtcagcgtgggcaatgaaaaagcagagaggtggactccggtgtggc cagtc cc tcctctgggccaggaatacttagttgtat tttgctcaggctagctgggacaaaaattaaaggcccctccatcttcatgc:aatgtgagccttagggaattggagagcagtgggtgagaatgtttctctgggact cagc cagttctggcctatggagcctgaacataaaatg

ctttacctccgcatgcaggttgtggaggggtatcagagtccactgtcaggggtattttctgactgtggctagggaacctggggtcagccatgctgcatgtgctccgaatcttttatttattggccttgaatttaagtgtagaaagcctttacaccaggggggcagcccctcgtggttactcttggacctgattatagacctcgcctttccttggggctggaatacctagaagggagaggcagatctaagaatattctgtt

aacccttctgcactgtgtgttgactgtccgaagtgaactggtttggcttgcagaccccagcagacccaggtctcctaccagaggcttgaaacatattttcacttttaattttttattt t tctcctgggctcaccactgtgagatttatccgttaattccttgggagggcagagtaaggtagtgacaaggggagagagtagccctgggtttagttcaatgatttagtaccctcccatcctttcctaacatgtttaaataaa

ttcatcggga 1956gtgcatgtgt 2016tggaggggtg 2076tggtgtatgt 2136tgtgtcatgt 2196agcagtatta 2256tgtgcgggca 2316cttcggagcc 2376ctgttacaga 2436tgtaaatata 2496tttttctttt 2556attttttttt 2616caagcaatcc 2676cctgctttga 2736aatgtttact 2796gtgattgtga 2856cctgagagct 2916aaattgcatc 2976ctcctgttca 3036gagttgaggt 3096tggatcacta 3156ggtttatttt 3216aaactcttct 3276cgttccccag 3336tacattttat 3396cagacaaaac 3456

3464

<210> 7<211> 510<212> PRT<213> Homo sapiens

<400> 7Met pro Leu Ser Leu Gly Ala Glu Met Trp, Gly1 5 10

Leu Leu Leu Leu Leu Leu Ala Ser Phe Thr Gly25

Giu Leu Giu Thr Ser Asp Val Vai Thr Val Val

Pro Glu Ala Trp Leu

Arg Cys Pro Ala Gly

Leu Gly Gin Asp Ala

12/105

40

00 Lys Leu Pro Cys Phe Tyr Arg Gly Asp Ser Gly Glu Gin Val Gly Gin55

Val Ala Trp Ala Arg Val Asp Ala Gly Giu Gly Ala Gin Glu Leu Ala(I 65 70 75

Leu Leu His Ser Lys Tyr Gly Leu His Val Ser Pro Ala Tyr Giu Gly90

S Arg Val Glu Gin Pro Pro Pro Pro Arg Asn Pro Leu Asp Gly Ser Val100 105 110

Leu Leu Arg Asn Ala Val Gin Ala Asp Glu Gly Glu Tyr Giu Cys ArgC1115 120 125

Val Ser Thr Phe Pro Ala Gly Ser Phe Gin Ala Arg Leu Arg Leu Arg

130 135 140Val Leu Val Pro Pro Leu Pro Ser Leu Asn Pro Gly Pro Ala Leu Giu145 150 155 160Glu Gly Gin Gly Leu Thr Leu Ala Ala Ser Cys Thr Ala Glu Gly Ser

165 170 175Pro Ala Pro Ser Val Thr Trp Asp Thr Glu Val Lys Gly Thr Thr Ser

00180 185 190Ser Arg Ser Phe Lys His Ser Arg Ser Ala Ala Val Thr Ser Giu Phe

195 200 205His Leu Val Pro Ser Arg Ser Met Asn Gly Gin Pro Leu Thr Cys Val

210 215 220Val Ser His Pro Gly Leu Leu Gin Asp Gin Arg Ile Thr His Ile Leu225 230 235 240His Val Ser Phe Leu Ala Giu Ala Ser Val Arg Gly Leu Glu Asp Gin

245 250 255Asn Leu Trp His Ile Gly Arg Glu Gly Ala Met Leu Lys Cys Leu Ser

260 265 270Giu Gly Gin Pro Pro Pro Ser Tyr Asn Trp Thr Arg Leu Asp Gly Pro

275 280 285Leu Pro Ser Giy Val Arg Val Asp Gly Asp Thr Leu Gly Phe Pro Pro

290 295 300Leu Thr Thr Giu His Ser Gly Ile Tyr Val Cys His Val Ser Asn Giu305 310 315 320Phe Ser Ser Arg Asp Ser Gin Val Thr Val Asp Val Leu Asp Pro Gin

325 330 335Glu Asp Ser Gly Lys Gin Val Asp Leu Val Ser Ala Ser Val Val Val

340 345 350Val Gly Vai Ile Ala Ala Leu Leu Phe Cys Leu Leu Val Val Val Val

355 360 365Val Leu Met Ser Arg Tyr His Arg Arg Lys Ala Gin Gin Met Thr Gin

370 375 380Lys Tyr Giu Giu Giu Leu Thr Leu Thr Arg Giu Asn Ser Ile Arg Arg385 390 395 400Leu His Ser His His Thr Asp Pro Arg Ser Gin Pro Giu Giu Ser Val

405 410 415Gly Leu Arg Ala Glu Gly His Pro Asp Ser Leu Lys Asp Asn Ser Ser

420 425 430Cys Ser Val Met Ser Glu Giu Pro Giu Gly Arg Ser Tyr Ser Thr Leu

435 440 445Thr Thr Val Arg Glu Ile Glu Thr Gin Thr Giu Leu Leu Ser Pro Gly

450 455 460Ser Gly Arg Ala Glu Giu Giu Glu Asp Gin Asp Giu Giy Ile Lys Gin465 470 475 480Ala Met Asn His Phe Val Gin Giu Asn Gly Thr Leu Arg Ala Lys Pro

485 490 495Thr Gly Asn Giy Ile Tyr Ile Asn Gly Arg Gly His Leu Val,

500 505 510

13/ 105

00

00

<210><211><212><213>

834G4DNAHomo sapiens

<220><221> CDS<222> (264)

<400> 8ggccgtcgttacggcttctttcccctagtgcagttccttagctgggcagt

(1796)

gttggccacagggggtagctgagacccaagttcaagtctgctgcctttca

gcgtgggaag cagctctggg ggagctcgga gctcccgatcacggctgggt gtgtagaacg gggccggggc tggggctgggtgcgagaggc aagaactctg cagcttcctg ccttctgggtcagccggctc ccagggagat ctcggtggaa cttcagaaacacc atg ccc ctg tcc ctg gga gcc gag atg tgg

Met Pro Leu Ser Leu Gly Ala Glu Met Trp

ggg cct gag gccGly Pro Glu Ala

tggTrp

ctg ctg ctg ctgLeu Leu Leu Leu

cta ctg ctg gca tca ttt acaLeu Leu Leu Ala Ser Phe Thr20

acc tca gac gtg gta act gtgThr Ser Asp Val Val Thr Val

ggc cgg tgcGly Arg Cys

gtg ctg ggcVal Leu Gly

gcg ggt gag ctgAla Gly Glu Leu

389

cag gac gca aaaGin Asp Ala Lys

ccc tgc ttc tacPro Cys Phe Tyr

ggg gac tccGly Asp Ser

ggc gagGly Glu

caa gtg ggg caaGin Val Gly Gin

gca tgg gct cggAla Trp Ala Arg

gac gcg ggc gaaAsp Ala Gly Glu

ggcGly

gcc cag gaa ctaAla Gin Glu Leu

gcgAla

cta ctg cac tccLeu Leu His Ser

tac ggg ctt catTyr Chly Leu His

agc ccg gct tacSer Pro Ala Tyr

ggc cgc gtg gagGly Arg Val Glu

ccg ccg ccc ccaPro Pro Pro Pro

cgc aacArg Asn105

ccc ctg gacPro Leu Asp

ggc gag tacGly Glu Tyr

125

tca gtg ctc ctgSer Val Leu Leu

aac gca gtg cagAsn Ala Val Gin

gcg gat gagAla Asp Glu120

agc ttc cagSer Phe Gin

gag tgc c99 gtcGlu Cys Arg Val

acc ttc ccc gccThr Phe Pro Ala

ggcGly135

gcg cggAl a Arg

140

ctg cgg ctc cgaLieu Arg Leu Arg

ctg gtg cct cccLeu Val Pro Pro

ccc tca ctg aatPro Ser Leu Asn

cctPro155

ggt cca gca cta gaa gag ggc cag ggcGly Pro Ala Leu Glu Glu Gly Gin Gly

ctg acc ctg gca gcc tccLieu Thr Lieu Ala Ala Ser165 170

773

821tgc aca gct gag ggc agc cca gcc ccc agc gtg acc tgg gac acg gag

14/105

Cys Thr Ala Glu Gly175

Ser Pro Ala Pro Ser180

Val Thr Trp Asp Thr Glu18500

0

gtc aaa ggcVal Lys Gly

gco gtc accAla Val Thr

205

acg tcc agc cgtThr Ser Ser Arg

tccSer195

tto aag cac tooPhe Lys His Ser

cgc tct goctArg Ser Ala200

atg aat gggMet Asn Gly

tca gag ttc cacSer Giu Phe His

gtg cct agc cgoVal Pro Ser Arg

cag ccaGin Pro

220

ctg act tgt gtgLeu Thr Cys Val

gtgVal225

tcc cat cot ggcSer His Pro Gly

ctgLeu230

ctc cag gac caaLeu Gin Asp Gin

869

917

965

1013

1061

aggArg235

ato aco cac atoIle Thr His Ile

cac gtg too ttcHius Val Ser Phe

got gag gco totAla Glu Ala Ser

gtgVal250

agg 990: ctt gaaArg Gly Leu Giu

gacAsp255

caa aat ctg tggGin Asn Leu Trp

att ggc aga gaaIle Gly Arg Giu

gga gotGly Ala265

atg otc aagMet Leu Lys

aca 099 otgThr Arg Leu

285

ctg agt gaa gggLeu Ser Giu Gly

cagGin275

ccc cct coo tcaPro Pro Pro Ser

tao aac tggTyr Asn Trp280

gat ggg gaoAsp Gly Asp

1109

1157gat ggg cot ctgAsp Gly Pro Leu

agt 999 gta. ogaSer Gly Val Arg

gtgVal295

act ttgThr Leu

300

990 ttt Occ ocaGly Phe Pro Pro

ctgLeu305

aco act gag cacThr Thr Giu His

agoSer310

ggc ato tac gtoGly Ile Tyr Val

1205

1253cat gtc ago aatHis Val Ser Asn

ttc too tca aggPhe Ser Ser Arg

tot cag gto actSer Gin Val Thr

gtgVal1330

gat gtt Ott gaoAsp Val Leu Asp

cooPro335

cag gaa gao tot ggg aag oag gtg gaoGin Giu Asp Ser Gly Lys Gin Val Asp

340

ota. gtgLeu Val345

1301

toa goc togSer Ala Ser

ott ctg gtgLeu Leu Val

365

gtgVal350

gtg gtg gtg ggtVal Val Val Gly

ato 900 goa otoIle Ala Ala Leu

ttg tto tgoLeu Phe Cys360

099 090: aagArg Arg Lys

1349

1397gtg gtg gtg gtgVal Val Val Val

otoLeu370

atg too cga taoMet Ser Arg Tyr

900 cagAla Gin

380

cag atg aco cag aaa tat gag gag gagGin Met Thr Gin Lys Tyr Giu Giu Giu

385

ctgLeu390

aco ctg aco aggThr Leu Thr Arg

1445

aac too ato 099

Asn Ser Ile Argotg cat too oatLeu His Ser His

caoHis405

acg gao coo aggThr Asp Pro Arg

1493

oag ccg gag gag agt gta ggg otg aga goc gag ggc cac oct gat agt 1541

105

Gin Pro Giu Giu Ser Val Gly Leu Arg Ala Glu Gly His Pro Asp Ser

00ctc aag gacLeu Lys Asp

cgc agt tacArg Ser Tyr

445

aacAsn430

agt agc tgc tct gtg atg agt gaa gag ccc gag ggc

Ser Ser Cys Ser Val Met Ser Glu Glu Pro Giu Gly435 440

tcc acg ctg accSer Thr Leu Thr

acg gtgThr Val450

agg gag ataArg Glu Ile

gaaGlu455

aca cag actThr Gin Thr

1589

1637

1685gaa ctgGlu Leu

460

ctg tct ccaLeu Ser Pro

ggc tctGly Ser

465

ggg cgg gcc gagGly Arg Ala Giu

gagGlu470

gag gaa gat cagGiu Glu Asp Gin

gatAsp475

gaa ggc atc aaa cag gcc atg aac catGiu Gly Ile Lys Gin Ala Met Asn His

tttPhe485

gtt cag gagVal Gin Giu

aat gggAsn Gly

490

1733

1781acc cta cgg gccThr Leu Arg Ala

aagLys495

ccc acg ggc aatPro Thr Gly Asn

ggcGly500

atc tac atcIle Tyr Ile

aat ggg cggAsn Gly Arg

505

gga cac ctg gtc tga cccaggcctg cctcccttcc ctaggcctgg ctccttctgt 1836

Gly His Leu Val510

tgacatgggaagatgctcccgggctccacgcctgtgtgaactgtgtccggccacgggatggctgtgtgtatgatgcagatagctggagcatgggggcaaagccctctgccatgcgccggttttttcttgagagatggagtcctgcctcaatcctttacgactgggattgaaggggctacggtagagtctcaccattgttatagtggtgtgaggtgaaggattcaaggcttagctggcctagtctgaaaccagcctagggtaaatatgtttgaaaaa

gattttagctcatcccactgaattgagtctgtgttgactgtggtgtgtatt tgagtggttgacctctgccggttggaggatggaatctgcgtgtgaagcacctctggtgggagcttcttgccctttccattctcactatggcctccctagaagagaaaaacttaaagtgattccaaggcagaaattagggtgtgataccttggggagagaaggtgctgggcttctggatgacccagatactctgctggatacttcgaatggcatatttgt

catcttggggactgcttgacctcccaccatactgtgtgtgtatgctgtcagcgtgggcaatgaaaaagcagagaggtggactccagtgtggccagtccctcctctgggccaggaatacttagttgtattttgctcaggctagctgggacaaaaattaaaggcccctccatcttcatgcaatgtgagccttagggaattggagagcagtgggtgagaatgtttctctgggactcagccagttctggcctatggagcctgaacataaaatg

gcctccttaat t tacCt ccgcatgcaggttgtggaggggtatcagagtccactgtcaggggtattttctgactgtggctagggaacctggggtcagccatgctgcatgtgctccgaatcttttatttattggccttgaatttaagtgtagaaagcctttacaccaggggggcagCccctcgtggttactcttggacctgattatagactcgcCtttcttggggctggaatacctagaagggagaggcagatctaagaatat t ctgt t

acacccccataacccttctgcactgtgtgttgactgtccgaagtgaactggtt tggcgtg,cagaccccagc aga ccc aggtctcctaccagaggcttgaaacatattttcacttttaattttttatttttctcctgggctcaccactgtgagatttatccgttaattccttgggagggcagagtaaggtagtgacaaggggagagagtagccctgggtttagttcaatgatttagtaccctcccatcctttcctaacatgtttaaataaa

ttcttgcgga 1896ttcatcggga 1956gtgcatgtgt 2016tggaggggtg 2076tggtgtatgt 2136tgtgtcatgt 2196agcagtatta 2256tgtgcgggca 2316cttcggagcc 2376ctgttacaga 2436tgtaaatata 2496tttttctttt 2556attttttttt 2616caagcaatcc 2676cctgctttga 2736aatgtttact 2796gtgattgtga 2856cctgagagct 2916aaattgcatc 2976ctcctgttca 3036gagttgaggt 3096tggatcacta 3156

ggtttatttt 3216aaactcttct 3276cgttccccag 3336tacattttat 3396cagacaaaac 3456

3464

4210> 9<211> 510<212> PRT<213> Homo sapiens

16/105

00 <400> 9Met Pro Leu Ser Leu Gly Ala Glu Met Trp Gly Pro Glu Ala Trp Leu

1 5 10 Leu Leu Leu Leu Leu Leu Ala Ser Phe Thr Gly Arg Cys Pro Ala Gly

25

c~Glu Leu Giu Thr Ser Asp Val Val Thr Val Val Leu Gly Gin Asp AlaLysLe 40 LsLuPro Cys Phe Tyr Arg Gly Asp Ser Gly Glu Gln Val Gly Gin

55 Val Ala Trp Ala Arg Val Asp Ala Gly Glu Gly Ala Gin Giu Leu Ala

70 75 Leu Leu His Ser Lys Tyr Gly Leu His Val Ser Pro Ala Tyr Glu Gly1-85 90 Arg Val Giu Gin Pro Pro Pro Pro Arg Asn Pro Leu Asp Gly Ser Val

C1100 105 110Leu Leu Arg Asn Ala Val Gin Ala Asp Glu Gly Giu Tyr Giu Cys Arg

115 120 125

00 Val Ser Thr Phe Pro Ala Gly Ser Phe Gin Ala Arg Leu Arg Leu Arg130 135 140

Val Leu Val Pro Pro Leu Pro Ser Leu Asn Pro Gly Pro Ala Leu GluC1 145 150 155 160

Glu Gly Gin Gly Leu Thr Leu Ala Ala Ser Cys Thr Ala Glu Gly Ser165 170 175

Pro Ala Pro Ser Val Thr Trp Asp Thr Giu Val Lys Gly Thr Thr Ser180 185 190

Ser Arg Ser Phe Lys His Ser Arg Ser Ala Ala Val Thr Ser Giu Phe

195 200 205His Leu Val Pro Ser Arg Ser Met Asn Gly Gin Pro Leu Thr Cys Val

210 215 220Val Ser His Pro Gly Leu Leu Gin Asp Gin Arg Ile Thr His Ile Leu225 230 235 240His Val Ser Phe Leu Ala Glu Ala Ser Vai Arg Gly Leu Giu Asp Gin

245 250 255Asn Leu Trp His Ile Gly Arg Glu Gly Ala Met Leu Lys Cys Leu Ser

260 265 270Glu Gly Gin Pro Pro Pro Ser Tyr Asn Trp Thr Arg Leu Asp Gly Pro

275 280 285Leu Pro Ser Gly Val Arg Val Asp Gly Asp Thr Leu Gly Phe Pro Pro

290 295 300Leu Thr Thr Giu His Ser Gly Ile Tyr Val Cys His Val Ser Asn Giu305 310 315 320Phe Ser Ser Arg Asp Ser Gin Val Thr Vai Asp Val Leu Asp Pro Gin

325 330 335Glu Asp Ser Gly Lys Gin Val Asp Leu Vai Ser Ala Ser Val Val Val

340 345 350Val Gly Val Ile Ala Ala Leu Leu Phe Cys Leu Leu Val Val Val Val

355 360 365Val Leu Met Ser Arg Tyr His Arg Arg Lys Ala Gin Gin Met Thr Gin

370 375 380Lys Tyr Glu Glu Giu Leu Thr Leu Thr Arg Glu Asn Ser Ile Arg Arg385 390 395 400Leu His Ser His His Thr Asp Pro Arg Ser Gin Pro Giu Glu Ser Val

405 410 415

Gly Leu Arg Ala Giu Gly His Pro Asp Ser Leu Lys Asp Asn Ser Ser420 425 430

Cys Ser Val Met Ser Giu Giu Pro Giu Gly Arg Ser Tyr Ser Thr Leu435 440 445

Thr Thr Val Arg Giu Ile Glu Thr Gin Thr Glu Leu Leu Ser Pro Gly450 455 460

17/105

Ser Gly Arg Ala Giu Glu GJlu Glu Asp Gin Asp Giu Gly Ile Lys Gin

465 470 475 480

Ala Met Asn His Phe Val Gin Glu Asn Gly Thr Leu Arg Ala Lys Pro485 490 495

Thr Gly Asn Gly Ile Tyr Ile Asn Gly Arg Gly His Leu Val

500 505 510

<210> <211> 3464<212> DNA<213> Homo sapiens

<220><221> CDS<222> (264) (1796)

00

<400> ggccgtcgttacggcttctttcccctagtgcagttccttagctgggcagt

gttggccaCagggggtagctgagacccaagttcaagtctgctgcctttca

gcgtgggaag cagctctggg ggagctcgga gctcccgatcacggctgggt gtgtagaacg gggccggggc tggggctgggtgcgagaggc aagaactctg cagcttcctg ccttctgggtcagccggctc ccagggagat ctcggtggaa cttcagaaac

acc atg ccc ctg tcc ctg gga gcc gag atg tggMet Pro Leu Ser Leu Gly Ala Glu Met Trp

ggg cct gag gcc tgg ctg ctg ctg ctgGay Pro Glu Ala Trp Leu Leu Leu Leu

cta ctg ctg gca. tca ttt aca.Leu Leu Leu Ala Ser20

Phe Thr

ggc cgg tgcGly Arg Cys

gtg ctg ggcVal Leu Gly

ccc gcgPro Ala

ggt gag ctgGly Glu Leu

acc tca gac gtgThr Ser Asp Val

gta act gtgVal Thr Val

ggg gac tccGly Asp Ser

cag gac gca aaa.Gin Asp Ala Lys

ctgLeu50

ccc tgc ttc tacPro Cys Phe Tyr

cgaArg

ggc gagGly Giu

caa. gtg ggg caa.Gin Val Gly Gin

gca. tgg gct cggAla Trp Ala Arg

gac gcg ggc gaaAsp Ala Giy Glu

gycGly

9CC cag gaa ctaAla Gin Glu Leu

gcgAla

cta ctg cac tccLeu Leu His Ser

tac ggg cU: catTyr Gly Leu His

agc ccg gct tacSer Pro Ala Tyr

gagGlu

ggc cgc gtg gagGly Arg Val Giu

ccg ccg ccc ccaPro Pro Pro Pro

cgc aacArg Asn105

ccc ctg gacPro Leu Asp

tca gtg ctc ctgSer Val Leu Leu

aac gca gtg cagAsn Ala Val Gin

ggc gag tac gagGly Giu Tyr Giu

125

tgcC9 cg tcCys Arg Val

agcSer130

acc ttc ccc gccThr Phe Pro Ala

ggcGly135

gcg gat gagAla Asp Glu120

agc ttc cagSer Phe Gin

tca ctg aatSer Leu Asngcg cgg ctg cgg ctc cga. gtg ctg gtg

Ala Arg Leu Arg Leu Arg Val Leu Valcct ccc ctg CCCPro Pro Leu Pro

725

18/105

145 150

oct ggt cca gca ota gaa gag ggc cag ggcPro Gly Pro Ala Leu Giu Glu Gly Gin Gly

155 160

ctgLeu165

acc ctg gca gcThr Leu Ala Ala

tgc aca gct gagCys Thr Ala Glu

ago cca gcc cccSer Pro Ala Pro

agcSer180

gtg acc tgg gaoVal Thr Trp, Asp

acg gagThr Giu185

gtc aaa ggcVal Lys Gly

goc gtc accAla Val Thr

205

acaThr190

acg tcc agc cgtThr Ser Ser Arg

toc ttc aag cacSer Phe Lys His195

gtg cct agc cgcVal. Pro Ser Arg

tcc

Ser

agcSer215

090 tct gct

Arg Ser Ala200

atg aat gggMet Asn Giy

tca gag ttc cacSer Giu Phe His

ttgLeu210

cag ocaGin Pro

220

ctg act tgt gtgLeu Thr Cys Val

gtgVal225

too cat oct ggcSer His Pro Gly

otgLeu230

oto cag gao oaaLeu Gin Asp Gin

869

917

965

1013

1061

aggArg235

ato aco cac atoIle Thr His Ile

otoLeu240

cac gtg tco ttoHis Val Ser Phe

got gag goc totAla Glu Ala Ser

gtgVal250

agg ggo ott gaaArg Gly Leu Giu

gaoAsp255

oaa aat otg tggGin Asn Leu Trp

att ggo aga gaaIle Gly Arg Glu

gga gctGly Ala265

atg ote aagMet Leu Lys

aca ogg otgThr Arg Leu

285

tgoCys270

otg agt gaa gggLeu Ser Glu Gly

oagGin275

000 oct 000 tcaPro Pro Pro Ser

tao aac tggTyr Asn Trp280

gat ggg gaoAsp Gly Asp

1109

1157gat ggg cot otgAsp Gly Pro Leu

cooPro290

agt ggg gta ogaSer Gly Val. Arg

act ttgThr Leu

300

ggc ttt coo ocaGly Phe Pro Pro

ace act gag cacThr Thr Glu His

990 ato tao gtoGly Ile Tyr Val

1205

1253cat gto ago aatHis Val Ser Asn

ttc too toa aggPhe Ser Ser Arg

gatAsp325

tot cag gtc actSer Gln Val Thr

gat gtt ott gaoAsp Val Leu Asp

cag gaa gao totGin Giu Asp Ser

aag cag gtg gao ota gtgLys Gin Val Asp Leu Val

.345

1301

tca 900 tcg

Ser Ala Ser

ott ctg gtgLeu Leu Val

365

gtgVal350

gtg gtg gtg ggt gtg ato 900 goa otoVal Val Val Gly Val Ile Ala Ala Leu

355

ttg ttc tgcLeu Phe Cys360

099 cgc aag

Arg Arg Lys

1349

gtg gtg gtg gtgVal Val Val Val

oto

Leu370

atg too cga taoMet Ser Arg Tyr

1397

goc cag cag atg aco cag aaa tat gag gag gag otg aco ctg aco aggAla Gin Gin Met Thr Gin Lys Tyr Giu Giu Glu Leu Thr Leu Thr Arg

1445

19/105

380 80385 390

gag aac tcc atc cggGlu Asn Ser Ile Arg

aggArg400

ctg cat tce catLeu His Ser His

ggg ctg aga. 9CCGly Leu Arg Ala

420

cacHis405

acg gac ccc aggThr Asp Pro Arg

1493

1541cag ccg gag gagGin Pro Glu Glu

agt gta.Ser Val415

gag ggc cac cct gat agtGiu Gly His Pro Asp Ser

425

ctc aag gacLeu Lys Asp

aacAsn430

agt agc tgc tctSer Ser Cys Ser

gtgVal435

atg agt gaa gagMet Ser Glu Glu

ccc gag ggcPro Giu Gly440

aca cag actThr Gin Thr

1589

cgc agtArg Ser

tacTyr445

tcc acg ctg accSer Thr Leu Thr

acgThr450

gtg agg gag ataVal Arg Glu Ile

gaaGiu455

gaaGlu

etg ctg tet cca. ggcLeu Leu Ser Pro Gly460

gaa ggc ate aaa cagGiu Gly Ile Lys Gin

ggg cgg gcc gagGly Arg Ala Glu

gagGiu470

gag gaa gat cagGlu Giu Asp Gin

1637

1685

1733

1781

480

cccPro

gCC atg aacAla Met Asn

acg gge aatThr Gly Asn

cat ttt gtt cag gag aatHis Phe Val Gin Glu Asn

485

acc cta egg gccThr Leu Arg Ala

ggcGly500

ate tac atc aatIle Tyr Ile Asn

ggg cggGly Arg505

gga cacGly His

ctg gte tga cccaggcctg ectcettcc ctaggectgg etccttctgtLeu Val*

510

1836

tgacatgggaagatgctcccgggctccaccgcctgtgtgaactgtgtccggccacgggatggctgtgtgtatgatgcagatagctggagcatgggggcaaagccctctgC!catgcgccggttttttcttgagagatggagtcctgcctcaatcctttacgactgggattgaaggggctacggtagagtctcaccattgttatagtggtgtgaggtgaaggattcaaggettagctggcectagtctgaaaccagcctagg

gattttagcteatccactgaattgagtctgtgttgactgtggtgtgtatttgagtggttgacctetgccggttggaggatggaatetgcgtgtgaagca.eetctggtgggagcttettgccctttccattctcactatggactcetagaagagaaaaaettaaagtgattccaaggcagaaattagggtgtgataccttggggagagaaggtgctgggcttctggatgacecagatactetgctggatacttcgaatg

eatettggggactgettgaccteceaccatactgtgtgtgtatgctgtca.gcgtgggcaa.tgaaaaagcagagaggtggactccggtgtggceagtceet.cctctgggeCcaggaatacttagttgtattttgctcaggctagctgggacaaaaattaaaggcccetceatcttcatgcaatgtgagccttagggaattggagageagtgggtgagaatgtttctctgggactcagecagttctggectatggagcctga

gectccttaactttacctccgcatgcaggttgtggaggggtatcagagtecactgtcaggggtattttctgactgtggctagggaacctggggtcagccatgctgcatgtgctccgaatcttttatttattggccttgaatttaagtgtagaaagcctttacaccaggggggcagcccctcgtggttactcttggacctgattatagacetcgcctttCCttggggctggaatacctagaagggagaggcagatctaaga

acacceccataaccttetgcactgtgtgttgactgtccgaagtgaactggtt tggcgtgcagaccccagcagacccaggteteetaccagaggcttgaaaeatattttcacttttaattttttatttttetcctgggctcaccaetgtgagat ttat ccgttaattcettgggagggcagagtaaggtagtgaeaaggggagagagtagccc tgggt ttagttcaatgatt tagt acecctcccatectttcctaacatg

ttettgcgga 1896ttcatcggga 1956gtgeatgtgt 2016tggaggggtg 2076tggtgtatgt 2136tgtgtcatgt 2196agcagtatta 2256tgtgcgggca 2316etteggagec 2376ctgttaeaga 2436tgtaaatata 2496tttttctttt 2556attttttttt 2616caagcaatec 2676eetgetttga 2736aatgtttact 2796gtgattgtga 2856cctgagagct 2916aaattgcatc 2976ctcctgttca 3036gagttgaggt 3096tggatcacta 3156ggtttatttt 3216aaactcttct 3276cgttccccag 3336tacattttat 3396

20/105

gtaaatatgt gcatatttgt acataaaatg atattctgtt tttaaataaa cagacaaaac 3456S ttgaaaaa 3464

0S <210> 11

<211> 510<212> PRT<213> Homo sapiens

<400> 11

0 Met Pro Leu Ser Leu Gly Ala Glu Met Trp Gly Pro Glu Ala Trp LeuC1 1 5 10

Leu Leu Leu Leu Leu Leu Ala Ser Phe Thr Gly Arg Cys Pro Ala Gly25

S Glu Leu Glu Thr Ser Asp Val Val Thr Val Val Leu Gly Gln Asp Ala40

C1 Lys Leu Pro Cys Phe Tyr Arg Gly Asp Ser Gly Glu Gln Val Gly Gin55

Val Ala Trp Ala Arg Val Asp Ala Gly Glu Gly Ala Gin Glu Leu Ala

00 65 70 75 Leu Leu His Ser Lys Tyr Gly Leu His Val Ser Pro Ala Tyr Glu Gly

90 C( Arg Val Glu Gln Pro Pro Pro Pro Arg Asn Pro Leu Asp Gly Ser Val

100 105 110Leu Leu Arg Asn Ala Val Gin Ala Asp Glu Gly Glu Tyr Glu Cys Arg

115 120 125Val Ser Thr Phe Pro Ala Gly Ser Phe Gln Ala Arg Leu Arg Leu Arg

130 135 140.Val Leu Val Pro Pro Leu Pro Ser Leu Asn Pro Gly Pro Ala Leu Glu145 150 155 160Glu Gly Gin Gly Leu Thr Leu Ala Ala Ser Cys Thr Ala Glu Gly Ser

165 170 175Pro Ala Pro Ser Val Thr Trp Asp Thr Glu Val Lys Gly Thr Thr Ser

180 185 190Ser Arg Ser Phe Lys His Ser Arg Ser Ala Ala Val Thr Ser Glu Phe

195 200 205His Leu Val Pro Ser Arg Ser Met Asn Gly Gin Pro Leu Thr Cys Val

210 215 220Val Ser His Pro Gly Leu Leu Gln Asp Gin Arg Ile Thr His Ile Leu225 230 235 240His Val Ser Phe Leu Ala Glu Ala Ser Val Arg Gly Leu Glu Asp Gin

245 250 255Asn Leu Trp His Ile Gly Arg Glu Gly Ala Met Leu Lys Cys Leu Ser

260 265 270Glu Gly Gin Pro Pro Pro Ser Tyr Asn Trp Thr Arg Leu Asp Gly Pro

275 280 285Leu Pro Ser Gly Val Arg Val Asp Gly Asp Thr Leu Gly Phe Pro Pro

290 295 300Leu Thr Thr Glu His Ser Gly Ile Tyr Val Cys His Val Ser Asn Glu305 310 315 320Phe Ser Ser Arg Asp Ser Gin Val Thr Val Asp Val Leu Asp Pro Gin

325 330 335Glu Asp Ser Gly Lys Gin Val Asp Leu Val Ser Ala Ser Val Val Val

340 345 350Val Gly Val Ile Ala Ala Leu Leu Phe Cys Leu Leu Val Val Val Val

355 360 365Val Leu Met Ser Arg Tyr His Arg Arg Lys Ala Gin Gin Met Thr Gin

370 375 380Lys Tyr Glu Glu Glu Leu Thr Leu Thr Arg Glu Asn Ser Ile Arg Arg385 390 395 400Leu His Ser His His Thr Asp Pro Arg Ser Gin Pro Glu Glu Ser Val

21/105

Gly Leu Arg405

Ala Giu420

Gly His Pro410

Asp Ser425Giu Gly

Leu Lys Asp Asn415Ser Ser

00Cys Ser Val Met Ser Giu Giu

435

Thr Thr Val Arg Giu Ile Glu450 455

Ser Gly Arg Ala Giu Giu Giu

Pro440Thr

Arg Ser Tyr445

Giu Leu Leu

Ser Thr Leu

Ser Pro GlyGin Thr460GiuGlu Asp Gin

465Al a

Asp475Thr

Giy Ile Lys

Met Asn His Phe485Ile

Gin Glu Asn G ly490Arg

Leu Arg Ala

Thr Gly Asn Tyr Ile Asn Gly505

Gly His Leu

'210> 12<211> 3344<212> DNA<213> HOMO sapiens

<220><221> CDS<222> (789) (1676)

<400> 12ggccgtcgttacggcttctttcccctagtgcagttccttaagctggagactctaccgagggcgaaggcgccttacgagggtcctgcgcaaccgccggcagtgaatcctggctgagggcaggccgttcctt

gttggccaca.gggggtagctgagacccaagttcaagtctgctcagacgtgggactccggcccaggaacta.ccgcgtggagcgcagtgcagcttccaggcgtccagcactacccagccccccaagcactc

gcgtgggaagacggctgggttgcgagaggcctactgctgggtaactgtgggagcaagtgggcgctactgccagccgccgcgcggatgaggcggctgcggcgaagagggccagcgtgacctcgctctgctg

cagctctggggtgtagaacgaagaactctgcatcatttactgctgggccaggcaagtggcactccaaataccccacgcaagcgagtacgatccgagtgctagggcctgacgggacacggaccgtcacctc

ggagctcggagggccggggCcagcttcctgaggccggtgcggacgcaaaaatgggctcggcgggcttcatccccctggacgtgccgggtcggtgcctccccctggcagccggtcaaaggcagagttccac

gctcccgatctggggctgggccttctgggtcccgcgggtgctgccctgctgtggacgcgggtgagcccggggctcagtgcagcaccttccctgccctcactcctgcacagacaacgtccattggtgccta.

120180240300360420480540600660720780830

gccgcagc atg aat ggg cag cca. ctg act tgt gtg gtg tcc cat: ccc ggcMet Asn Gly Gin Pro Leu Thr Cys Val Val Ser His Pro Gly

ctgLeu

ctc cag gac caa. aggLeu Gin Asp Gin Arg

20

atc acc cacIle Thr His

ggc ctt gaa.Gly Leu Giu

atc ctcIle Leu

25

cac gtg tccHis Val Ser

ttc cttPhe Leu

cac attHis Ile

878

926gct gag gcc tct gtg agAla Glu Ala Ser Val Arg

gac caa. aat ctg tggAsp Gin Asn Leu Trp,40

ggc aga gaa. gga. gct. atg ctc aagGly Arg Glu Gly Ala Met Leu Lys

ctg agt gaa gggLeu Ser Giu Gly

cag ccc cctGin Pro Pro

agt ggg gtaSer Gly Valccc tca tac

Pro Ser Tyraac tgg aca cggAsn Trp Thr Arg

gat ggg cct ctgAsp Gly Pro Leu

1022

cga gtg gat ggg gac act ttg ggc ttt

Arg Val Asp Gly Asp Thr Leu Gly Pheccc cca ctg acc act gag cacPro Pro Leu Thr Thr Glu His

1070

22/105

agcSer

ggc atc tac gtcGly Ile Tyr Val

tgcCys100

cat gtc agc aatHis Val Ser Asn

gagGlu105

ttc tcc tca agg gatPhe Ser Ser Arg Asp

1118

tct cag gtc actSer Gin Val Thr

gtg gat gtt ott gao ccc cag gaa gaoVal Asp Val Leu Asp Pro Gin Glu Asp115 120

cag gtg gacGin Val Asp

gca ctc ttgAla Leu Leu

145

ctaLeu130

gtg tca gcc tcgVal Ser Ala Ser

gtgVal135

gtg gtg gtg ggtVal Val Val Gly

tct ggg aagSer Gly Lys

125

gtg atc gccVal Ile Ala140

atg too cgaMet Ser Arg

ttc tgo ctt ctgPhe Cys Leu Leu

1166

gtgVal150

gtg gtg gtg gtgVal Val Val Val

tao oatTyr His

160

cgg cgc aag gcArg Arg L~ys Ala

cag atg aco cagGin Met Thr Gin

tat gag gag gagTyr Giu Glu Giu

1214

1262

1310

1358

1406

ctgLeu175

acc otg acc aggThr Leu Thr Arg

aac tcc atc cggAsn Ser Ile Arg

ctg cat tcc catLeu His Ser His

aog gao ccc aggThr Asp Pro Arg

cag cog gag gagGin Pro Glu Giu

gta ggg ctg agaVal Gly Leu Arg

goc gagAla Glu205

ggc cac cotGly His Pro

gaa gag cccGlu Glu Pro

225

gatAsp210

agt otc: aag gaoSer Leu Lys Asp

aacAsn215

agt agc tgc totSer Ser Cys Ser

gtg atg agtVal Met Ser220

gtg agg gagVal Arg Giu

1454

1502gag ggc cgc agtGlu Gly Arg Ser

tacTyr230

tcc acg ctg acoSer Thr Leu Thr

acgThr235

ata gaaIle Giu

240

aca cag act gaaThr Gin Thr Glu

o tgLeu245

ctg tct oca ggcLeu Ser Pro Gly

ggg cgg goc gagGly Arg Ala Glu

gagGiu255

gag gaa gat cagGlu Giu Asp Gin

gaa ggo atc aaaGiu Gly Ile Lys

gcc atg aac catAla Met Asn His

1550

1598

1646.

1696

gtt cag gag aatVal Gin Giu Asn

acc cta cgg gccThr Leu Arg Ala

ccc acg ggc aatPro Thr Gly Asn

ggc atcGly Ile285

tac atc aatTyr Ilie Asn

gg gGly290

cgg gga cac ctgArg Gly His Leu

gtc tgaVal*295

cccaggcctg cctccottc

ctaggcctggacaccoocataacottctgcactgtgtgttgactgtcogaagtgaactg

otocttctgtttcttgcggattcatogggagtgcatgtgttggaggggtgtggtgtatgt

tgacatgggaagatgctcccgggctccaccgcctgtgtgaactgtgtccggccacgggat

gattttagotcatcccaotgaattgagtctgtgttgactgtggtgtgtatttgagtggtt

catcttggggactgcttgac:otcccacoatactgtgtgtgtatgctgtcagcgtgggcaa

goctocttaactttacctocgoatgcaggttgtggaggggtatcagagtocactgtcagg

175618161876193619962056

23/105

00

00

gtttggcgtgcagaccccagcagacccaggtctcctaccagaggcttgaaacatattttcact t ttaat tttttatttttct cc tgggc tcaccactgtgagatttatccgttaattccttgggagggcagagtaaggtagtgacaaggggagagagtagccctgggtttagttcaatgatttagtaccctcccatcctttcctaacatgtttaaataaa

tgtgtcatgtagcagtattatgtgcgggcacttcggagccctgttacagatgtaaatatatttttcttttatttttttttcaagcaatcccctgctttgaaatgtttactgtgattgtgacctgagagctaaattgcatcctcctgttca.gagttgaggttggatcactaggtttattttaaactcttctcgttccccagtacattttatcagacaaaac

ggctgtgtgtatgatgcagatagctggagcatgggggcaaagccctctgccatgcgccggttttttcttgagagatggagtcctgcctcaatcctttacgactgggattgaaggggctacggtagagtctcaccattgttatagtggtgtgaggtgaaggattcaaggcttagctggccctagtctgaaacc ag cc tagggtaaatatgtttgaaaaa

gacctctgccggttggaggatggaatctgcgtgtgaagcacctctggtgggagcttcttgccctttccattctcactatggcct ccc tagaagagaaaaacttaaagtgattccaaggcagaaattagggtgtgataccttggggagagaaggtgctgggcttctggatgacccagatactctgctggatacttcgaatggcatatttgt

tgaaaaagcagagaggtggactccggtgtggccagtccctcctctgggcccaggaatacttagttgtattttgctcaggctagctgggacaaaaattaaaggcccctccatcttcatgcaatgtgagccttagggaattggagagcagtgggtgagaatgtttctctgggactcagccagttctggcctatggagcctgaacataaaatg

ggtattttct 2116gactgtggct 2176agggaacctg 2236gggtcagcca 2296tgctgcatgt 2356gctccgaatc 2416ttttatttat 2476tggccttgaa 2536tttaagtgta 2596gaaagccttt 2656acaccagggg 2716ggcagcccct 2776cgtggttact 2836cttggacctg 2896attatagacc 2956tcgcctttcc 3016ttggggctgg 3076aatacctaga 3136agggagaggc 3196agatctaaga 3256atattctgtt 3316

3344

<210> 13<211> 295<212> PRT<213> H-omo sapiens

<400> 13Met Asn Gly Gin Pro Leu Thr Cys1

Oin Asp Gin Arg Ile

Ser Val Arg GlyAla

Thr His Ile

Leu Glu Asp40

Lys Cys Leu

Val Val10

Leu His25Gin Asn

Val Ser Phe

Leu Trp

Ser His Pro Gly

Glu Giy Ala

Leu Leu

His

Pro

Leu Ala Glu

Ile Gly Arg

Pro Pro SerMet Leu Ser Giu Giy

Asn55Asp

Gin

SerTyr

Asp

Trp Thr Arg Gly Pro Leu Pro

Thr

Gly Val Arg

Gly Asp Thr Leu Phe Pro Pro Thr Glu His Ser G.ly

HisIle Tyr Val

Val Thr Val115

Asp Leu Val

Cys100Asp

Val Ser Asn Giu105Gin

Ser Ser Arg Asp Ser Gin110Lys Gin ValVal Leu Asp Pro

120Val

Glu Asp Ser Gly125IleSer Ala Ser Val Val Gly Ala Ala Leu

130Lell Phe Cys Leu Leu145Arg

ValI50Gin

Val Val Val Leu155Tyr

Ser Arg Tyr

Arg Lys Ala Gin Met Thr Gin Lys170Leu

Glu Glu Glu Leu Thr175

Leu Thr Arg

Pro Arg Ser195

Pro Asp Ser210

Pro Glu Gly

Glu180Gin

Asn Ser Ile Arg Arg185Val

His Ser His

Pro Glu Glu Ser200Ser

Gly Leu Arg

His Thr Asp190Giu Gly His

Ser Glu GiuLeu Lys Asp

Arg Ser Tyr230

Asn215Ser

Ser Cys Ser

225Thr

Thr Leu Thr Thr235

Pro Giy Ser Gly

Vai Arg Glu Ile Glu240

Arg Ala Glu Giu GiuGin Thr Glu Leu Leu Ser

24/105

00

245Glu Asp Gin Asp Giu Gly Ile

260Giu Asn Gly Thr Leu Arg Ala

275Asn Gly Arg Gly His Leu Val

290 295

250 255Lys Gin Ala Met Asn His Phe Val. Gin

265 270Lys Pro Thr Gly Asn Gly Ile Tyr Ile280 285

<210> 14<211> 3389<212> DNA<213> Homo sapiens

<220><221> CDS<222> (264) (1721)

<400> 14ggcCgtcgttacggcttctttcccctagtgcagttcctta*gctgggcagt

gttggccacagggggtagctgagacccaagttcaagtctgctgcctttca

gcgtgggaag cagetctggg ggagctcgga gctcccgatcacggctgggt gtgtagaacg gggccggggc tggggctgggtgcgagaggc aagaactctg cagcttcctg ccttctgggtcagccggctc ccagggagat ctcggtggaa cttcagaaacacc atg ccc ctg tcc ctg gga gcc gag atg tgg

Met Pro Leu Ser Leu Gly Ala Glu Met Trp,1 5

ggg ect gag gcc tgg ctg ctg ctg ctgGly Pro Giu Ala Trp Leu Leu Leu Leu

ctaLeu20

ctg ctg gca tea ttt acaLeu Leu Ala Ser Phe Thr

ggc cgg tgcGly Arg Cys

gtg ctg ggcVal Leu Gly

ccc gcgPro Ala

ggt gag ctgGly Giu Leu

gag acc tea gac gtg gta act gtgGiu Thr Ser Asp Val Val. Thr Vai35

ccc tgc ttc tac cga ggg gac tccPro Cys Phe Tyr Arg Gly Asp Ser

cag gac gca aaaGin Asp Ala Lys

ggc gagGly Giu

eaa gtg ggg caaGin Val Gly Gin

gca tgg gct eggAla Trp Ala Arg

gac geg gge gaaAsp Ala Gly Giu

485

ggc gee cag gaa cta geg eta ctg cac teeGly Ala Gin Giu Leu Ala Leu Leu His Ser

aaaLys

tac ggg ctt catTyr Gly Leu His

age ceg get tacSer Pro Ala Tyr

ggc ege gtg gagGly Arg Val Giu

cagGin100

ceg cog ccc ecaPro Pro Pro Pro

cgc aacArg Asn105

eec etg gacPro Leu Asp

ggc gag tacGly Giu Tyr

125

ggcGly110

tea gtg etc etgSer Val Leu Leu

aae gca gtg cagAsn Ala Val. Gin

geg gat gagAla Asp Giu120

age ttc eagSer Phe Gin

gag tge egg gteGiu Cys Arg Val.

ace ttc ccc geeThr Phe Pro Ala

ggcGly135

gcg egg ctg egg etc ega gtg ctg gtg cet ccc etg ccc tea ctg aat 725

25/105

Ala Arg Leu Arg Leu Arg Val. Leu Val Pro Pro Leu Pro Ser Leu Asn

140 145 .15000

0 cct ggt cca gca cta gaa gag ggc cag ggc ctg acc ctg gca gcc tcc 773

Pro Gly Pro Ala Leu Giu Giu Gly Gin Gly Leu Thr Leu Ala Ala Ser

155 160 165 170

tgc aca gct gag ggc agc cca gcc ccc agc gtg acc tgg gac acg gag 821

Cys Thr Ala Giu Gly Ser Pro Ala Pro Ser Val Thr Trp Asp Thr Giu

175 180 185

gtc aaa ggc aca acg tcc agc cgt tcc ttc aag cac tcc cgc tct gct 869

Val Lys Gly Thr Thr Ser Ser Arg Ser Phe Lys His Ser Arg Ser Ala

190 195 200

gcc gtc acc tca gag ttc cac ttg gtg cct agc cgc agc atg aat ggg 917

Ala Val Thr Ser Giu Phe His Leu Val Pro Ser Arg Ser Met Asn Gly205 210 215

00 cag cca ctg act tgt gtg gtg tcc cat cct ggc ctg ctc cag gac caa 965'

Gin Pro Leu Thr Cys Val Val Ser His Pro Gly Leu Leu Gin Asp Gln

220 225 230

agg atc acc cac atc ctc cac gtg tcc ttc ctt got gag gcc tct gtg 1013

Arg Ile Thr His Ile Leu His Val Ser Phe Leu Ala Glu Ala Ser Val

235 240 245 250

agg ggc ctt gaa gac caa aat ctg tgg cac att ggc aga gaa gga gct 1061

Arg Gly Leu Giu Asp Gin Asn Leu Trp His Ile Gly Arg Glu Gly Ala

255 260 265

atg ctc aag tgc otg agt gaa ggg cag ccc cct ccc tca tac aac tgg 1109

Met Leu Lys Cys Leu Ser Glu Gly Gin Pro Pro Pro Ser Tyr Asn Trp,

270 275 280

aca cgg ctg gat ggg cct. ctg ccc agt ggg gta cga gtg gat ggg gao 1157

Thr Arg Leu Asp Gly Pro Leu Pro Ser Gly Val Arg Val Asp Gly Asp

285 290 295

act ttg ggc ttt ccc cca ctg acc act gag cac agc ggc atc tao gtc 1205

Thr Leu Gly Phe Pro Pro Leu Thr Thr Giu His Ser Gly Ile Tyr Val

300 305 310

tgc cat gtc ago aat gag ttc tcc tca agg gat tct cag gtc act gtg 1253

Cys His Val Ser Asn Giu Phe Ser Ser Arg Asp Ser Gin Val Thr Val

315 320 325 330

gat gtt ctt gao ccc cag gaa gao tct ggg aag cag gtg gac cta gtg 1301

Asp Val Leu Asp Pro Gin Giu Asp Ser Gly Lys Gin Val. Asp Leu Val335 340 345

tca gcc tcg gtg gtg gtg gtg ggt gtg atc gcc gca ctO ttg ttc tgc 1349

Ser Ala Ser Val Val Val Val Gly Vai Ile Ala Ala Leu Leu Phe Cys

350 355 360

ott ctg gtg gtg gtg gtg gtg otc atg too cga tao cat cgg cgc aag 1397

Leu Leu Val Val. Val Val Val Leu Met Ser Arg Tyr His Arg Arg Lys

365 370 375

gcc cag cag atg aco cag aaa tat gag gag gag ctg aco ctg aco agg 1445

26/105

Ala Gin380

Gin Met Thr Gin Lys385

Tyr Giu Giu Giu Leu390

Thr Leu Thr Arg

00

00

aac tcc atc cggAsn Ser Ile Arg

aggArg400

ctg cat tcc catLeu His Ser His

cacHis405

acg gac ccc aggThr Asp Pro Arg

agcSer410

cag agt gaa. gagGin Ser Giu Giu

gag ggc cgc agtGiu Gly Arg Ser

tacTyr420

tcc acg ctg accSer Thr Leu Thr

acg gtgThr Val425

agg gag ata.Arg Glu Ile

gaa.Glu430

aca. cag act gaa.Thr Gin Thr Giu

ctgLeu435

ctg tct cca. ggcLeu Ser Pro Gly

tct ggg cggSer Gly Arg440

gcc atg aacAla Met Asn

1493

1541

1589

1637

1685

1731

.gcc gag gag gag gaa gat cagAla Giu Glu Giu Giu Asp Gin

gaa ggc atc aaa.Glu Gly Ile Lys

cat tttHis Phe

460

gtt cag gag aatVal Gin Glu Asn

gggGly465

acc cta cgg gccThr Leu Arg Ala Pro Thr Gly Asn

cccaggcctgggcGly475

atc tac atc aatIle Tyr Ile Asn

cgg gga. cac ctg gtc tga.Arg Gly His Leu Val*

485

cctcccttccgcctccttaactttacctccgcatgcaggttgtggaggggtatcagagtccactgtcaggggtattttctgactgtggctagggaacctggggtcagccatgctgcatgtgctccgaatcttttatttattggccttgaatttaagtgtagaaagcctttacaccagggggggagcccctcgtggttactcttggacctgattatagacctcgcctttccttggggctggaatacctagaagggagagg cagatctaagaatattctgtt

ctaggcctggacacccccataacccttctgcactgtgtgttgactgtccgaagtgaactggtttggcgtgcagaccccagcagacccaggtctcctaccagaggcttgaaacatattttcacttttaattttttatttttctcctgggctcaccactgtgagatttatccgttaattccttgggagggcagagtaaggtagtgacaaggggagagagtagccctgggtttagttcaatga.tttagtaccctcccatcctttcctaacatgtttaaataaa

ctccttctgtttcttgcgga.ttcatcgggagtgcatgtgttggaggggtgtggtgtatgttgtgtcatgtagcagtattatgtgcgggca.cttcggagccctgttacagatgtaaatatatttttcttttatttttttttcaagcaatcccctgctttga.aatgtttactgtgattgtgacctgagagctaaattgcatcctcctgttcagagttgaggttggatcacta.ggtttattttaaactcttctcgttccccagtacattttatcagacaaaac

tgacatgggaagatgctcccgggctccaccgcctgtgtgaactgtgtccggccacgggatggctgtgtgtatgatgcagatagctggagcatgggggcaa.agccctctgccatgcgccggttttttcttgagagatggagtcctgcctca.atcctttacgactgggattgaaggggctacggtagagtctcaccattgttatagtggtgtgaggtgaaggattcaaggcttagctggccctagtctgaaaccagcctagggtaaatatgtttgaaaaa

gattttagctcatcccactgaattgagtctgtgttgactgtggtgtgtatttgagtggttgacctctgccggttggagga.tggaatctgcgtgtgaagca.cctctggtgggagcttcttgccctttccattctcactatggcctccctagaagagaaaaacttaaagtgattccaaggca.gaaattagggtgtgataccttggggagagaaggtgctgggcttctggatga ccc aga tactctgctggatacttcgaatggcatatttgt

catcttggggactgcttgacctcccaccatactgtgtgtgtatgctgtca.gcgtgggcaatgaaaaagcagagaggtggactccggtgtqgccagtccctcctctgggcccaggaatacttagttgtattttgctcaggctagctgggacaaaaattaaaggcccctcca,tcttcatgca.atgtgagccttagggaattggagagcagtgggtgagaatgt tt ctc tgggact cagc cagttctggcctatggagcctga.acataaaatg

1791185119111971203120912151221122712331239124512511257126312691275128112871293129913051311131713231329133513389

<210> <211> 485<212> PRT<213> Homo sapiens

27/105

<400>

00 Met Pro Leu Ser Leu Gly Ala Glu Met Trp Gly Pro Glu Ala Trp Leu

1 5 10

Leu Leu Leu Leu Leu Leu Ala Ser Phe Thr Gly Arg Cys Pro Ala Gly

C120 25

S Glu Leu Giu Thr Ser Asp Val Val Thr Val Val Leu Gly Gln Asp Ala

40

55

Val Ala Trp Ala Arg Val Asp Ala Gly Glu Gly Ala Gln Glu Leu Ala

70 75

Leu Leu His Ser Lys Tyr Gly Leu His Val Ser Pro Ala Tyr Giu Gly

90

Arg Val Giu Gin Pro Pro Pro Pro Arg Asn Pro Leu Asp Gly Ser Val

c1100 105 110

Leu Leu Arg Asn Ala Val Gin Ala Asp Glu Gly Glu Tyr Giu Cys Arg

115 120 125

Vai Ser Thr Phe Pro Ala Gly Ser Phe Gin Ala Arg Leu Arg Leu Arg

00 130 135 140

Val Leu Val Pro Pro Leu Pro Ser Leu Asn Pro Gly Pro Ala Leu Glu

145 150 155 160

Glu Gly Gin Gly Leu Thr Leu Ala Ala Ser Cys Thr Ala Glu Gly Ser

165 170 175

Pro Ala Pro Ser Val Thr Trp Asp Thr Glu Val Lys Gly Thr Thr Ser

180 185 190

Ser Arg Ser Phe Lys His Ser Arg Ser Ala Ala Val Thr Ser Giu Phe

195 200 205

His Leu Val Pro Ser Arg Ser Met Asn Gly Gin Pro Leu Thr Cys Val

210 215 220

Val Ser His Pro Gly Leu Leu Gin Asp Gin Arg Ile Thr His Ile Leu

225 230 235 240

His Val Ser Phe Leu Ala Giu Ala Ser Val Arg Gly Leu Glu Asp Gin

245 250 255

Asn Leu Trp His Ile Gly Arg Giu Gly Ala Met Leu Lys Cys Leu Ser

260 265 270

Glu Gly Gin Pro Pro Pro Ser Tyr Asn Trp Thr Arg Leu Asp Gly Pro

275 280 285

Leu Pro Ser Gly Val Arg Val Asp Gly Asp Thr Leu Gly Phe Pro Pro

290 295 300

Leu Thr Thr Giu His Ser Gly Ile Tyr Val Cys His Val Ser Asn Giu

305 310 315 320

Phe Ser Ser Arg Asp Ser Gin Val Thr Val Asp Val Leu Asp Pro Gin

325 330 335

Giu Asp Ser Gly Lys Gin Val Asp Leu Val Ser Ala Ser Val Val Val

340 345 350

Val Gly Vai Ile Ala Ala Leu Leu Phe Cys Leu Leu Val Val Val Val

355 360 365

Val Leu Met Ser Arg Tyr His Arg Arg Lys Ala Gin Gin Met Thr Gin

370 375 380

Lys Tyr Glu Giu Glu Leu Thr Leu Thr Arg Glu Asn Ser Ile Arg Arg

385 390 395 1 400

Leu His Ser His His Thr Asp Pro Arg Ser Gin Ser Glu Giu Pro Glu

405 410 415

Gly Arg Ser Tyr Ser Thr Leu Thr Thr Val Arg Glu Ile Glu Thr Gin

420 425 430

Thr Giu Leu Leu Ser Pro Gly Ser Gly Arg Ala Glu Giu Giu Giu Asp

435 440 445

Gin Asp Giu Gly Ile Lys Gin Ala Met Asn His Phe Val Gin Glu Asn

450 455 460

28/105

Gly Thr Leu Arg Ala Lys Pro Thr Gly Asn Gly Ile Tyr Ile Asn Gly465 470 475 480Arg Gly His Leu Val.

485

<210> 16<211> 3401'212> DNA<213> Homo sapiens

<220><221> CDS<222> (264) (1796)

<400> 16ggCcgtcgttacggcttctttcccctagtgcagttccttagctgggcagt

gttggccacagggggtagctgagacccaagttcaagtctgctgcctttca

gcgtgggaag cagctctggg ggagctcgga gctcccgatcacggctgggt gtgtagaacg gggccggggc tggggctgggtgcgagaggc aagaactctg cagcttcctg ccttctgggtcagccggctc ccagggagat ctcggtggaa cttcagaaacacc atg ccc ctg tcc ctg gga gcc gag atg tgg

Met Pro Leu Ser Leu Gly Ala Giu Met Trp

gyg cct gag gccGly Pro Glu Ala

ctg Ctg ctg CtgLeu Leu Leu Leu

ctg ctg gca tcaLeu Leu Ala Ser

ttt acaPhe Thr

341

389ggc cgg tgcGly Arg Cys

gtg ctg ggcVal Leu Gly

cccPro

gcg ggt gag ctgAla Gly Glu Leu

acc tca gac gtg gta act gtgThr Ser Asp Val Val Thr Val

cag gac gca aaaGin Asp Ala Lys

ccc tgc ttc tacPro Cys Phe Tyr

ggg gac tccGly Asp Ser

ggc gagGly Glu

caa gtg ggg caaGin Val Gly Gin

gtgVal65

gca tgg gct cggAla Trp Ala Arg

gtg gac gcg ggc gaaVal Asp Ala Gly Giu

tac ggg ctt cat gtgTyr Gly Leu His Val

ggcGly

gcc cag gaa ctaAla Gin Glu Leu

cta ctg cac tccLeu Leu His Ser

aaaLys

485

533

581agc ccg gct tacSer Pro Ala Tyr

ggc cgc gtg gagGly Arg Val Glu

ccg ccg ccc ccaPro Pro Pro Pro

cgc aacArg Asn105

ccc ctg gacPro Leu Asp

ggc gag tacGly Glu Tyr

125

ggcGly110

tca gtg ctc ctgSer Val Leu Leu

aac gca gtg cagAsn Ala Val Gin

gcg gat gagAla Asp Giu120

gag tgc cgg gtcGiu Cys Arg Val

acc ttc ccc gcc ggc agc ttc cagThr Phe Pro Ala Gly Ser Phe Gin

135

gcg cggAla Arg

140

ctg cgg ctc cgaLeu Arg Leu Arg

ctg gtg cct cccLeu Val Pro Pro

ccc tca ctg aatPro Ser Leu Asn

29/105

00

0

cct ggt oca gcaPro Gly Pro Ala155

tgc aca gct gagCys Thr Ala Glu

cta gaa gag ggc cag ggc ctgLeu Giu

160Giu Gly Gin Gly Leu

acc ctg gcaThr Leu Ala

gco tccAla Ser

170

aog gagThr Glu185

ggcGly175

agc cca gcc cccSer Pro Ala Pro

agoSer180

gtg acc tgg gacVal Thr Trp Asp

gtc aaa ggc aca acg tcc agc cgt

Val Lys Gly Thr Thr Ser Ser ArgtccSer195

ttc aag cac tcoPhe Lys His Ser

090 tct gctArg Ser Ala200

atg aat gggMet Asn Gly

773

821

869

917

965

1013

9CC gtc acc

Ala Val. Thr205

tca gag ttc cac

Ser Glu Phe HisttgLeu210

gtg cct agc cgcVal Pro Ser Arg

agcSer215

cag coaGin Pro

220

ctg act tgt gtgLeu Thr Cys Val

gtgVal225

toc cat oct ggoSer His Pro Gly

ctgLeu230

ctc cag gac caaLeu Gin Asp Gin

atc acc cac atc:Ile Thr His Ile

cac gtg too ttoHis Val Ser Phe

ottLeu245

got gag goc totAla Glu Ala Ser

agg ggc ott gaaArg Gly Leu Glu

gaoAsp255

oaa aat otg tgg cac att ggo aga gaaGin Asn Leu Trp His Ile Gly Arg Glu

260

gga gotGly Ala265

1061

atg oto aagMet Leu Lys

aoa ogg otgThr Arg Leu

285

otg agt gaa gggLeu Ser Giu Gly

ccc cot coo toaPro Pro Pro Ser

tao aac tggTyr Asn Trp280

gat ggg gaoAsp Gly Asp

1109

1157gat ggg oct ctgAsp Gly Pro Leu

agt ggg gta ogaSer Gly Val Arg

act ttgThr Leu

300

ggo ttt coo coaGly Phe Pro Pro

aco act gag cacThr Thr Glu His

990 ato tao gtoGly Ile Tyr Val

tgoCys315

oat gto ago aatHis Val Ser Asn

tto too tca aggPhe Ser Ser Arg

gatAsp325

tot cag gto actSer Gin Val Thr

1205

1253

1301gat gtt ott gao:Asp Val Leu Asp

cag gaa gao totGin Glu Asp Ser

aag cag gtg gaoLys Gin Val Asp

cta gtgLeu Val345

toa goo togSer Ala Ser

ott otg gtgLeu Leu Val

365

gtg gtg gtg ggtVal Val Val Gly

ato goc gca otoIle Ala Ala Leu

ttg tto tgoLeu Phe Cys360

1349

gtg gtg gtg gtg oto atg too oga taoVal Val Val Val Leu Met Ser Arg Tyr

370

oat cgg cgc aagHis Arg Arg Lys375

1397

goc cagAla Gin

380

cag atg aod cagGln Met Thr Gin

aaaLys385

tat gag gag gag Otg aco otg acc aggTyr Glu Glu Giu Leu Thr Leu Thr Arg

390

1445

30/1

gagGlu395

aac tcc atc cggAsn Ser Ile Arg

agg ctgArg Leu400

cat tcc catHis Ser His

cacHis405

acg gac ccc aggThr Asp Pro Arg

agcSer410

1493

00

00

cag ccg gag gagGin Pro Glu Glu

agtSer415

gta. ggg ctg agaVal Gly Leu Arg

gag ggc cac cctGiu Gly His Pro

gat agtAsp Ser425

cte aag gacLeu Lys Asp

cgc agt tacArg Ser Tyr

445

aacAsn430

tccSer

agt agc tgc tctSer Ser Cys Ser

acg ctg acc acgThr Leu Thr Thr

450

gtgVal1435

atg agt gaa gagMet Ser Giu Giu

ccc gag ggcPro Glu Gly440

aca cag actThr Gin Thr

gtg agg gag ataVal Arg Giu Ile

gaaGiu455

1541

1589

1637

1685

1733

1781

gaa ctgGiu Leu

460

ctg tct cca ggcLeu Ser Pro Gly

tctSer465

ggg cgg gcc gagGly Arg Ala Glu

gag gaa. gat cagGlu Giu Asp Gin

gatAsp475

gaa ggc atc aaaGiu Gly Ile Lys

cagGin480

gcc atg aac catAla Met Asn His

tttPhe485

gtt cag gag aatVal Gin Giu Asn

gggGly490

acc cta cgg gccThr Leu Arg Ala

aagLys495

ccc acg ggc aatPro Thr Gly Asn

ggcGly500

atc tac atc aatIle Tyr Ile Aan

ggg cggGly Arg505

gga cac ctg gtc tgaGiy His Leu Val*

510

cccaggcctg cctcccttcc ctaggcctgg ctccttctgt 1836

tgacatggga gattttagctagatgctcccgggctccaccgcctgtgtgaactgtgtccggccacgggatggctgtgtgtatgatgcagatagctggagcatgggggcaaagccctctgccatgcgccggttttttcttgagagatggagtcctgcctcaatcctttacg

aaggggctacggtagagtctgtggtgttgggtgaaggaggcaaggctcttctggcccacctctgaaatctgcctaggactaatatgtgcaaaaaa

catcccactgaattgagtctgtgttgactgtggtgtgtatt tgagtggttgacctctgccggttggaggatggaatctgcgtgtgaagcacctctggtgggagcttcttgccctttccattctcactatggcctccctagaagagaaaaacttaaagtgattccaaggcagaaattagggggagagagagtgctgggggtctggatgtttcagatacactgctggatttctcgaatgtggtatttgtaca

catcttggggactgcttgacctcccaccatactgtgtgtgtatgctgtcagcgtgggcaatg aaa aagc agagaggtggactccggtgtggccagtccctcctctgggcccaggaatacttagttgtattttgctcaggctagctgggacaaaaat taaaggcccctccatcttcatgcaatgtgagcctagcagtgattgagaatgtcgctctgggttgcagccagaattggcctaaggagcctgaagataaaatgata

gcctccttaactttacctccgcatgcaggttgtggaggggtatcagagtccactgtcaggggtattttctgactgtggctagggaacctggggtcagccatgctgcatgtgctccgaatcttttatttattggccttgaatttaagtgtagaaagcctttacaccaggggggcagcccctcgtgctggtgatagaccgagcctttcccccgggctggagtacctagatttgagaggctcctctaagatccttctgttttt

acacccccataacccttctgcactgtgtgttgactgtccgaagtgaactggtttggcgtgcagaccccagcagacccaggtctcctaccagaggcttgaaacatattttcacttttaattttttattttt.ctcctgggctcaccactgtgagatttatccgttaattccttgggagggcaacaagggctcagagtaggagtgggttttggtcaatgaggtagt accc aaacatccttcgt.taacatgtacaaataaacag

ttcttgcgga 1896ttcatcggga 1956gtgcatgtgt 2016tggaggggtg 2076tggtgtatgt 2136tgtgtcatgt 2196agcagtatta 2256tgtgcgggca 2316cttcggagcc 2376ctgttacaga 2436tgtaaatata 2496tttttctttt 2556attttttttt 2616caagcaatcc 2676cctgctttga 2736aatgtttact. 2796gtgattgtga 2856cctgagagct 2916ctgttcaata 2976ttgaggtgag 3036atcactaatt 3096ttatttttag 3156ctcttcttag 3216tccccagcca 3276attttatgta 3336acaaaacttg 3396

3401

311105

<210> 17<211> 510<212> PRT<213> Homo sapiens

00

00

<400> 17Met Pro Leu Ser Leu Gly Ala Glu Met Trp Gly Pro Glu Ala

T

1 5 10

Leu L

Glu Li

Lys L

Val A

Leu L

Arg V

Leu L

Val S2

Val I145Glu C

Pro 2

Ser 2

His

Val225His

Asn

Glu

Leu

Leu305Phe

Glu

Val

Val

Lys385Leu

eu L

eu G3

eu P0la T

eu H

al G

eu P

er 1.30

ieu

fly

kla

krg

Leu210Ser

Val

Leu

Gly

Pro290Thr

Ser

Asp

Gly

Leu370Tyr

His

eu

lu5ro

rp

.is

Ilu

rg

:hr

lal

31n

Pro

Ser195Val

His

Sei

TrE

G1x27!Se

Thl

Se:

Sce

Va

Me

GI

Se

Leu Leu Leu

Thr Ser Asp

Cys Phe Tyr

Ala Arg Val70

Sen Lys Tyr

Gin Pro Pro100Asn Ala Val

Phe Pro Ala

Pro Pro Leu150

Gly Leu Thr165

Sen Val Thr180Phe Lys His

Pro Ser Arc

Pro Gly Let23(

Phe Leu Al245

His Ile Gi1260

i Pro Pro Pr

r Gly Val Ar

r Glu His Se31

r Arg Asp Sc325

r Gly Lys Gi340

1 lie Ala Al5t Ser Arg Ty

u Glu Glu Le

39

r His His T1405

s

Y

c

c

1

1

I

Ala S

Val V4

Arg G55Asp A

Gly L

Pro P

Gin .P

Gly 135Pro

Leu 2

Trp 2

Ser

Ser I215Leu

Glu

Arg

Sen

Val295Gly

r Gin

n Val

a Leu

r His375

u Thr0r Asp

er P2

al T0

ly A

la G

eu F

~ro

lia 220,er I

3er

kla

%sp

Arg200Met

Gin

Ala

Glu

Tyr280Asp

Ile

Val

Asp

Leu360Arg

Leu

Pro

he5

hr

sp

ly

is

L.rg

105sp

?he

Leu

Ala

Thx185Sex

Asr

Asr

Se

Gi126!As

G1

TY:

Th

Le34Ph

Ar

Th

Ar

Thr Gly A

Val Val L

Ser Gly G6

Glu Gly A75

Val Ser P90Asn Pro I

Glu Gly C

Gin Ala 2

Asn Pro155

Ser Cys170Glu Val

Ala Ala

Gly Gin

Gin Arg235

Val Arg250

r Ala Met

i Trp Thr

y Asp Thr

r Val Cys315

r Val Asp330

u Val Ser5e Cys Leu

g Lys Ala

.r Arg Glu395

g Ser Gin410

rg

eu

lu0la

'ro

ieu

flu

rg140

.iy

rhr

Lys

Val

Pro220Ile

Gly

Let

ArS

Le

Hi

Va

Al

Le

Gi38As

Cys P3

Gly G

Gin V

Gin G

Ala T

Asp G1

Tyr G125Leu P

Pro I

Ala C

Gly

Thr205Leu

Thr

Leu I

Lys

Leu285Gly

s Val

1 Leu

a Ser

u Val365

n Gin0n Ser

ro A0in A

al G

iu I

-yrC

ly 5

lu

Lrg

1 a

flu

rhr190Ser

rhr

His

G1u

Cys270Asp

Phe

Ser

Asp

Val350Val

Met

Ile

'rp

I a

sp

ily

ieu

flu

3er

:ys

Leu

Leu

31y175Thr

Glu

Cys

IlE

Asi

Let

G1'

Pr

As

Pr33Va

Va

Th

Ar

Leu

Gly

Ala

Gin

Ala

Gly

Val

Arg

Arg

Glu160Ser

Ser

Phe

Val

Leu240Gin

i Ser

e Pro

o Pro

n Glu320

o Gln

1 Val

1 Val

.r Gin

g Arg400

Pro Glu Giu Ser Val415

Gly Leu Arg Glu Gly His Pro Ser Leu Lys Asp Asn Ser Ser

430

32/105

00

Cys Ser Val.435

Thr Thr Val450

Per Gly Arg

Met Ser Giu Giu Pro440Thr

Glu Giy Arg Ser Tyr445Leu

Ser Thr Leu

Ser Pro GlyArg Giu Ile

Ala Giu Glu

Glu455Glu

Gin Thr Giu

Giu Asp Gin Asp475Thr

Gly Ile Lys Gin480ProMet Asn His Gin Glu Asn Gly

490Arg

Leu Arg Aia

Thr Gly Asn Gly500

Tyr Ile Asn Gly His Leu

<210> 18<211> 1669<212> DNA<213> Homo sapiens

<220><221> CDS<222> (708)..(1121)

<400> 18gtctgacccattagctcatcccactgactggagtctctcctgactgactggtgtattatggtggttgcgttctgcctgaaggaggagagaatctgcctccgaagcagccatggtggcctc

ggcctgcctcttgggggcctcttgacctttcaccatgcattgtgtgtgtgctgtcatatcgggcaacactaaagcaggtaggtggagactggtgtgaggggtccctgggttgggcctgct

cc t tccc tagccttaaacacacctccaaccgcaggtcactgaggggtgacagagtcaagtgtcagggtttttttctcagagtggctcagaaacctgtctccagccagagggcatgtacat

gCctggctccccccatttctcttctgttcagtgtgtgtgctgtccgtggagaactgtggtggcgtgtgtgccccagagcacccaggtgtgctaccacttccttgaactgtattttctgta

ttctgttgactgcggaagattcgggagggcatgtgtgcctggggtgactggtatgtgccatcatgtggctgtattaatgacgggcatagcggagccatggtacagaagcc

atgggagattgctccccatctccaccaattgtgtgagtgttgtccgtggtcgggatttgagtgtgtgacctgcagaggtttggagctggagggcaagtgtctctgccctc

120180240300360420480540600660716aatatac atg cgc cgg

Met Arg Arg:I

gag cttGiu Leu

ctt gca gga ataLeu Ala Gly Ile

ctc cga. atc actLeu Arg Ile Thr

ttt aatPhe Asn

ttt ttt cttPhe Phe Leu

tttPhe

ttt ttc ttg cccPhe Phe Leu Pro

cca tta gtt gtaPro Leu Val Val. Phe Ile Tyr Phe

764

812

860Phe Tyr Phe Phe

ttaLeu

gag atg gag tctGlu Met Giu Ser

tat gtt gct cagTyr Val Ala Gin

gct ggcAla Gly

ctt gaa ctcLeu Glu Leu

gct ggg act

Ala Gly Thr

ggc tca agc aatGiy Ser Ser Asn

cctPro

cct gcc tcaPro Ala Ser

gcc tcc cta gtaAla Ser Leu Val

gaa tcc ttt acgGiu Ser Phe Thr

tta agt gta cacLeu Ser Val His

tgt gcc tgc tttCys Ala Cys Phe

aag agaLys Arg

aaa aaa aaa tta aag aaa gcc ttt aga ttt atc caa tgt ttaLys Lys Lys Leu Lys Lys Ala Phe Arg Phe Ile Gin Cys Leu

1004

331105

00cta ctg gga ttg ctt aaa gtg agg ccc ctc caa cac cag ggg gtt aat

Leu Leu Gly Leu Leu Lys Val Arg Pro Leu Gin His Gin Gly Val Asn

100 105 110 115

tcc tgt gat tgt gaa agg ggc tac ttc caa ggc atc ttc atg cag gca

Ser Cys Asp Cys Giu Arg Gly Tyr Phe Gin Gly Ile Phe Met Gin Ala

120 125 130

gcc cct tgg gag ggc acc tga gagctggtag agtctgaaat tagggatgtg

Ala Pro Trp Giu Gly Thr*135

1052

1100

1151

agcctcgtggaattgcttggcagtgattatgaatgtcgccctgggttggggccagaatacgcctaagggacctgaagatcaaatgatat t

ttactgagtaacctggtgacagaccgagagtttccccctggctggagttcctagatttaggaggctcccataagatcctactgtttttaa

aggtaaaattaagggctcctagtaggagttggttttggataatgaggttttacccaaacttccttcgttcacatgtacatataaacagac

gcatccaccagttcaatagtgaggtgaggtc act aat t caatttttagctcttcttagtccccagccagctttatgtaaaaaaacttg

ttgtttgtgaggtgttgggggaaggaggtgaggctcttctggcccacccatgaaatctgcctaggacttctatgtgcata

taccttagggagagagagagctgggggtgaggatgtttctgatacactcatggatttctggaatgtggagtttgtacata

121112711331139114511511157116311669

<210> 19<211> 137<212> PRT<213> Homo sapiens

<400> 19Met Arg Arg Giu Leu Leu Ala Gly Ile Leu

Phe Pro

Leu Arg Ile Thr Phe Asn

Phe Phe Leu Phe Phe Phe Leu Pro

Tyr Phe Tyr Phe Tyr Phe Phe Leu40

Gin Ala Gly Leu Glu Leu Leu Giy55

Ser Leu Vai Ala Giy Thr Leu Ser70

Ser Phe Thr Lys Arg Lys Lys Lys

Leu Val Val25Glu Met Giu Ser His

Pro

Phe Phe Ile

Tyr Val Ala

Ala Ser AlaSer Ser Asn Pro

CysVal His His

Lys

Ala Cys Phe

Leu Ala Phe Arg Phe Ile

Gin Cys Leu Leu Leu Gly Leu Leu Lys100 105

Gly Val Asn Ser Cys Asp Cys Giu Arg2.15 120

Met Gin Ala Ala Pro Trp Giu Gly Thr

130 135

Arg Pro Leu Gin His Gin110

Tyr Phe Gin Gly Ile Phe125

Giy

<210> <211> 3464<212> DNA<213> Homo sapiens

<220><221> CDS<222> (264) (1796)

<400>

ggccgtcgtt gttggccaca gcgtgggaag cagctctggg ggagctcgga gctcccgatc

34/105

00

00

acggcttctt. gggggtagct acggctgggt. gtgtagaacg gggccggggc tggggctgggtcccctagtg gagacccaag tgcgagaggc aagaactctg cagcttcctg ccttctgggt-cagttcctta ttcaagtctg cagccggctc ccagggagat ctcggtggaa cttcagaaacgctgggcagt ctgcctttca acc: atg ccc ctg tcc ctg gga gcc gag atg tgg

Met Pro Leu Ser Leu Gly Ala Glu Met Trp

ggg cct gag gccGly Pro Glu Ala

ggc cgg tyc cccGly Arg Cys Pro

gtg ctg ggc cagVal Leu Gly Gin

ctg ctg ctg ctgLeu Leu Leu Leu

ctg ctg gca tcaLeu Leu Ala Ser

ttt acaPhe Thr

gcg ggt gag ctgAla Gly Glu Leu

acc tca gac gtg gta act gtgThr Ser Asp Val Val. Thr Val

gac gca aaaAsp Ala Lys

ctgLeu50

ccc tgc ttc tacPro Cys Phe Tyr

cgaArg

ggg gac tccGly Asp Ser

341

389

437

485

533

581

ggc gagGly Glu

caa gtg ggg caaGin Val Gly Gin

gca tgg gct cggAla Trp Ala Arg

gac gcg ggc gaaAsp Ala Gly Giu

ggc gcc cag gaa ctaGly Ala Gin Glu Leu

agc ccg gct tac gagSer Pro Ala Tyr Glu

cta ctg cac tccLeu Leu His Ser

tac ggg ctt. catTyr Gly Leu His

ggc cgc gtg gagGly Arg Val Glu

ccg ccg ccc ccaPro Pro Pro Pro

cgc aacArg Asn105

ccc ctg gacPro Leu Asp

ggc gag tacGly Glu Tyr

125

tca gtg ctc ctgSer Val Leu Leu

aac gca gtg cagAsn Ala Val Gin

gcg gat gagAla Asp Glu120

agc ttc cagSer Phe Gin

gag tgc cgg gtcGlu Cys Arg Val

acc ttC ccc gccThr Phe Pro Ala

gcg CggAla Arg

140

ctg cgg ctc cgaLeu Arg Leu Arg

gtgVal145

ctg gtg cct cccLeu Val Pro Pro

ccc tca ctg aatPro Ser Leu Asn

ggt cca gca ctaGly Pro Ala Leu

gaaGlu160

gag ggc cag ggcGlu Gly Gin Gly

acc ctg gca gccThr Leu Ala Ala

tgc aca gct gagCys Thr Ala Glu

agc cca gcc cccSer Pro Ala Pro

gtg acc tgg gacVal Thr Trp Asp

acg gagThr Giu185

gtc aaa ggcVal Lys Gly

gcc gtc accAla Val Thr

205

acg tcc agc cgtThr Ser Ser Arg

ttc aag cac tccPhe Lys His Ser

cgc tct. gctArg Ser Ala200

atg aat gggMet Asn Gly

869

917tca gag ttc cacSer Glu Phe His

ttgLeu210

gtg cct agc cgcVal Pro Ser Arg

agc:Ser215

cag cca ctg act tgt gtg gtg tcc cat cct ggc ctg ctc: cag gac caa

35/105

Gin Pro Leu Thr Cys Val Val Ser His Pro Gly Leu Leu Gin Asp Gin220

00

00

agg aArg I235

agg 9Arg G

atg c

Met L.

aca c

Thr P

acttThr

tgcCys315

gatAsp'

teaSer

cttLeu

geeAla

gagGlu395

cagGin

etcLeu

cgeArg

tcle

goly

to

~rg

tgjeu00

atIi S

gttVal

gccAla

ctLet

cacG1x381

aa(As~

eecPr

aaLy

agSe

aec cThr H

ott gLeu C

aagtLys

ctgLeu285

ggcGly

gteVal

ottLeu

tcgSer

gtg1Val

365

3 eag.i Gin0

*teeSer

9 gago Giu

ac ate[is Ile

~aa gaoflu Asp

255

:90 ctgys Leu270

3at gggksp Gly

ttt cooPhe

ageSer

gaoAsp

gtgVal350

gtgVal

atgMet

ateIle

gagGlu

aaeAsn430

tooSer

Pro

aatAsn

cooPro335

gtgVal

gtgVal

aceThr

eggArg

ag tSer415

agtSer

acThi

225

ctc eac g1Eieu His V~240

caa aat cGln Asn L

agt gaa 9Ser Glu G

eet otg oPro Leu P

2

eca ctg aPro Leu T1

305

gag tte tGlu Phe E320

cag gaaGin Glu2

gtg gtgVal Val

gtg gtgVal Val

cag aaaGin Lys

385

agg ctgArg Leu400

gta 999*Val Gly

*age tgoSe8r Cys

ctg ace*Leu Thr

Lg tal S

tg teu T

99 Cly G

2

cc a'ro S90

ccO E'hrJ

cce~er

3ac%sp

ggtGly

CtcLeu370

cecer

ggrp

agin75

igter

~ctLhr

:caSer

tSer

gtgVal355

atgMet

tPhe

cacHi s260

CccPro

gggGly

gagGlu

aggArg

gggGiy340

at cI le

tcSei

2

ott gLeu A~

245

attIle G

cot CPro I

gtaVail

cacHis

gatAsp325

aagLys

geeAla

ogaArg

igefly

-ccro

-ga.rg

agoSer310

totScr

cagGin

gcaAl a

tacTyr

agaArgC

tea8cr

gtgVal295

990

Gly

cagGin

gtgVal

etcLeu

catHis375

'ct gag geela Giu Ala

~aaiu

tac['yr280

gatAsp

ateIle

gteVal

gaoAsp

t t9Leu360

C99Arc

etcLet

cc(Pr

eelPr

tet gtgSer Vai

250

gga getGly Ala265

aac tggAsn Trp

ggg gaoGly Asp

tac gteTyr Val

act gtgThr Val

330

eta gtgLeu Val345

ttC tgcPhe Cys

ego aagIArg Lys

ace aggThr Arg

agg ago)Arg Ser

410

tgat agto Asp Ser425

cgag ggc0 Giu Gly0

a cag actr Gin Thr

a gat cag

1013

1061

1109

1157

1205

1253

1301

1349

1397

1445

1493

1541

1589

1637

1685

9S

tr

gaoAsp

taoTyr

tat gag gag gag ctgTFyr Giu Giu Giu Leu

390

eat toe eat cac aegHis Ser His His Thr

405

etg aga gee gag 990

Leu Arg Ala Giu Gly420

tot gtg atg agt gaaSer Val Met Scr Giu

435

aog gtg agg gag ataThr Val Arg Glu Ile450

999 099 gee gag gag

Thr

gaoAsp

cacHis

gag eccGiu

gaaGlu455

gag

Pr44

acTh

gagaa etg etg tot eca ggo tot

36/105

00

Glu Leu Leu Ser Pro Gly Ser Gly Arg Ala Giu Glu Glu Giu Asp Gin460 465 470

gat gaa ggc atc aaa cag gcc atg aac cat ttt gtt cag gag aat gggAsp Giu Gly Ile Lys Gin Ala Met Asn His Phe Val Gin Glu Asn Giy475 480 485 490

acc cta cgg gcc aag ccc acg ggc aat ggc atcThr Leu Arg Ala Lys Pro Thr Gly Asn Gly Ile

495 500

tac atc aat ggg cggTyr Ile Asn Giy Arg

505

gga cac ctg gtc tga cccaggcctg cctcccttcc ctaggcctgg ctccttctgtGly His Leu Vail

510

tgacatgggaagatgctcccgggctccaccgcctgtgtgaactgtgtccggccacgggatggctgtgtgtatgatgcagatagctggagcatgggggcaaagccctctgccatgcgccggttttttcttgagagatggagtcctgcctcaatcctttacgactgggattgaaggggctacggtagagtctcaccattgttatagtggtgtgaggtgaaggattcaaggcttagctggccctagtctgaaaccagcctagggtaaatatgtttgaaaaa

gattttagctcatcccactgaattgagtctgtgttgactgtggtgtgtatttgagtggttgacctctgccggttggaggatggaatctgcgtgtgaagcacctctggtgggagcttcttgccctttccattctcactatggcctccctagaagagaaaaacttaaagtgattccaaggcagaaattagggtgtgataccttggggagagaaggtgctgggcttctggatgacccagatactctgctggatacttcgaatggcatatttgt

catcttggggactgcttgacctcccaccatactgtgtgtgtatgctgtcagcgtgggcaatgaaaaagcagagaggtggactccggtgtggccagtccctcctctgggcccaggaatacttagttgtattttgctcaggctagctgggacaaaaattaaaggcccctccatcttcatgcaatgtgagccttagggaattggagagcagtgggtgagaatgtttctctgggactcagccagttctggcctatggagcctgaacataaaatg

gcctccttaactttacctccgcatgcaggttgtggaggggtatcagagtccactgtcaggggtattttctgactgtggctagggaacctggggtcagccatgctgcatgtgctccgaatcttttatttattggcct tgaatttaagtgtagaaagcctttacaccaggggggcagcccctcgtggttactcttggacctgattatagacctcgcctttccttggggctggaatacctagaagggagaggcagatctaagaatattctgtt

acacccccataacccttctgcactgtgtgttgactgtccgaagtgaactggtttggcgtgcagaccccagcagacccaggtctcctaccagaggct tgaaacatat tt tcacttttaattttttatttttctcctgggctcaccactgtgagatttatcc.gttaattccttgggagggcagagtaaggtagtgacaaggggagagagtagccctgggtttagttcaatgatttagtaccctcccatcctttcctaacatgtttaaataaa

ttcttgcggattcatcgggagtgcatgtgttggaggggtgtggtgtatgttgtgtcatgtagcagtattatgtgcgggcacttcggagccctgttacagatgtaaatatatttttcttttatttttttttcaagcaatcccctgctttgaaatgtttactgtgattgtgacctgagagctaaattgcatcctcctgttcagagttgaggttggatcactaggtttattttaaactcttctcgttccccagtacattttatcagacaaaac

1733

1781

1836

1896195620162076213621962256231623762436249625562616267627362796285629162976303630963156321632763336339634563464

<210> 21<211> 510<212> PRT<213> Homo sapiens

<400> 21Met Pro Leu Ser Leu Gly Ala Giu Met

1 5Leu Leu Leu Leu Leu Leu Ala

Giu Leu Gly Thr Ser Asp Val

Lys Leu Pro Cys Phe Tyr Arg55

Val Ala Trp Ala Arg Val Asp70

Trp10Thr

Gly Pro Giu Ala Trp Leu

Ser Phe25

Val Thr

Gly Asp

Gly Arg Cys

Val Val Leu

Ser Gly Giu

Giu Gly Ala

Pro Ala Gly

Gin Asp Ala

Val Gly Gin

Ala Gly Gin Glu Leu

37/105

Leu Leu His Ser Lys Tyr Gly Leu His Val Ser Pro Ala Tyr Giu Gly

cqf

00

00

Arg V

Leu L

Val S1

Val L145Glu G

Pro A

Ser I

His I

Val 5225His

Asn

Glu

Leu,

Leu305Phe

Glu

Va1

Val

Lye385Leu

Gly

Cys

Thr

Ser465Ala

al

eu

er30eu

Ily

la

Lrg

.eu

'er

lal

Leu

31)

Prc29(Th

Sei

As]

Gi

Le37

Ty

Hi

Le

Se

Th

GI

Glu GI

Arg A(115Thr P1

Val P:

Gin G

Pro S1

Ser P195Val P

His P

Ser P

Trp F2

Gin 1275Ser C

Thr

r Ser

p Ser

y Vai355

u Met0r Glu

s Ser

u Arg

:r Val435

lr Val00.y Arg

~t Asn

3n00sn

he

ro

ly

er80he

ro

ro

he

'is60'ro

ly

;lu

ArS

3Gl34(Ile

Sei

Gl

Hi

Al42Me

Ar

Al

Hi

Pro P:

Ala V

Pro A

Pro L1

Leu T165Val T

Lys H

Ser P

Gly I

Leu I245Ile

Pro

Val

His

Asp325

r Lye

a Ala

r Arg

u Glu

s His405

a Glu0t Ser

g Glu

a Glu

s Phe

ro P

al G

ia G1

eu P50hr L

hr TI

is S

rg E

ieu I!30la

3ily

Pro

A.rg

Ser310Ser

Gin

Ala

Tyr

Leu390Thr

Gly

Glu

Ile

Glu470Val

ro

in

ly35ro

eu

'rp

er

jer15aeu

ilu

krg

Ser

Val295Gly

Gir

Val

Lei

Hii37!Th

As

Hi

Gi

Gi45Gi

Gi

Pro A:1

Ala A120Ser P

Ser L

Ala A

Asp T1

Arg S200Met

Gin I

Ala

Glu

Tyr280Asp

Ile

Val

Asp

a Leu360

s Arg

r Leu

p Pro

a Pro

u Pro440

u Thr5u Glu

n Glu

rg05

sp

he

eu

.la

hr.85er

~sn

sp

er

31y265ksn

Gl

Tyi

Th

Lei34!Ph~

Ar

Th

Ar

As42Gi

Gi

As

As

Asn

Glu

Gin

Asn

Ser170Glu

Ala

Gly

Gin

Val250Ala

Trp

Asp

Val

Va33(

a Va

e Cy

g Ly:

r Ar

g Se41

p Se5u Gi

n Th

p Gl

In Gl

Pro L

Gly G:

Ala A1

Pro G155Cys T

Val L

Ala V

Gin P2

Arg I235Arg C

Met I

Thr I

Thr

Cys I315

1 Asp0

1 Ser

s Leu

s Ala

g Glu395

r Gin0r Leu

y Arg

.r Glu

.n Asp475

.y Thr

lu

rg

ly

hr

ye

'al

1ro

.le

fly

ieu

rq

eu

His

Val

Al~

Le

Gl38As

Pr

Ly

Se

Le46Gi

Le

Asp G1

Tyr G125Leu A

Pro A

Ala G

Gly T1

Thr S205Leu T

Thr H

Leu G

Lys C

Leu I285Gly I

Val

Leu

i Ser

i Vai365

n Gin0n Ser

o Glu

Asp

r Tyr445

u Leu0u Gly

u Arg

Ly

lu

rg

la

lu

hr

er

hr

[is

flu

.ys

ksp

?he

Ser

Asp

Val

Val

Mel

I1

GlI

As43Se

Se

I

Al

Ser V

Cys A

Leu A

Leu G1

Gly S175Thr S

Glu P

Cys N

Ile I

Asp C255Leu

Gly

Pro

Asn

Pro335Val

Val

t Thr

e Arg

a Ser415

n Ser0r Thr

r Pro

e Lys

a Lye495

al

rg

rg

lu

er

er

,he

Pal

ieu

31n

3er

Pro

Pro

Glu320Gin

Val

Va1

Gin

Arg400Val

Ser

Leu

Giy

Gin480Pro

485

Thr Giy Asn Ile Tyr Ile Asn Arg Gly His Leu Vai510

<210> 22<211> 3464<212> DNA<213> Homo sapiens

38/105

00<220><221> CDS<222> (264) (1796)

<400> 22ggccgtcgtt

acggcttctttcccctagtgcagttccttagctgggcagt

gttggccaca. gcgtgggaag cagctctggg ggagctcgga gctcccgatc

gggggtagct acggctgggt gtgtagaacg gggccggggc tggggctggggagacccaag tgcgagaggc aagaactctg cagcttcctg ccttctgggtttcaagtctg cagccggctc ccagggagat ctcggtggaa cttcagaaacctgcctttca acc atg ccc ctg tcc ctg gga 9CC gag atg tgg

Met Pro Leu Ser Leu Gly Ala Gin Met Trp

120180240293

.gg9 cct gag gccGly Pro Gin Ala

ctg ctg ctg ctgLen Leui Leu Len

ctg ctg gca tcaLeu Len Ala Ser

ttt acaPhe Thr

ggc cgg tgcGly Arg Cys

gtg ctg ggcVal Leu Gly

gcg ggt gag ctgAla Gly Gin Len

acc tca gac gtgThr Ser Asp Val

gta act gtgVal Thr Val

ggg gac tccGly Asp Ser

341

389

437cag gac gca aaaGin Asp Ala Lys

ctg

Len50

CCC tgc ttc tacPro Cys Phe Tyr

cgaArg

ggc gagGly Gin

caa gtg ggg caaGin Val Gly Gin

gca tgg gct cggAla Trp Ala Arg

gac gCg ggC gaaAsp Ala Gly Glu

9gCGly

gCC cag gaa ctaAla Gin Glu Leu

Cta Ctg cac tCCLen Leu Hius Ser

tac ggg cztt cat

Tyr Gly Len His

agc ccg gct tac gag ggc c9c gtg gagSer Pro Ala Tyr Gin Gly Arg Val Gin

c agGin100

CCg CCg CCC cca

Pro Pro Pro Procgc aacArg Asn105

CCC ctg gacPro Len Asp

ggC gag taCGly Gln Tyr

125

tCa gtg CtC ctgSer Val Len Len

aac gca gtg cagAsn Ala Val Gin

gCg gat gagAla Asp Gin120

agc ttc cagSer Phe Gin

gag tgc cgg gtCGin Cys Arg Val

agcSer130

acc ttc CCC 9CC

Thr Phe Pro Ala99CGly135

gcg CggAla Arg

140

ctg cgg ctc cgaLen Arg Len Arg

atg gtg cct CCCMet Val Pro Pro

ccc tca ctg aatPro Ser Len Asn

ct

Pro155

ggt cca gca ctaGly Pro Ala Leu

gaaGin160

gag ggc cag ggcGin Gly Gin Gly

acc ctg gca gCCThr Leu Ala Ala

tcc

Ser170

725

773

821tgC aca gct gagCys Thr Ala Giu

99cGly175

agc cca 9CC CCCSer Pro Ala Pro

gtg aCC tgg gac

Val Thr Trp, Asp

acg gagThr Giu185

gtC aaa ggc aca acg tCC agc cgt tCC ttC aag cac tCC CgC tct gct

Val Lys Gly Thr Thr Ser Ser Arg Ser Phe Lys His Ser Arg Ser Ala

39/ 105

9CC gtc acc tca

Ala Val Thr Ser205

gag ttc cacGlu Phe His

ttgLeu210

gtg cct agc cgc agc atg aat gggVal Pro Ser Arg Ser Met Asn Gly

215

cag ccaGin Pro

220

ctg act tgt gtg gtg tcc cat cct ggcLeu Thr Cys Val Val Ser His Pro Gly

ctg ctc cag gac caaLeu Leu Gin Asp Gin230

917

965

1013aggArg235

atc acc cac atcIle Thr His Ile

ctcLeu240

cac gtg tcc ttc ctt gct gag gcc tctHis Val Ser Phe Leu Ala Giu Ala Ser

245

agg ggc ctt gaaArg Gly Leu Giu

gacAsp255

caa aat ctg tggGin Aen Leu Trp,

cacHis260

att ggc aga gaaIle Gly Arg Giu

gga gctGly Ala265

atg ctc aagMet Leu Lys

aca cgg ctgThr Arg Leu

285

tgcCys270

ctg agt gaa 999Leu Ser Giu Giy

ccc cct ccc tcaPro Pro Pro Ser

tac aac tggTyr Asn Trp280

gat ggg gacAsp Gly Asp

1061

1109

1157gat ggg cct ctgAsp Gly Pro Leu

cccPro290

agt ggg gta cgaSer Gly Val Arg

act ttgThr Leu

300

ggc ttt ccc ccaGly Phe Pro Pro

ctgLeu305

acc act gag cacThr Thr Giu His

ggc atc tac gtcGly Ile Tyr Val

tgcCys315

cat gtc agc aatHis Val Ser Asn

ttc tcc tca aggPhe Ser Ser Arg

tct cag gtc actSer Gin Val Thr

1205

1253

1301gat gtt ctt gacAsp Vai Leu Asp

cag gaa gac tctGin Giu Asp Ser

999Gly340

aag cag gtg gacLys Gin Val Asp

cta gtgLeu Val345

tca gcc tcgSer Ala Ser

ctt ctg gtgLeu Leu Vai

365

gtg gtg gtg ggtVal Val Val Gly

atc gCC gca ctcIle Ala Ala Leu

ttg ttc tgcLeu Phe Cys360

cgg cyc aagArg Arg Lys

1349

1397gtg gtg gtg gtgVal Val Val Val

atg tcc cga tacMet Ser Arg Tyr

9CC cagAla Gin

380

cag atg acc cagGin Met Thr Gin

tat gag gag gagTyr Giu Glu Giu

ctgLeu390

acc ctg acc aggThr Leu Thr Arg

1445

gagGlu395

aac tcc atc cggAsn Ser Ile Arg

ctg cat tcc cat cac acg gac ccc agg agcLeu His Ser His His Thr Asp Pro Arg Ser

405 410

1493

cag ccg gag gag agt gta ggg ctg agaGin Pro Giu Giu Ser Val Gly Leu Arg

415

9CC

Ala420

gag ggc cac cctGiu Gly His Pro

gat agtAsp Ser425

1541

1589ctc aag gac aac agt agc tgC tct gtg atg agt gaa gag ccc gag ggcLeu Lys Asp Asn Ser Ser Cys Ser Val Met Ser Giu Glu Pro Giu Gly

40/105

430

cgc agt tacAry Ser Tyr

445

tcc acg ctg accSer Thr Leu Thr

acgThr450

gtg agg gag ataVal Arg Giu Ile

aca cag actThr Gin Thr

1637

gaa ctgGiu Leu

460

ctg tct cca ggcLeu Ser Pro Gly

t ctSer465

ggg cgg gcc gagGly Arg Ala Giu

gagGiu470

gag gaa gat cagGlu Glu Asp Gin

1685

1733gaa ggc atc aaaGlu Gly Ile Lys

cagGin480

gcc atg aac catAla Met Asn His

tttPhe485

gtt cag gag aatVal Gin Giu Asn

acc cta cgg gccThr Leu Arg Ala

ccc acg ggc aatPro Thr Gly Asn

ggcGly500

atc tac atc aatIle Tyr Ile Asn

ggg cggGiy Arg505

gga cac ctgGiy His Leu

tgacatgggaagatgctcccgggctccaccgcctgtgtgaactgtgtccggccacgggatggctgtgtgtatgatgcagatagctggagcatgggggcaaagccctctgccatgcgccggttttttcttgagagatggagtcctgcctcaatcctttacgactgggattgaaggggctacggt agagt ctcaccattgttatagtggtgtgaggtgaaggattcaaggcttagctggccctagtctgaaaccagcctagggtaaatatgtttgaaaaa

gtc tga ccVal510

gattttagctcatcccactgaattgagtctgtgttgactgtggtgtgtatttgagtggttgacctctgccggttggaggatggaatctgcgtgtgaagcacctctggtgggagcttcttgccctttccattctcactatggcctccctagaagagaaaaacttaaagtgattccaaggcagaaattagggtgtgataccttggggagagaaggtgctgggcttctggatgacccagatactctgctggatacttcgaatggcatatttgt

:caggcctg cctcccttcc ctaggcctgg ctccttctgt

catcttggggactgcttgacctcccaccatactgtgtgtgtatgctgtcagcgtgggcaatgaaaaagcagagaggtggactccggtgtggccagtccctcctctgggcccaggaatacttagttgtattttgctcaggctagctgggacaaaaattaaaggcccctccatcttcatgcaatgtgagccttagggaattggagagcagtgggtgagaatgtttctctgggactcagccagttctggcctatggagcctgaacataaaatg

gcctccttaactttacctccgcatgcaggttgtggaggggtatcagagtccactgtcaggggtattttctgactgtggctagggaacctggggtcagccatgctgcatgtgctccgaatcttttatttattggccttgaatttaagtgtagaaagcctttacaccaggggggcagcccctcgtggttactcttggacctgattatagacctcgcctttccttggggctggaatacctagaagggagaggcqgatctaagaatattctgtt

acacccccataacccttctgcactgtgtgttgactgtccgaagtgaactggtttggcgtgcagaccccagcagacccaggtctcctaccagaggcttgaaacatattttcacttttaattttttatttttctcctgggctcaccactgtgagatttatccgttaattccttgggagggcagagtaaggtagtgacaaggggagagagtagccctgggtttagttcaatgatttagtaccctcccatcctttcctaacatgtttaaataaa

ttcttgcggattcatcgggagtgcatgtgttggaggggtgtggtgtatgttgtgtcatgtagcagtattatgtgcgggcacttcggagccctgttacagatgtaaatatatttttcttttatttttttttcaagcaatcccctgctttgaaatgtttactgtgattgtgacctgagagctaaattgcatcctcctgttcagagttgaggttggatcactaggtttattttaaactcttctcgttccccagtacattttatcagacaaaac

1781

1836

1896195620162076213621962256231623762436249625562616267627362796285629162976303630963156321632763336339634563464

<210> 23<211> 510<212> PRT<213> Homo sapiens

<400> 23Met Pro Leu Ser Leu Gly Ala Glu Met Trp Gly Pro Glu Ala Trp Leu

1 5 10 Leu Leu Leu Leu Leu Leu Ala Ser Phe Thr Gly Arg Cys Pro Ala Gly

41/105

Gin Asp AlaGlu Leu Glu Thr Ser Asp Val Val Thr Val Val Len Gly

00

00

Lys

Va1

Leu

Arg

Len

Val

Va1145Glu

Pro

Ser

His

Val225His

Asn

Glu

Leu

Leu305Phe

Gl

Val

Va

Ly38!Let

G1'

Cy:

Th

Se46Al

Leu P

Ala T

Len H

Val G

Leu A1

Ser I130Met

Gly C

Ala I

Arg

Leu210Ser

Val

Len

Gly

Pro290Thr

ser

1 Asp

Gly

L Leu370

s Tyr

u His

y Leu

s Ser

r Thr450

r Gly5a Met

ro

rp

.is

lu

~rg.15'hr

ral

ln

!ro

3er

Jal

His

Ser

rrp

Gin275Ser

Thr

Ser

Sei

Val

Met

Gli

Se

Arc

Va43Va

Ar

As

Cys

Ala

Ser

Gin100Asn

Phe

Pro

Gly

Ser180Phe

Pro

Pro

Phe

His260Prc

Gl

Gl1L

Arc

GI)34(L

Se

Gi

r Hi

g Al.42

1 Me51 Ar

g Al

n Hi

Phe T

Arg V7

Lys

Pro P

Ala V

Pro A

Pro L2

Leu 165Vai

Lys I

Ser 2

Gly

Leu245Ile

Pro

Vai

His

Asp325Lys

e Ala

r Arg

u Glu

s His405

a Glu0t Ser

g Glu

a Glu

s Phe485

yr A5

al A0lyr G

'ro P

ral G

la C

reu I50hr I

[hr

Uss

krg

Leu230Ala

Giy.

Pro

Arg

Ser310Ser

Gin

Ala

Tyr

Len390Thr

Gly

Glu

Ile

Glu470Val

rg5sp

ly

'ro

;In

ily.35,ro

ieu

Crp

Ser

Ser215Leu

G1u

Arg

Ser

Val295Gl)

Gli

Va

Let

Hir37!Th:

As]

Hi

G1

G145Gi

G1

Gly A

Ala G

Len H

Pro A1

Ala A120Ser P

Ser I

Ala

Asp

Arg200Met I

*Gin 2

Ala

Glu

Tyr280Asp

r Ile

i Val

1 Asp

.i Leu360

s Arg

r Len

p Pro

s Pro

u Pro440

n Thr5u Glu

n Glu

sp

ly

.is

*rg05~sp

,he

leu

~la

'hrL853er

ksn

ksp

Ser

Gly265Asn

Gly

Tyr

Thr

Leu345Phe

Arc

Thi

Ar

Asi42!Gli

Gl

As]

As

Ser

Glu

Val90Asn

Glu

Gin

Asn

Ser170Glu

Ala

Gly

Gin

Val250Ala

Trp

Asp

Val

Val330Val

CyE

Ly,

.Arc

SSe

41(Sei

u Gl

n Th:

p Gi:

n G149

y Ar

Gly Glu

Gly Ala75Ser Pro

Pro Len

Gly Glu

Ala Arg140

Pro Gly155Cys Thr

Val Lys

Ala Val

Gin Pro220

Arg Ile235Arg Gl

Met Lei

Thr Ar

Thr Lei

Cys Hi315Asp Va

Ser Al

Len Le

Ala Gi138

Glu As395

c Gin Pr

r Leu Ly

y Arg Se

r Glu Le46

n Asp GI475

y Thr Le

0g Gly Hi

Gin

Gin

r

1

3

1

3

c

rCr

c

r

1

Ala T

Asp C1

Tyr 2125Leu I

Pro 1

Ala

Gly

Thr205Len

Thr

Leu

Lys

Leu285Gly

Val

Len

Ser

Val365

i Gin

i Ser

:>Glu

s Asp

r Tyr445

u Len

0u Gly

u Arg

s Len

yr

;ly

3lu

rg

kla

3lu

rhr190Ser

rhr

His

Glu

Cys270Asp

Phe

Ser

Asp

Val350Val

Met

lie

GIL

Asi43(Se

Sei

Il

Al

Va

Gly G

Len A8

Glu G

Ser V

Cys P

Leu P

Leu C2

Gly175Thr

Glu I

cys

Ile

Asp255Len

Gly

Pro

Asn

Pro335Val

Val

Thr

Arg

1 Ser415

i Ser

Thr

Pro

Lys

Lys495

1

In

.la0ly

ral

~rg

irg

flu

jer

er

?he

lal

LIeu240Gln

Ser

Pro

Pro

Glu320Gin

Va1

Val

Gin

Arg400Val

Ser

Len

Gly

Gin480Pro

Thr Gly Asn Gly Ile Tyr lie Asn Gi:

42/105

00

<210> 24<211> 3464<212> DNA<213> Homo sapiens

<220><221> CDS<222> (264) (1796)

<400> 24ggccgtcgttacggcttctttcccctagtgcagttccttagctgggcagt

gttggccacagggggtagctgagacccaagttcaagtctgctgcctttca

gcgtgggaag cagctctggg ggagctcgga gctcccgatcacggctgggt gtgtagaacg gggccggggc tggggctgggtgcgagaggc aagaactctg cagcttcctg ccttctgggtcagccggctc ccagggagat ctcggtggaa ctztcagaaacacc atg ccc ctg tcc ctg gga gcc gag atg tgg

Met Pro Leu Ser Leu Gly Ala Glu Met Trp

ggg cct gag gccGly Pro Glu Ala

tggTrp

ctg ctg ctg ctgLeu Leu Leu Leu

ctg ctg gca tcaLeu Leu Ala Ser

ttt acaPhe Thr

ggc cgg tgcGly Arg Cys

gtg ctg ggcVal Leu Gly

gcg ggt gag ctgAla Gly Glu Leu

gagGlu

acc tca gac gtgThr Ser Asp Val

gta act gtgVal Thr Val.

ggg gac tccGly Asp Ser

389

437cag gac gca aaaGin Asp Ala Lys

ccc tgc ttc tacPro Cys Phe Tyr

ggc gagGly Glu

caa gtg ggg caaGln Val Gly Gin

gca tgg gct cggAla Trp Ala Arg

gac gcg ggc gaaAsp Ala Gly Glu

ggcGly

gcc cag gaa ctaAla Gin Glu Leu

gcgAl a

cta ctg cac tccLeu Leu His Ser

tac ggg ctt catTyr Gly Leu His

agc ccg gct tacSer Pro Ala Tyr

gagGlu

ggc cgc gtg gagGly Arg Val Glu

ccg ccg ccc ccaPro Pro Pro Pro

cgc aacArg Asn105

ccc ctg gacPro Leu Asp

ggcGly110

tca gtg ctc ctgSer Val Leu Leu

aac gca gtg cagAsn Ala Val Gin

gcg gat gagAla Asp Glu120

agc ttc cagSer Phe Gin

629

677ggc gag tac gagGly Glu Tyr Glu

125

tgc cgg gtcCys Arg Val.

acc ttc ccc gccThr Phe Pro Ala

ggcGly135

gcg cgg ctg cgg ctc cga gtgAla Arg Leu Arg Leu Arg Val

140 145

cct ggt cca gca cta gaa gagPro Gly Prc Ala Leu Glu Glu155 160

ctg gtg cct cccLeu Val Pro Pro

ctg ccc tca ctg aatLeu Pro Ser Leu Asn150

acc ctg gca gcc tccThr Leu Ala Ala Ser

ggc cag ggcGly Gin Gly

43/105

00

tgc aca gct gagCys Thr Ala Giu

gtc aaa ggc acaVal Lys Gly Thr

190

gcc gtc acc t .caAla Val Thr Ser

205

ggc agc ccaGly Ser Pro175

gcc ccc agc gtg acc tgg gac acg gagAla Pro Ser Val Thr Trp Asp Thr Glu

acg tcc agc cgt tcc ttc aag cac tccThr Ser Ser Arg Ser Phe Lys His Ser

cgc tct gctAry Ser Ala200

atg aat gggMet Asn Gly

gag ttc cacGlu Phe His

ttgLeu210

gtg cct agc cgcVal Pro Ser Arg

cag ccaGin Pro

220

ctg act tgt gtgLeu Thr Cys Val

tcc cat cct ggcSer His Pro Gly

ctgLeu230

ctc cag gac caaLeu Gin Asp Gin

aggArg235

atc acc cac atcIle Thr His Ile

cac gtg tcc ttcHis Val Ser Phe

cttLeu245

gct gag gcc tctAla Glu Ala Ser

965

1013

1061agg ggc ctt gaaArg Gly Leu Glu

caa aat ctg tggGin Asn Leu Trp

cacHis260

att ggc aga gaaIle Gly Arg Glu

gga gctGly Ala265

atg ctc aagMet Leu Lys

aca cgg ctgThr Arg Leu

285

ctg agt gaa gggLeu Ser Giu Gly

cagGin275

ccc cct ccc tcaPro Pro Pro Ser

tac aac tggTyr Asn Trp,280

gat ggg gacAsp Gly Asp

1109

1157gat ggg cct ctgAsp Gly Pro Leu

cccPro290

agt ggg gta cgaSer Gly Val Arg

act ttgThr Leu

300

ggc ttt ccc ccaGly Phe Pro Pro

acc act gag cacThr Thr Giu His

ggc atc tac gtcGly Ile Tyr Val

cat gtc agc aatHis Val Ser Asn

gagGiu320

ttc tcc tca aggPhe Ser Ser Arg

tct cag gtc actSer Gin Val Thr

1205

1253

1301gat gtt ctt gacAsp Val Leu Asp

cag gaa gac tctGin Giu Asp Ser

gggGiy340

aag cag gtg gacLys Gin Val Asp

cta gtgLeu Val345

tca gcc tcgSer Ala Ser

ctt ctg gtgLeu Leu Val

365

gtg gtg gtg ggtVal Val Val Gly

atc gcc gca ctcIle Ala Ala Leu

ttg ttc tgcLeu Phe Cys360

cgg cgc aagArg Arg Lys

1349

1397gtg gtg gtg gtgVal Val Val Val

atg tcc cga tacMet Ser Arg Tyr

gcc cagAla Gin

380

gag aacG1u Asn395

cag atg acc cag aaaGin Met Thr Gin Lys

385

tat gag gag gag ctg acc ctg acc aggTyr Giu Giu Giu Leu Thr Leu Thr Arg

390

1445

tcc atc cggSer Ile Arg

agg ctgArg Leu400

cat tcc catHis Ser His

acg gac ccc aggThr Asp pro Arg

agcS er410

1493

44/105

00

00

cag ccg gag gag agt gta ggg ctg agaGin Pro Glu Glu Ser Val Gly Leu Arg

gccAla420

gag ggc cac cct gat agtGiu Gly His Pro Asp Ser

ctc aag gacLeu Lys Asp

tgc agt tacCys Ser Tyr

445

gaa ctg ctgGiu Leu Leu

460

aacAsn430

agt agc tgc tctSer Ser Cys Ser

gtgVal.435

atg agt gaa gagMet Ser Glu Giu

ccc gag ggcPro Glu Gly440

aca cag actThr Gin Thr

tcc acg ctg accSer Thr Leu Thr

gtg agg gag ataVal Arg Glu Ile

gaaGiu455

1541

1589

1637

1685

1733

1781.

tct cca ggcSer Pro Gly

ggg cgg gcc gagGly Arg Ala Glu

gagGlu470

gag gaa gat cagGlu Glu Asp Gin

gatAsp475

gaa ggc atc aaaGiu Gly Ile Lys

gcc atg aac catAla Met Asn His

gtt cag gag aatVal Gin Glu Asn

gggGly490

acc cta cgg gccThr Leu Arg Ala

aagLys495

ccc acg ggc aatPro Thr Gly Asn

atc tac atc aatIle Tyr Ile Asn

ggg CggGly Arg505

gga cac ctgGly His Leu

tga cccaggcctg cctcccttcc ctaggcctgg ctccttctgt 1836

tgacatgggaagatgctcccgggctccaccgcctgtgtgaactgtgtccggccacgggatggctgtgtgtatgatgcagatagctggagcatgggggcaaagccctctgcCatgcgccggttttttcttgagagatggagtcctgcctcaatcctttacgactgggattgaaggggctacggtagagtctcaccattgttatagtggtgtgaggtgaaggattcaaggcttagctggccctagtctgaaaccagcctagggtaaatatgtttgaaaaa

<210> <211> 510

gattttagctcatcccactgaattgagtctgtgttgactgtggtgtgtatttgagtggttgacctctgccggttggaggatggaatctgcgtgtgaagcacctctggtgggagcttcttgccctttccattctcactatggcctccctagaagagaaaaacttaaagtgattccaaggcagaaat tagggtgtgataccttggggagagaaggtgctgggcttctggatgacccagatactctgctggatacttcgaatggcatatttgt

catcttggggactgcttgacctcccaccatactgtgtgtgtatgctgtcagcgtgggcaatgaaaaagcagagaggtggactccggtgtggccagtccctcctctgggcccaggaatacttagttgtattt tgc tc aggctagctgggacaaaaattaaaggcccctccatcttcatgcaatgtgagccttagggaattggagagcagtgggtgagaatgtttctctgggactcagccagttctggcctatggagcctgaacataaaatg

gcctccttaactttacctccgcatgcaggttgtggaggggtatcagagtccactgtcaggggtattttctgactgtggctagggaacctggggtcagccatgctgcatgtgctccgaatcttttatttattggccttgaatttaagtgtagaaagcctttacaccaggggggcagcccctcgtggttactCt tggac ctgattatagacctcgcctttccttggggctggaatacctagaagggagaggcagatctaagaatattctgtt

acacccccataacccttctgcactgtgtgttgactgtccgaagtgaactggtttggcgtgcagaccccagcagacccaggtctcctaccagaggct tgaaacatattttcacttttaattttttatttttctcctgggctcaccactgtgagatttatccgttaattccttgggagggcagagtaaggtagtgacaaggggagagagtagccctgggtttagttcaatgatttagtaccctcccatcctttcctaacatgtttaaataaa

ttcttgcggattcatcgggagtgcatgtgttggaggggtgtggtgtatgttgtgtcatgtagcagtattatgtgcgggcacttcggagccctgttacagatgtaaatatatttttcttttatttttttttcaagcaatcccctgctttgaaatgtttactgtgattgtgacctgagagctaaattgcatcctcctgttcagagttgaggttggatcactaggtttattttaaactcttctcgttccccagtacattttatcag~icaaaac

1896195620162076213621962256231623762436249625562616267627362796285629162976303630963156321632763336339634563464

105

<212> PRT<213> Homo sapiens

00<400>

Met Pro Leu Ser Leu Gly Ala Glu Met Trp Gly Pro Glu Ala Trp Leu

C 1 5 10 Leu Leu Leu Leu Leu Leu Ala Ser Phe Thr Gly Arg Cys Pro Ala Gly

25 Glu Leu Glu Thr Ser Asp Val Val Thr Val Val Leu Gly Gin Asp Ala

40

Lys Leu Pro Cys Phe Tyr Arg Gly Asp Ser Gly Glu Gin Val Gly Gin

1 50 55 Val Ala Trp Ala Arg Val Asp Ala Gly Glu Gly Ala Gin Glu Leu Ala

70 75

Leu Leu His Ser Lys Tyr Gly Leu His Val Ser Pro Ala Tyr Glu Gly

90

Arg Val Glu Gin Pro Pro Pro Pro Arg Asn Pro Leu Asp Gly Ser Val

100 105 110

Leu Leu Arg Asn Ala Val Gin Ala Asp Glu Gly Glu Tyr Glu Cys Arg

00 115 120 125

Val Ser Thr Phe Pro Ala Gly Ser Phe Gin Ala Arg Leu Arg Leu Arg

130 135 140

S Val Leu Val Pro Pro Leu Pro Ser Leu Asn Pro Gly Pro Ala Leu Glu

145 150 155 160

Glu Gly Gin Gly Leu Thr Leu Ala Ala Ser Cys Thr Ala Glu Gly Ser

165 170 175

Pro Ala Pro Ser Val Thr Trp Asp Thr Glu Val Lys Gly Thr Thr Ser

180 185 190

Ser Arg Ser Phe Lys His Ser Arg Ser Ala Ala Val Thr Ser Glu Phe

195 200 205

His Leu Val Pro Ser Arg Ser Met Asn Gly Gin Pro Leu Thr Cys Val

210 215 220

Val Ser His Pro Gly Leu Leu Gin Asp Gin Arg Ile Thr His Ile Leu

225 230 235 240

His Val Ser Phe Leu Ala Glu Ala Ser Val Arg Gly Leu Glu Asp Gin

245 250 255

Asn Leu Trp His Ile Gly Arg Glu Gly Ala Met Leu Lys Cys Leu Ser

260 265 270

Glu Gly Gin Pro Pro Pro Ser Tyr Asn Trp Thr Arg Leu Asp Gly Pro

275 280 285

Leu Pro Ser Gly Val Arg Val Asp Gly Asp Thr Leu Gly Phe Pro Pro

290 295 300

Leu Thr Thr Glu His Ser Gly Ile Tyr Val Cys His Val Ser Asn Glu

305 310 315 320

Phe Ser Ser Arg Asp Ser Gin Val Thr Val Asp Val Leu Asp Pro Gin

325 330 335

Glu Asp Ser Gly Lys Gin Val Asp Leu Val Ser Ala Ser Val Val Val

340 345 350

Val Gly Val Ile Ala Ala Leu Leu Phe Cys Leu Leu Val Val Val Val

355 360 365

Val Leu Met Ser Arg Tyr His Arg Arg Lys Ala Gin Gin Met Thr Gin

370 375 380

Lys Tyr Glu Glu Glu Leu Thr Leu Thr Arg Glu Asn Ser Ile Arg Arg

385 390 395 400

Leu His Ser His His Thr Asp Pro Arg Ser Gin Pro Glu Glu Ser Val

405 410 415

Gly Leu Arg Ala Glu Gly His Pro Asp Ser Leu Lys Asp Asn Ser Ser

420 425 430

Cys Ser Val Met Ser Glu Glu Pro Glu Gly Cys Ser Tyr Ser Thr Leu

435 440 445

46/105

Thr Thr Val Arg Glu Ile450

Ser Gly Arg Ala Glu Giu

Giu455Glu

Thr Gin Thr Giu Leu460Giu

Leu Ser Pro Gly

00 Giu Asp Gin Gly Ile Lys465Ala Met Asn

Thr Gly Asn

470His Phe Val

485Gly Ile Tyr500

Gin Giu Asn

Ile Asn Giy505

Gly490Arg

Leu Arg Ala

Gly His Leu

<210> 26;-211> 3467<212> DNA<213> Homo sapiens

<220><221> CDS<222> (264) (1799)

<400> 26ggccgtcgttacggc ttot ttcccctagtgcagttccttagotgggcagt

gttggccacagggggtagotgagacccaagttcaagtctgctgcctttca

gcgtgggaag oagctctggg ggagctogga gctcccgatcacggctgggt gtgtagaacg gggccggggc tggggctgggtgogagaggo aagaactctg oagcttcctg ccttctgggtoagccggctc ocagggagat ctcggtggaa cttcagaaacacc atg coo otg toc ctg gga. gcc gag atg tgg

Met Pro Leu Ser Leu Gly Ala Giu Met Trp

ggg cct gag goc tgg ctg ctg otg ctgGly Pro Glu Ala Trp, Leu Leu Leu Leu

otg ctg gca tcaLeu Leu Ala Ser

ttt acaPhe Thr

ggc ogg tgcGly Arg Cys

gcg ggt gag ctgAla Gly Giu Leu

acc tca gac gtgThr Ser Asp Val

gta act gtgVal Thr Val

ggg gao tcoGly Asp Ser

gtg otg ggc cag gao gca aaaVal Leu Gly Gin Asp Ala Lys

ccc tgc ttc taoPro Cys Phe Tyr

cgaArg

ggc gagGiy Giu

caa gtg ggg caaGin Val Gly Gin

gca tgg got cggAla Trp Ala Arg

gao gog ggc gaaAsp Ala Gly Giu

437

485

533

581

ggoGly

gcc cag gaa ctaAla Gin Giu Leu

cta ctg cac tooLeu Leu His Ser

tao ggg ott catTyr Gly Leu His

agc ccg gct tacSer Pro Ala Tyr

gagGiu

ggc cgc gtg gagGly Arg Val Giu

ccg ccg ccc ccaPro Pro Pro Pro

cgc aacArg Asn105

ccc ctg gacPro Leu Asp

ggoGly110

toa gtg ctc ctgSer Val Leu Leu

aac gca gtgAsn Ala Val

cag gcg gat gagGin Ala Asp Glu

120

ggc agc ttc cagGly Ser Phe Gin135

ggc gag tao gagGly Glu Tyr Giu

125

tgo cgg gtcCys Arg Val

acc ttc ccc gcThr Phe Pro Ala

47/105

gog cgg ctg cgg ctc cga gtg ctg gtg cot ccc ctg ccc tca ctg aat

Ala Arg Leu Arg Leu Arg Val. Leu Val Pro Pro Leu Pro Ser Leu Asn

140 145 150

cct ggt ccaPro Gly Pro

goa cta gaaAla Leu Giu

gag 990 cag ggcGiu Gly Gin Gly

ctgLeu165

aoc ctg goa 9CCThr Leu Ala Ala

tooSer170

725

773

821tgc aca got gagCys Thr Ala Glu

ago cca 9CC CCCSer Pro Ala Pro

agcSer180

gtg acc tgg gacVal Thr Trp Asp

acg gagThr Glu185

gtc aaa ggcVal. Lys Gly

9CC gtc accAla Val Thr

205

aog toc ago ogtThr Ser Ser Arg

tooSer195

ttc aag cac tooPhe Lys His Ser

ogc tot gotArg Ser Ala200

atg aat gggMet Asn Gly

toa gag tto oaoSer Giu Phe His

ttgLeu210

gtg cot ago 090Val Pro Ser Arg

agoSer215

cag ooaGin Pro

220

otg act tgt gtgLeu Thr Cys Val

gtgVal225

too oat oct ggoSer His Pro Gly

oto cag gao oaaLeu Gin Asp Gin

869

917

965

1013

1061

aggArg235

ato aoo oac atoIlie Thr His Ile

otoLeu240

cac gtg too ttoHis Val Ser Phe

got gag goo tot.Ala Giu Ala Ser

agg ggc ott gaaArg Gly Leu Giu

gacAsp255

oaa aat otg tggGin Asn Leu Trp

att 990 aga gaaIle Gly Arg Giu

gga gotGly Ala265

atg ctc aagMet Leu Lys

aoa 099 otgThr Arg Leu

285

otg agt gaa gggLeu Ser Glu Gly

cagGin2'75

000 oct 000 toaPro Pro Pro Ser

tao aao tggTyr Asn Trp280

gat ggg gaoAsp Gly Asp

1109

1157gat ggg oct ctgAsp Gly Pro Leu

000

Pro290

agt 999 gta ogaSer Gly Val Arg

gtgVal295

act ttgThr Leu

300

990 ttt coo ooaGly Phe Pro Pro

otgLeu305

acc act gag cacThr Thr Glu His

990 atc tac gtoGly Ie Tyr Val

tgoCys315

oat gtc ago aatHis Val Ser Asn

gagGiu320

ttc too toa aggPhe Ser Ser Arg

tct cag gtc actSer Gin Val Thr

1205

1253

1301gat gtt ott goaAsp Val Leu Ala

000 cag gaa gaoPro Gin Glu Asp

totSer340

999 aag cag gtgGiy Lys Gin Val

gao otaAsp Leu345

gtg toa 900Val. Ser Ala

gtg gtg gtg gtgVal Val Val Val

gtg gtg gtg gtgVal Val Val Val

370

ggtGly355

gtg ato 900

Val. Ile Alagca ctO ttg ttcAla Leu Leu Phe

360

tao oat 099 090Tyr His Arg Arg375

1349

1397tgo ott otg gtgCys Leu Leu Val

365

cto atg too ogaLeu Met Ser Arg

48/105

00

00

aag gceLys Ala

380

cag cag atg aceGin Gin Met Thr

aaa tat gag gagLys Tyr Giu Giu

gagGiu390

ctg ace ctg accLeu Thr Leu Thr

aggArg395

gag aac tcc ateGlu Asn Se Ile

agg etg cat teeArg Leu His Ser

catHis405

eae aeg gae cHis Thr Asp Pro

age eag ecg gagSer Gin Pro Giu

agt gta ggg etgSet Vai Giy Leu

agaArg420

gee gag gge cacAla Giu Gly His

eeL gatPro Asp425

1445

1493

1541

1589

1637

1685

agt etc aagSer Leu Lys

gge ege agtGly Arg Set

445

gacAsp430

aae agt age tgeAsn Ser Set Cys

gtg atg agt gaa gag ccc gagVal Met Set Giu Glu Pro Giu

tac tee acg etgTyr Set Thr Leu

aeg gtg agg gagThr Val Arg Giu

ataIle455

gaa aca eagGiu Thr Gin

act gaaTht Giu

460

etg ctg tet eeaLeu Leu Set Pro

Let ggg egg geeSet Gly Arg Ala

gagGiu470

gag gag gaa gatGiu Glu Giu Asp

cagGin475

gat gaa ggc ateAsp Giu Gly Ile

eag gee atg aac eat ttt gtt eag gagGin Ala Met Asn His Phe Val Gin Giu

485

1733

ggg ace eta eggGly Thr Leu Arg

aag eec aeg ggeLys Pro Thr Gly

aatAsn500

gge ate tae ateGly Ie Tyr Ile

aat gggAsn Giy505

1781

egg gga caeArg Gly His

etg gte LgaLeu Val.510

cecaggeetg ceteeettce etaggcctgg 1829

etccttetgtttettgeggattcategggagtgeatgtgttggaggggtgtggtgtatgttgtgteatgtageagtattatgtgegggcaetteggageectgttacagatgtaaatatatttttcttttattttttttteaagcaateceetgctttgaaatgtttaetgtgattgtgaeectgagagetaaattgcatccteetgttcagagttgaggttggateaetaggtttatttt

tgacatgggaagatgetecegggetccacegcetgtgtgaaetgtgtceggeeaegggatggetgtgtgtatgatgcagatagetggagcatgggggeaaagcetetgccatgcgeeggttttttettgagagatggagtcetgectcaateetttacgactgggattgaaggggetaeggtagagteteaceattgttatagtggtgtgaggtgaaggatteaaggettagctggccc

gattttagcteateeeactgaattgagtetgtgttgaetgtggtgtgtatt tgagtggt tgacctetgcggttggaggatggaatctgegtgtgaagcacctctggtgggagettettgcetttecattctcaetatggcetcectagaagagaaaaacttaaagtgatteeaaggeagaaattagggtgtgataccttggggagagaaggtge tgggcttetggatgaceeagatae

catcttggggaetgcttgacetceaceatactgtgtgtgtatgctgteagegtgggeaatgaaaaagcagagaggtggaetccggtgtggecagtectcetctgggeceaggaatacttagttgtattttgctcaggetagctgggacaaaaattaaaggeeeeteeatctteatgeaatgtgageettagggaattggagagcagtgggtgagaatgtttetctgggaetcagceag

gcetecttaa acacceecat 1889ctttaeetcegcatgcaggttgtggaggggtatcagagteeaetgtcaggggtattttctgaetgtggetagggaaeetggggtcagccatgetgcatgtgetccgaatettttatttattggcettgaatttaagtgtagaaageettta cace aggggggeagcccetegtggttaetcttggacctgattatagacetegcetttecttggggctggaataectaga

aaccettctgeaetgtgtgttgactgteegaagtgaaetggtttggegtgeagaccecagcagaeeeaggtcteetaccagaggcttgaaacatattttcaettttaattttttatttttctectgggcteaceaetgtgagat ttate egttaattcettgggagggeagagtaaggtagtga caaggggagagagtagcctgggtttagtteaatgatttagtacee

19492009206921292189224923092369242924892549260926692729278928492909296930293089314932093269

49/105

00

aaactcttct tagtctgaaa tctgctggat ttctggccta agggagaggc tcccatcctt 3329

cgttccccag ccagcctagg acttcgaatg tggagcctga agatctaaga tcctaacatg 3389

tacattttat gtaaatatgt gcatatttgt acataaaatg atattctgtt tttaaataaa 3449

cagacaaaac ttgaaaaa 3467

<210> 27<211> 511<212> PRT<213> Homo sapiens

<400> 27Met1

Leu

Glu

Lys

Val

Leu

Arg

Leu

Val

Val145Glu

Pro

Ser

His

Val225His

Asr

GIv

Let

Let

Ph

Gli

Va

Va

Pro L

Leu L

Leu G3

Leu I

Ala 9)

Leu I

Val

Leu

Ser130Leu

Gly

Ala

Arg

Leu210Ser

Val

Leu

i Gly

pro290

i Thr

Ser

x Glu

1 Val

1 Val

eu

.eu

;lu55,ro

rrp

Us

flu

%rg115rhr

Val

Gln

Pro

Ser195Val

His

Ser

Trp

Glr275Sei

Th3

Se

AsE

GlI

Lel

Cer Leu Gly Ala Glu Met Trp Gly Pro Glu Ala Trp Leu

Leu

Thr

Cys

Ala

Ser

Gin100Asn

Phe

Pro

Gly

Ser180Phe

Prc

Prc

Phe

His260Prc

*GI~

*G1i

Ar

Se34'

r Va5u Me'

5Leu I

Ser I

Phe

Arg

Lys

Pro

Ala

Pro

Pro

Leu165Val

Lys

Ser

Gly

Leu245Ile

Pro

r Val

i His

3 Asp325

r Gly01 Ile

t Ser

~eu

~sp

ryr

lal70ryr

Pro

Val

Ala

Leu150Thr

Thr

His

Arg

Leu230Ala

Gly

Pro

Arg

Ser310Ser

Lys

Ala

Arc

Ala S

Val 4

Arg C55Asp I

Gly I

Pro I

Gin I

Gly135Pro

Leu

Trp

Ser

Ser215Leu

Glu

Arg

Ser

Val295Gly

Gin

Gin

Ala

Tyr375

er

ral00fly

la

jeu

?ro

k1a1203er

Ser

Ala

Asp

Arg200Met

Gin

Ala

Glu

Tyr280Asp

Ile

Val

Val

Let36CHis

2'1

10he Thr5V'hr Val

Asp

Gly

His

Arg105Asp

Phe

Leu

Ala

Thr185Ser

Asn

Asp

Ser

Gly265Asn

Gly

Tyr

Thr

Asp345

1 Leu

Arg

,er

flu

lal30ksn

31u

3Gl

Asn

Ser170Glu

Ala

Gly

Gin

Val250Ala

Trp

Asy

Val

Va33(Let

Ph

Ar

Gly I

Val

Gly

Gly75Ser

Pro

Gly

Ala

Pro155Cys

Val

Ala

Gin

Arg235Arg

Met

Thr

Thr

Cys315

L Asp0.i Val

e Cys

g Lys

krg

Eeu

Glu

Ala

Pro

Leu

Glu

Arg140Gly

Thr

Lys

Val

Pro220Ile

Gly

Leu

Arg

Leu300His

Val

Sei

Let

Al

Cys 1

Gly C

Gin

Gin C

Ala

Asp

Tyr125Leu

Pro

Ala

Gly

Thr205Leu

Thr

Leu

Lys

Leu285Gly

Val

Leu

Ala

i Leu365

x Gin

)ro00fIn

Tal

.lu

ryr

Gly110Glu

Prg

Ala

Glu

Thr190Ser

Thr

His

Glu

Cys270Asp

Phe

Sei

Alz

Se

Va

Gb

Ala C

Asp I

Gly C

Leu

Glu

Ser

Cys

Leu

Leu

Gly175Thr

Glu

Cys

Ile

Asp255Leu

Gly

Pro

Asn

i Asp335Val

i Val

n Met

fly

la

'In

kla

Gly

Val

Arg

Arg

Glu160Ser

Ser

Phe

Val

Leu240Gin

Ser

Pro

Pro

Glu320Pro

Val

Val

Thr

370 380

Gin Lys Tyr Giu Giu Glu Leu Thr Leu Thr Arg Giu Asn Ser Ile Arg

50/105

385Arg

390His

395SerLeu His Ser His Thr Asp Pro Gin Pro Glu

400Giu Ser415

00

00

405AlaVal Gly Leu

Ser Cys Ser

Arg420Val

Glu Gly His Ser Leu Lys

Met Ser Giu Giu440Giu

Glu Gay Arg

Asp Asn Ser430Tyr Ser Thr

Leu Ser ProLeu Thr450

Gly Ser

Val Arg Giu Thr Gin Thr Giu460AspGly Arg Ala

465Gin

Giu470Phe

Glu Giu Asp Gin475Gly

Giu Gly Ile

Ala Met Asn His485Gly

Val Gin Giu Thr Leu Arg Al a495ValPro Thr Gly Ile Tyr Ile Arg Gly His Leu

510

<210> 28<211> 1669<212> DNA<213> Homo sapiens

<220><221> CDS<222> (708) (1121)

<400> 28gtctgacccattagctcatcccactgactggagtctctcctgactgactggtgtattatggtggttgcgttctgcctgaaggaggagagaatctgcctccgaagcagccatggtggcctc

ggcctgcctcttgggqgcctcttgacctttcaccatgcattgtgtgtgtgctgtcatatcgggcaacactaaagoaggtaggtggagactggtgtgaggggt ccc tggg ttgggcctgct

cc ttccc tagccttaaacacacctccaacogcaggt cactgaggggtgacagagtcaagtgtcagggtttttttctcaga.gtggctcaga.aacctgtctccagccagagggcatgtacat

gcctggct 00cccoatttotcttctgttca.gtgtgtgtgctgtccgtggagaactgtggt.ggcgtgtgtgccccagagcacccaggtgtgctaccacttccttgaactgtattttctgta

ttctgttgactgoggaagattcgggagggcatgtgtgoctggggtgactggtatgtgcca.tcatgtggctgtattaatgacgggcatagcggagccatggtacagaagcc

atgggagattgctcoooatctccaccaattgtgtgagtgttgtccgtggtcgggatttgagtgtgtgacctgcagaggtttggagotggagggcaagtgt.Ctctgccctc

120180240300360420480540600660716aatatac atg cgc cgg

Met Arg ArgI

gag cttGiu Leu

ott gca gga. ata.Leu Ala Gly Ile

ctgLeu10

otc cga. atc act ttt aat ttt ttt cttLeu Arg Ile Thr Phe Asn Phe Phe Leu

ttt ttc ttg CccPhe Phe Leu Pro

cca. tta gtt gtaPro Leu Val Val Phe Ile Tyr Phe Tyr

Phe Tyr Phe Phegag atg gag tctGiu Met Giu Ser

tat gtt got cagTyr Val Ala Gin

gct. ggcAla Gly

ott gaa ctcLeu Giu Leu

ctgLeu

ggc tca. agc aatGly Ser Ser Asn

oct oCc tca. gacPro Ala Ser Asp

tco ota. gta.Ser Leu Val

got ggg act tta. agt gta cac cac tgt gcc tgc ttt gaa tcc ttt acgAla Gly Thr Leu Ser Val His His Cys Ala Cys Phe Glu Ser Phe Thr

51/105

aag aga aaaLys Arg Lys

aaa aaa tta aag aaa gcc ttt aga ttt atc caa tgt ttaLys Lys Leu Lys Lys Ala Phe Arg Phe Ile Gin Cys Leu

ctaLeu100

ctg gga ttg cttLeu Gly Leu Leu

aaaLys105

gtg agg ccc ctc caa cac cag ggg gtt aatVal Arg Pro Leu Gin His Gin Gly Val. Asn

1004

1052

1100tcc tgt gat tgt gaa agg ggc tac ttcSer Cys Asp Cys Giu Arg Gly Tyr Phe

120

caa ggcGin Gly125

atc ttc atg cag gcaIle Phe Met Gin Ala

130

gcc oct tgSAla Pro Trr

agcctcgtggaattgcttggcagtgattatgaatgtcgcctgggttggggccagaatacgcctaagggacctgaagatcaaatgatatt

gag ggc acGlu Gly T1135

ttactgagtaacctggtgacagaccgagagtttccccctggctggagttcctagatttaggaggctcccataagatcctactgtttttaa

:c tga gagctggtag agtctgaaat tagggatgtgr*

aggtaaaattaagggctcctagtaggagttggttttggataatgaggttttacccaaacttccttcgttcacatgtacatataaacagac

gcatccaccagttcaatagtgaggtgaggtcactaattcaatttttagctcttcttagtccccagccagctttatgtaaaaaaacttg

ttgtttgtgaggtgttgggggaaggaggtgaggc tott ct

ggcccacccatgaaatctgcctaggacttctatgtgcata

taccttagggagagagagago tgggggtgaggatgtttctgatacactcatggatttctggaatgtggagtttgtacata

1151

121112711331139114511511157116311669

<210> 29<211> 137<212> PRT<213> HOMO sapiens

<400> 29Met Arg Arg1

Phe Phe Leu

Tyr Phe Tyr

Gin Ala Gly

Giu Leu Leu Ala Gly Ile Leu10Pro

Leu Arg Ile Thr Phe Asn

Phe

Phe

Phe Leu Pro Phe25Glu

Leu Val Val

Tyr Phe Phe Leu40Gly

Met Glu Ser His

Pro

Phe Phe Ile

Tyr Val Ala

Ala Ser AspLeu Glu Leu

Ser Leu

Ser Phe

Gin Cys

Leu

Leu

Ser Ser Asn

Val Ala (fly

Thr Lys Arg

Leu Leu Leu

Ser Val His Ala Cys Phe

Lys Lys Lys Leu Ala Phe Arg Phe Ile

Gly Leu Leu Arg Pro Leu

Gly Val Asn

Gin His Gin110Gly Ile PheCys Asp Cys Glu Arg

120Gly Thr

Gly Tyr Phe Gin125

Met Gin130

Ala Pro Trp

<210> <211> 510<212> PRT<213> Homo sapiens

<400>

52/105

Met Pro Leu Ser Leu Gly Ala Glu Met Trp Gly Pro Giu Ala Trp Leu

00 15 10 isLeu Leu Leu Leu Leu Leu Ala Ser Phe Thr Gly Arg Cys Pro Ala Gly

25 Giu Leu Glu Thr Ser Asp Val Val Thr Val Val Leu Gly Gin Asp Ala

40 S Lys Leu Pro Cys Phe Tyr Arg Gly Asp Ser Gly Clu Gin Val Gly Gin

55 Val Ala Trp Ala Arg Val Asp Ala Gly Giu Gly Ala Gin Giu Leu Ala

S 65 70 75 Leu Leu His Ser Lys Tyr Gly Leu His Val Ser Pro Ala Tyr Glu Gly

90 Arg Val Giu Gin Pro Pro Pro Pro Arg Asn Pro Leu Asp Gly Ser Val

100 105 110Leu Leu Arg Asn Ala Val Gin Ala Asp Giu Gly Glu Tyr Giu Cys Arg

C1115 120 125Val Ser Thr Phe Pro Ala Gly Ser Phe Gin Ala Arg Leu Arg Leu Arg

130 135 140

00 Val Leu Val Pro Pro Leu Pro Ser Leu Asn Pro Gly Pro Ala Leu Giu145 150 155 160

S Glu Gly Gin Gly Leu Thr Leu Ala Ala Ser Cys Thr Ala Giu Gly SerC1165 170 175Pro Ala Pro Ser Val Thr Trp Asp Thr Giu Val Lys Gly Thr Thr Ser

180 185 190Ser Arg Ser Phe Lys His Ser Arg Ser Ala Ala Val Thr Ser Glu Phe

195 200 205His Leu Val Pro Ser Arg Ser Met Asn Gly Gin Pro Leu Thr Cys Val

210 215 220Val Ser His Pro Gly Leu Leu Gin Asp Gin Arg Ile Thr His Ile Leu

225 230 235 240His Val Ser Phe Leu Ala Giu Ala Ser Val Arg Gly Leu Giu Asp Gin

245 250 255Asn Leu Trp His Ile Gly Arg Glu Gly Ala Met Leu Lys Cys Leu Ser

260 265 270

Giu Gly Gin Pro Pro Pro Ser Tyr Asn Trp Thr Arg Leu Asp Gly Pro275 280 285

Leu Pro Ser Gly Val Arg Val Asp Gly Asp Thr Leu Gly Phe Pro Pro290 295 300

Leu Thr Thr Glu His Ser Gly Ile Tyr Val Cys His Val Ser Asn Glu305 310 315 320Phe Ser Ser Arg Asp Ser Gin Val Thr Val Asp Val Leu Asp Pro Gin

325 330 335Glu Asp Ser Gly Lys Gin Val Asp Leu Val Ser Ala Ser Val Val Val

340 345 350Val Gly Val Ile Ala Ala Leu Leu Phe Cys Leu Leu Val Val Val Val

355 360 365Val Leu Met Ser Arg Tyr His Arg Arg Lys Ala Gin Gin Met Thr Gin

370 375 380Lys Tyr Giu Glu Giu Leu Thr Leu Thr Arg Giu Asn Ser Ile Arg Arg385 390 395 400Leu His Ser His His Thr Asp Pro Arg Ser Gin Pro Glu Giu Ser Val

405 410 415Gly Leu Arg Ala Glu Gly His Pro Asp Ser Leu Lys Asp Asn Ser Ser

420 425 430Cys Ser Val Met Ser Glu Giu Pro Giu Gly Arg Ser Tyr Ser Thr Leu

435 440 445Thr Thr Val Arg Glu Ile Giu Thr Gin Thr Glu Leu Leu Ser Pro Gly

450 455 460Ser Gly Arg Ala Giu Glu GlU GiU Asp Gin Asp Glu Gly Ile Lys Gin465 470' 475 480

53/105

Ala Met Asn His Phe Val Gin Giu Asn Gly Thr Leu Arg Ala Lys Pro

485 490 495

Thr Gly Asn Gly Ile Tyr Ile Asn Gly Arg Gly His Leu Val

500 505 510

<210> 31<211> 510

<212> PRT<213> HomO sapiens

<400> 31Met Pro Leu Ser Le

1 5Leu Leu Leu Leu Le

Glu Leu Giu Thr Se

Lys Leu Pro Cys Le

Val Ala Trp Ala Ar

Leu Leu His Ser Ly

Arg Val Glu Gin Pr100

Leu Leu Arg Asn Al115

Val Ser Thr Phe Pi130

Val Leu Val Pro PI145Glu Gly Gin Gly L

1~Pro Ala Pro Ser V~

180Ser Arg Ser Phe L'

195His Leu Val Pro Si

210Val Ser His Pro G

225His Val Ser Phe L

2

Asn Leu Trp His I260

Glu Gly Gln Pro P275

Leu Pro Ser Gly V290

Leu Thr Thr Glu H305Phe Ser Ser Arg P

3

Glu Asp Ser Gly L340

Val Gly Val Ile P

u Gly Ala Glu Met Trp Gly Pro Giu Ala Trp Leu10

u

r

u

'5

:0

aa

:0

r

ly65al

ys

er

ly

eu45le

rc

'a]

s2

yy

Leu

Asp

Tyr

Val70Tyr

Pro

Val

Ala

Leu150Thr

Thr

His

Arg

Leu23CAlz

Gl)

Prc

Arc

3 Sei31(

3 Se

s G1l

a Al

Ala S

Val V4

Arg G

55Asp P

Gly I

Pro I

Gin I

Gly135

Pro

Leu

Trp

Ser

Ser215

Leu

Glu

Arg

Ser

3 Val295

r Gly

0r Gin

n Val

a Leu

er

'al.0;ly

la

Jeu

!ro

klaL20

Ser

Ser

Ala

Asp

Arg200Met

Gin

Ala

Glu

Tyr280

Asp

Ile

Val

Asj

Let36(

Phe'Thr C

25Thr Val N

Asp Ser C

Gly Glu

His Val

90

Arg Asn105

Asp Glu

Phe Gin

Leu Asn

Ala Ser170

Thr Glu185

Ser Ala

Asf Gly

Asp Gin

Ser Val250

Gly Ala265

Asn Trp

Gly Asp

Tyr Val

Thr Vai330

Leu Val

345

i phe Cys

fly

Tal

Sly

flY

75Ser

Pro

3iy

Ala

Pro155Cys

Va1

Ala

Gin

Arg235Arg

Met

Th2

Thi

Cy31!Asj

Se

Le

Arg C

Leu G4

Glu C

Ala C

Pro

Leu I

Glu

Arg140

Gly

Thr

Lys

Val

Pro220

Ile

Gly

Leu

Arg

T Leu

300

s His

Val

r Ala

u Leu

a Gin

380

.ys

fly

l1n

ln

kla

sp

ryr125Eeu

Pro

Ala

Gly

Thr205Leu

Thr

Leu

Lys

Leu285Gl

Val

Let

Se3

Va36!

Pro P

Gin I

Vai C

Glu I

Tyr

Gly110

Glu

Arg

Ala

Glu

Thr190Ser

Thr

His

Glu

Cys270

Asp

Phe

Ser

i Asp

Val

3501 Val

la

~sp

Sly

jeu

31u

Ser

cys

Leu

Leu

Gly175Thr

Glu

Cys

Ile

Asp255Leu

Gl

Prc

Asi

Prc33!Va

Va

Gly

Ala

Gin

Ala

Gly

Val

Arg

Arg

Glu160Ser

Ser

Phe

Val

Leu240Gin

Ser

Pro

Pro

i Glu320Gin

1 Val

1 Val

r GinVal Leu370

Met Ser Arg Tyr Arg Arg Lys Al: Gin Met Th:

54/105

Lys Tyr Glu Giu Giu Leu Thr Leu Thr Arg Giu Asn Ser Ile Arg Arg

00 385 390 395 400Leu His Ser His His Thr Asp Pro Arg Ser Gin Pro Giu Glu Ser Val

405 410 415

rN~ Gly Leu Arg Ala Giu Gly His Pro Asp Ser Leu Lys Asp Asn Ser Ser420 425 430

ct Cys Ser Val Met Ser Giu Glu Pro Giu Gly Arg Ser Tyr Ser Thr Leu435 440 445

Thr Thr Vai Arg Glu Ile Giu Thr Gin Thr Giu Leu Leu Ser Pro Gly450 455 460

Ser Gly Arg Ala Giu Giu Glu Giu Asp Gin Asp Giu Gly Ile Lys Gin465 470 475 480Ala Met Asn His Phe Val Gin Giu Asn Gly Thr Leu Arg Ala Lys Pro

485 490 495Thr Gly Asn Giy Ile Tyr Ile Asn Gly Arg Gly His Leu Val

500 505 510

00 .<210> 32<211> 295<212> PRT<213> Homo sapiens

<400> 32Met Asn Gly Gin Pro Leu Thr Cys Vai Val Ser His Pro Gly Leu Leu1 5 10

Gin Asp Gin Arg Ile Thr His Ile Leu His Val Ser Phe Leu Ala Glu25

Ala Ser Val Arg Gly Leu Glu Asp Gin Asn Leu Trp His Ile Gly Arg40

Glu Gly Ala Met Leu Lys Cys Leu Ser Glu Gly Gin Pro Pro Pro Ser55

Tyr Asn Trp Thr Arg Leu Asp Gly Pro Leu Pro Ser Gly Val Arg Val70 75

Asp Gly Asp Thr Leu Gly Phe 'Pro Pro Leu Thr Thr Giu His Ser Giy90

Ile Tyr Val Cys His Val Ser Asn Giu Phe Ser Ser Arg Asp Ser Gin100 105 110

Val. Thr Val Asp Val Leu Asp Pro Gin Glu Asp Ser Gly Lys Gin Val115 120 125

Asp Leu Val Ser Ala Ser Val Val Val Vai Gly Val Ile Ala Ala Leu130 135 140

Leu Phe Cys Leu Leu Val Val Val Val Val Leu Met Ser Arg Tyr His145 i50 155 160Arg Arg Lys Ala Gin Gin Met Thr Gin Lys Tyr Giu Glu Giu Leu Thr

165 170 175Leu Thr Arg Giu Asn Ser Ile Arg Arg Leu His Ser His His Thr Asp

180 185 190Pro Arg Ser Gin Pro Giu Giu Ser Vai Gly Leu Arg Ala Giu Gly His

195 200 205Pro Asp Ser Leu Lys Asp Asn Ser Ser Cys Ser Val Met Ser Glu Giu

210 215 220Pro Glu Gly Arg Ser Tyr Ser Thr Leu Thr Thr Val Arg Giu Ile Giu225 230 235 240Thr Gin Thr Giu Leu Leu Ser Pro Gly Ser Gly Arg Ala Giu Glu Giu

245 250 255Giu Asp Gin Asp Giu Gly Ile Lys Gin Ala Met Asn His Phe Val Gin

260 265 270Glu Asn Gly Thr Leu Arg Ala Lys Pro Thr Gly Asn Gly Ile Tyr Ile

275 280 285

55/105

Asn Gly Arg Gly His Leu Val

290 295

00

00

<210> 33<211> 485<212> PRT<213> Homo sapiens

<400> 33Met Pro Leu Ser Leu Gly Ala Glu Met Trp Gly Pro Giu Ala Trp Leu

1

Leu

Glu

Lys

Val65Leu

Arg

Leu

Va1

Val145Glu

Pro

Ser

His

Val225His

Asn

Glu

Leu

Leu305Phe

Glu

Val

Val

Leu

Leu

Leu

Ala

Leu

Val

Leu

Ser130Leu

Gly

Ala

Arg

Leu210Ser

Val

Leu

Gly

Pro290Thr

Ser

Asp

Gly

Leu370

Leu

Glu

Pro

Trp

His

Glu

Arg115Thr

Val

Gin

Pro

Ser195Val

His

Ser

Trp

Gin275Ser

Thr

Ser

Ser

Val355Met

eu

Thr

Cys

Ala

Ser

Gin100Asn

Phe

Pro

Gly

Ser180Phe

Pro

Pro

Phe

His260Pro

Gl)

Gl

Arc

G134(I1

Sei

Leu

Ser

Phe

Arg

Lys

Pro

Ala

Pro

Pro

Leu165Val

Lys

Ser

Gly

Leu245Ile

Pro

Val

i His

I Asp325Lys

e Ala

r Arg

Leu

Asp

Tyr

Val70Tyr

Pro

Val

Ala

Leu150Thr

Thr

His

Arg

Leu230Ala

Gly

Pro

Arg

Ser310Sey

Glr

Alz

Tyl

Ala

Val

Arg55Asp

Gly

Pro

Gin

Gly135Pro

Leu

Trp

Ser

Ser215Leu

Glu

Arg

Ser

Val295Gly

Gin

Val

Leu

His375

3er

lal

3iy

Ala

Leu

Pro

Ala120Ser

Ser

Ala

Asp

Arg200Met

Gin

Ala

Glu

Tyr280Asp

Ile

Val

Asp

Lev360Arc

Phe I

Thr

Asp

Gly

His

Arg105Asp

Phe

Leu

Ala

Thr185Ser

Asn

Asp

Ser

Gly265Asn

Gly

Tyr

Thr

Leu345Phe

Arg

hr

Ial

jer

'lu

lal

%sn

Glu

Gin

Asn

Ser170Glu

Ala

Gly

Gin

Val250Ala

Trp

Asp

Val

Val330Val

Cyc

LyE

Gly 2

Val

Gly

Gly75Ser

Pro

Gly

Ala

Pro155Cys

Val

Ala

Gin

Arg235Arg

Met

Thr

Thr

Cys315Asp

Ser

Leu

3 Ala

k.rg

Leu

Glu

Ala

Pro

Leu

Glu

Arg140Gly

Thr

Lys

Val

Pro220Ile

Gly

Leu

Arg

Leu300His

Val

Ala

Leu

Gir

Cys 1

Gly C

Gin N

Gin

Ala

Asp

Tyr125Leu

Pro

Ala

Gly

Thr205Leu

Thr

Leu

Lys

Leu285Gly

Va1

Leu

Ser

Val365Gin

~ro00ln I

Ial

'lu

yr

3,111031u

Arg

Ala

Glu

Thr190Ser

Thr

His

Glu

Cys270Asp

Phe

Ser

Asp

Val350Val

Met

kla

ksp

ly

Leu

Glu

Ser

eys

Leu

Leu

Gly175Thr

Glu

Cys

Ile

Asp255Leu

Gly

Pro

Asn

Pro335Val

Val

Thi

Gly

Ala

Gin

Ala

Gly

Val

Arg

Arg

Glu160Ser

Ser

Phe

Val

Leu240Gin

Ser

Pro

Pro

Glu320Gin

Val

Val

Gln

380

Lys Tyr Glu Glu Giu Leu Thr Lou Thr Arg Giu Asn Ser Ile Arg Axg

385 390 395 400

56/105

00

Leu

Gly

Thr

Gin

Gly465Arg

His

Arg

Glu

Asp450Thr

Gly

Ser His His405

Ser Tyr Ser420

Leu Leu Ser435Glu Gly Ile

Leu Arg Ala

His Leu Val485

Thr Asp Pro Arg Ser410

Thr Leu Thr Thr Val425

Pro Gly Ser Gly Arg440

Lys Gin Ala Met Asn455

Lys Pro Thr Gly Asn470

Gin Ser Glu Glu Pro415

Arg Giu Ile Giu Thr430

Ala Giu Giu Glu Glu445

His Phe Val Gin Glu460

Gly Ile Tyr Ile Asn475

Glu

Gin

Asp

Asn

Gly480

00

<210> 34<211> 510<212> PRT<213> Homo sapiens

<400> 34Met1

Leu

Glu

Lys

Val1

Leu

Arg

Leu

Val1

Val1145Glu

Pro

Ser

His

Val225His

Asn

Giu

Leu

Leu305

Pro

Leu

Leu

Leu

Ala

Leu

Val

Leu

Ser130Leu

Gly

Ala

Arg

Leu210Ser

Val

Leu

Gly

Pro290Thr

Leu

Leu

Gly

Pro

Trp

His

Giu

Arg115Thr

Val

Gin

Pro

Ser195Val1

His

Ser

Trp

Gin275Ser

Thr

Ser

Leu

Thr

Cys

Ala

Ser

Gin100Asn

Phe

Pro

Gly

Ser180Phe

Pro

Pro

Phe

His260Pro

Gly

Glu

Leu

Leu

Ser

Phe

Arg

Lys

Pro

Al a

Pro

Pro

Leu165Val

Lys

Ser

Gly

Leu245Ile

Pro

Val

His

Gly

Leu

Asp

Tyr

Val

Tyr

Pro

Val

Al a

Leu150Thr

Thr

His

Arg

Leu230Al a

Giy

Pro

Arg

Ser310

Ala

Ala

Val

Arg

Asp

Gly

Pro

Gin

Gly135Pro

Leu

Trp

Ser

Ser215Leu

Glu

Arg

Ser

Val295Gly

Giu

Ser

Val40Gly

Al a

Leu

Pro

Ala120Ser

Ser

Ala

Asp

Arg200Met

Gin

Ala

Glu

Tyr280Asp

Ile

Met

Phe25Thr

Asp

Gly

His

Arg105Asp

Phe

Leu

Al a

Thr185Ser

Asn

Asp

Ser

Gly265As n

Gly

Tyr

Trp10Thr

Val

Ser

Glu

Val90Asn

Glu

Gin

Asn

Ser170Clu

Al a

Gly

Gin

Val1250Ala

Trp

Asp

Val

Gly

Giy

Val

Gly

Gly75Ser

Pro

Gly

Al a

Pro155Cys

Val

Ala

Gln

Arg235Arg

Met

Thr

Thr

Cys315

Giu

Cys

Gly

Gin

Gin

Al a

Asp

Tyr125Leu

Pro

Al a

Gly

Thr205Leu

Thr

Leu

Lys

Leu285Gly

Val

Ala

Pro

Gin

Val

Glu

Tyr

Gly110Glu

Arg

Ala

Giu

Thr190Ser

Thr

His

Giu

Cys270Asp

Phe

Ser

Trp

Al a

Asp

Gly

Leu

Glu

Ser

Cys

Leu

Leu

Gly175Thr

Glu

Cys

Ile

Asp255Leu

Gly

Pro

Asn

Leu

Gly

Ala

Gin

Al a

Gly

Val

Arg

Arg

Giu160Ser

Ser

Phe

Val

Leu240Gin

Ser

Pro

Pro

Glu320

57/105

Phe Ser Ser Arg Asp Ser Gin Val Thr Val Asp Val Leu Asp Pro Gin

325 330 335

00 Glu Asp Ser Gly Lys Gin Val Asp Leu Val Ser Ala Ser Val Vai Vai

0340 345 350

0 Val Gly Val Ile Ala Aia Leu Leu Phe Cys Leu Leu Val Val Vai Val

rl355 360 365

SVal Leu met Ser Ary Tyr His Arg Arg Lys Ala Gin Gin Met Thr Gin

370 375 380

Lys Tyr Giu Giu Glu Leu Thr Leu Thr Arg Glu Asn Ser Ile Arg Arg

385 390 395 400

Leu His Ser His His Thr Asp Pro Arg Ser Gin Pro Giu Giu Ser Vai

rl405 410 415

Gly Leu Arg Ala Glu Gly His Pro Asp Ser Leu Lye Asp Asn Ser Ser

420 425 430

Cys Ser Vai Met Ser Glu Glu Pro Glu Gly Arg Ser Tyr Ser Thr Leu

435 44045

Thr Thr Val Arg Giu Ile Giu Thr Gin Thr Giu Leu Leu Ser Pro Giy

450 455 460

C1 Ser Giy Arg Ala Giu Giu Giu Giu Asp Gin Asp Giu Gly Ile Lys Gin

00 465 470 475 480

Ala Met Asn His Phe Val Gln Giu Asn Giy Thr Leu Arg Ala Lye Pro

485 490 495

Thr Gly Asn Giy Ile Tyr Ile Asn Gly Arg Gly His Leu Val

500 505 510

<210> <211> 510<212> PRT

<213> Homo sapiens

<400>

Met Pro Leu Ser Leu Gly Ala Glu Met Trp Giy Pro Giu Ala Trp Leu

1 5 10

Leu Leu Leu Leu Leu Leu Ala Ser Phe Thr Gly Arg Cys Pro Ala Gly

25

Glu Leu Giu Thr Ser Asp Vai Val Thr Val Val Leu Gly Gin Asp Ala

40

Lys Leu Pro Cys Phe Tyr Arg Gly Asp Ser Gly Glu Gin Val Gly Gin

55

Val Ala Trp Ala Arg Val Asp Ala Gly Glu Gly Ala Gin Giu Leu Ala

70 75

Leu Leu His Ser Lys Tyr Gly Leu His Val. Ser Pro Ala Tyr Glu Gly

90

Arg Val Glu Gin Pro Pro Pro Pro Arg Asn Pro Leu Asp Gly Ser Val

100 105 110

Leu Leu Arg Asn Ala Val Gin Ala Asp Glu Gly Glu Tyr Glu Cys Arg

115 120 125

Vai Ser Thr Phe Pro Ala Gly Ser Phe Gln Ala Arg Leu Arg Leu Arg

130 135 140

Val Met Val Pro Pro Leu Pro Ser Leu Asn Pro Gly Pro Ala Leu Glu

145 150 155 160

Glu Gly Gin Gly Leu Thr Leu Ala Ala Ser Cys Thr Ala Glu Giy Ser

165 170 175

Pro Ala Pro Ser Val Thr Trp Asp Thr Giu Val Lys Gly Thr Thr Ser

180 185 190

Ser Arg Ser Phe Lye His Ser Arg Ser Ala Ala Val Thr Ser Giu Phe

195 200 205

His Leu Val. Pro Ser Arg Ser Met Asn Gly Gin Pro Leu Thr Cys Val

210 215 220

58/ 105

Val Ser His Pro Gly Leu Leu Gin Asp Gin Arg Ile Thr His Ile Leu

225 230 235 24000 His Val Ser Phe Leu Ala Giu Ala Ser Val Arg Gly Leu Giu Asp Gin

245 250 255

Asn Leu Trp His Ile Gly Arg Giu Gly Ala Met Leu Lys Cys Leu Ser

260 265 270

Glu Gly Gin Pro Pro Pro Ser Tyr Asn Trp Thr Arg Leu Asp Gly Pro

275 280 285

Leu Pro Ser Gly Val Arg Val Asp Gly Asp Thr Leu Gly Phe Pro Pro

290 295 300

Leu Thr Thr Giu His Ser Gly Ile Tyr Val Cys His Val Ser Asn Giu

305 310 315 320

Phe Ser Ser Arg Asp Ser Gin Val Thr Vai Asp Val Leu Asp Pro Gin

325 330 335

Glu Asp Ser Gly Lys Gin Val Asp Leu Val Ser Ala Ser Vai Val Vai

C1340 1 345 350

Val Giy Vai Ile Ala Ala Leu Leu Phe Cys Leu Leu Val Val Val Val

355 360 365

Val Leu Met Ser Arg Tyr His Arg Arg Lys Ala Gin Gin Met Thr Gin

370 375 380

Lys Tyr Giu Giu Giu Leu Thr Leu Thr Arg Giu Asn Ser Ile Arg Arg

CNI 385 390 395 400

Leu His Ser His His Thr Asp Pro Arg Ser Gin Pro Giu Giu Ser Val

405 410 415*Giy Leu Arg Ala Giu Gly His Pro Asp Ser Leu Lys Asp Asn Ser Ser

420 425 430

Cys Ser Val Met Ser Giu Giu Pro Glu Gly Arg Ser Tyr Ser Thr Leu

435 440 445

Thr Thr Val Arg Giu Ile Giu Thr Gin Thr Giu Leu Leu Ser Pro Gly

450 455 460

Ser Gly Arg Ala Glu Giu Giu Giu Asp Gin Asp Giu Gly Ile Lys Gin

465 470 475 480

Ala Met Asn His Phe Vai Gin Giu Asn Gly Thr Leu Arg Ala Lys Pro

485 490 495

Thr Gly Asn Gly Ile Tyr Ile Asn Gly Arg Giy His Leu Val

500 505 510

<210> 36<211> 510<212> PRT<213> Homo sapiens

<400> 36Met Pro Leu Ser Leu Gly Ala Giu Met Trp Gly Pro Giu Ala Trp Leu

1 5 10 Leu Leu Leu Leu Leu Leu Ala Ser Phe Thr Gly Arg Cys Pro Ala Gly

25

Giu Leu Giu Thr Ser Asp Val Val Thr Val Val Leu Gly Gin Asp Ala

40

Lys Leu Pro Cys Phe Tyr Arg Gly Asp Ser Giy Giu Gin Val Gly Gin

55 Val Ala Trp Ala Arg Val Asp Ala Giy Giu Gly Ala Gin Giu Leu Ala

70 75

Leu Leu His Ser Lys Tyr Gly Leu His Val Ser Pro Ala Tyr Giu Gly90

Arg Val Giu Gin Pro Pro Pro Pro Arg Asn Pro Leu Asp Gly Ser Val

100 105 110

Leu Leu Arg Asn Ala Val Gin Ala Asp Glu Gly Giu Tyr Glu Cys Arg

115 120 125

59/105

Val Ser Thr Phe Pro Ala Gly Ser Phe Gin Ala Arg Leu Arg Leu Arg

130 135 140

00 Val Leu Val Pro Pro Leu Pro Ser Leu Asn Pro Gly Pro Ala Leu Glu

S 145 150 155 160

Glu Gly Gin Gly Leu Thr Leu Ala Ala Ser Cys Thr Ala Glu Gly SerC 165 170 175

Pro Ala Pro Ser Val Thr Trp Asp Thr Glu Val Lys Gly Thr Thr Ser

180 185 190

Ser Arg Ser Phe Lys His Ser Arg Ser Ala Ala Val Thr Ser Glu Phe

195 200 205

His Leu Val Pro Ser Arg Ser Met Asn Gly Gin Pro Leu Thr Cys Val

210 215 220

Val Ser His Pro Gly Leu Leu Gin Asp Gin Arg Ile Thr His Ile Leu

225 230 235 240

His Val Ser Phe Leu Ala Glu Ala Ser Val Arg Gly Leu Glu Asp Gin245 250 255

Asn Leu Trp His Ile Gly Arg Glu Gly Ala Met Leu Lys Cys Leu Ser

260 265 270

C Glu Gly Gin Pro Pro Pro Ser Tyr Asn Trp Thr Arg Leu Asp Gly Pro

00 275 280 285

Leu Pro Ser Gly Val Arg Val Asp Gly Asp Thr Leu Gly Phe Pro Pro

290 295 300

Leu Thr Thr Glu His Ser Gly Ile Tyr Val Cys His Val Ser Asn Glu

305 310 315 320

Phe Ser Ser Arg Asp Ser Gin Val Thr Val Asp Val Leu Asp Pro Gin325 330 335

Glu Asp Ser Gly Lys Gin Val Asp Leu Val Ser Ala Ser Val Val Val

340 345 350

Val Gly Val Ile Ala Ala Leu Leu Phe Cys Leu Leu Val Val Val Val

355 360 365

Val Leu Met Ser Arg Tyr His Arg Arg Lys Ala Gin Gin Met Thr Gin

370 375 380

Lys Tyr Glu Glu Glu Leu Thr Leu Thr Arg Glu Asn Ser Ile Arg Arg

385 390 395 400

Leu His Ser His His Thr Asp Pro Arg Ser Gin Pro Glu Glu Ser Val

405 410 415

Gly Leu Arg Ala Glu Gly His Pro Asp Ser Leu Lys Asp Asn Ser Ser

420 425 430

Cys Ser Val Met Ser Glu Glu Pro Glu Gly Cys Ser Tyr Ser Thr Leu

435 440 445

Thr Thr Val Arg Glu Ile Glu Thr Gin Thr Glu Leu Leu Ser Pro Gly

450 455 460

Ser Gly Arg Ala Glu Glu Glu Glu Asp Gin Asp Glu Gly Ile Lys Gin

465 470 475 480

Ala Met Asn His Phe Val Gln Glu Asn Gly Thr Leu Arg Ala Lys Pro

485 490 495

Thr Gly Asn Gly Ile Tyr Ile Asn Gly Arg Gly His Leu Val

500 505 510

<210> 37<211> 511<212> PRT<213> Homo sapiens

<400> 37Met Pro Leu Ser Leu Gly Ala Glu Met Trp Gly Pro Glu Ala Trp Leu

1 5 10

Leu Leu Leu Leu Leu Leu Ala Ser Phe Thr Gly Arg Cys Pro Ala Gly

25

60/105

Giu Leu Glu Thr Ser Asp Val Val Thr Val Val Leu Gly Gin Asp Ala

00

00

Lys

Val

Leu

Arg

Leu

Val1

Val145Giu

Pro

Ser

His

Val225His

Asn

Giu

Leu

Leu305Phe

Gin

Val

Val

Gin385Arg

Val

Ser

Leu

Gly465Gin

Pro

Leu

Al a

Leu

Val1

Leu

Ser130Leu

Gly

Ala

Arg

Leu210Ser

Val

Leu

Gly

Pro290Thr

Ser

Glu

Val

Val1370Lys

Leu

Gly

Cys

Thr450Ser

Ala

Thr

Pro

Trp,

His

Glu

Arg115Thr

Val1

Gin

Pro

Ser195Val

His

Ser

Trp

Gin275Ser

Thr

Ser

Asp

Gly355Leu

Tyr

Hi s

Leu

Ser435Thr

Gly

Met

Gly

Cys

Al a

Ser

Gin100Asn

Phe

Pro

Gly

Ser180Phe

Pro

Pro

Phe

His260Pro

Gly

GlU

Arg

Ser340Val1

Met

Giu

Ser

Arg420Val

Val1

Arg

Asn

As n500

Phe

Arg

Lys

Pro

Ala

Pro

Pro

Leu165Val

Lys

Ser

Gly

Leu245Ile

Pro

Val

His

Asp325Gly

Ile

Ser

Giu

His405Ala

Met

Arg

Ala

His485Gly

Tyr

Val70Tyr

Pro

Val

Al a

Leui50Thr

Thr

His

Arg

Leu230Al a

Gly

Pro

Arg

Ser310Ser

Lys

Ala

Arg

Giu390His

Glu

Ser

Glu

Glu470Phe

Ile

Arg55Asp

Gly

Pro

Gin

Gly135Pro

Leu

Trp

Ser

Ser215Leu

Giu

Arg

Ser

Val1295Gly

Gin

Gin

Ala

Tyr375Leu

Thr

Gly

Giu

Ile455Giu

Val

Tyr

40Gly

Ala

Leu

Pro

Ala120Ser

Ser

Ala

Asp

Arg200Met

Gin

Al a

Giu

Tyr280Asp

Ile

Val1

Val1

Leu360His

Thr

Asp

His

Giu440Giu

Glu

Gin

Ile

Asp

Gly

His

Arg105Asp

Phe

Leu

Ala

Thr185Ser

Asn

Asp

Ser

Gly265Asn

Gly

Tyr

Thr

Asp345Leu

Arg

Leu

Pro

Pro425Pro

Thr

Glu

Giu

Asn505

Ser

Giu

Val190Asn

Glu

Gin

Asn

Ser170Giu

Ala

Gly

Gin

Val250Al a

Trp

Asp

Val1

Val330Leu

Phe

Arg

Thr

Arg410Asp

Giu

Gin

Asp

Asn490Gly

Gly

Gly75Ser

Pro

Gly

Al a

Pro155Cys

Val

Al a

Gin

Arg235Arg

Met

Thr

Thr

Cys315Asp

Val1

Cys

Lys

Arg395Ser

Ser

Gly

Thr

Gin475Gly

Arg

Giu Gin

Ala Gin

Pro Ala

Leu Asp

Giu Tyr125

Arg Leu140Gly Pro

Thr Ala

Lys Gly

Val Thr205

Pro Leu220Ile Thr

Gly Leu

Leu Lys

Arg Leu285

Leu Gly300His Val

Val Leu

Ser Ala

Leu Leu365

Ala Gin380Giu Asn

Gin Pro

Leu Lys

Arg Ser445

Giu Leu460Asp Giu

Thr Leu

Gly His

Val

Giu

Tyr

Gly110Glu

Arg

Ala

Glu

Thr190Ser

Thr

His

Glu

Cys270Asp

Phe

Ser

Ala

Ser350Val

Gin

Ser

Glu

Asp430Tyr

Leu

Gly

Arg

Leu510

Gly

Leu

Giu

Ser

Cys

Leu

Leu

Gly175Thr

Giu

Cys

Ile

Asp255Leu

Gly

Pro

Asn

Asp335Val1

Val

Met

Ile

Giu415Asn

Ser

Ser

Ile

Ala495Val

Gin

Ala

dGy

Val1

Arg

Arg

Giu160Ser

Ser

Phe

Val

Leu240Gin

Ser

Pro

Pro

Glu320Pro

Val

Val

Thr

Arg400Ser

Ser

Thr

Pro

Lys480Lys

61/105

00 <210> 38<211> 137<212> PRT

rN~ <213> Homo sapiens

<400> 38S Met Arg Arg Glu Leu Leu Ala Gly Ile Leu Leu Arg Ile Thr Phe Asn

1 5 10 Phe Phe Leu Phe Phe Phe Leu Pro Phe Pro Leu Val Val Phe Phe Ile

C120 25 Tyr Phe Tyr Phe Tyr Phe Phe Leu Glu Met Glu Ser His Tyr Val Ala

40 Gin Ala Gly Leu Giu Leu Leu Gly Ser Ser Asn Pro Pro Ala Ser Ala

55 Ser Leu Val Ala Gly Thr Leu Ser Val His His Cys Ala Cys Phe Giu

70 75

Ser Phe Thr Lys Arg Lys Lys Lys Leu Lys Lys Ala Phe Arg Phe Ile

0085 90 Gin Cys Leu Leu Leu Gly Leu Leu Lys Val Arg Pro Leu Gin His Gin

100 105 110Gly Val Asn Ser Cys Asp Cys Giu Arg Gly Tyr Phe Gin Gly Ile Phe

115 120 125

Met Gin Ala Ala Pro Trp Giu Gly Thr130 135

<210> 39<211> 137<212> PRT<213> Homo sapiens

<400> 39Met Arg Arg Giu Leu Leu Ala Gly Ile Leu Leu Arg Ile Thr Phe Asn

1 5 10 Phe Phe Leu Phe Phe Phe Leu Pro Phe Pro Leu Val Val Phe Phe Ile

25 Tyr Phe Tyr Phe Tyr Phe Phe Leu Giu Met Glu Ser His Tyr Val Ala

40

Gin Ala Giy Leu Giu Leu Leu Gly Ser Ser Asn Pro Pro Ala Ser Asp55

Ser Leu Val Ala Giy Thr Leu Ser Val His His Cys Ala Cys Phe Glu70 75

Ser Phe Thr Lys Arg Lys Lys Lys Leu Lys Lye Ala Phe Arg Phe Ile90

Gin Cys Leu Leu Leu Gly Leu Leu Lye Val Arg Pro Leu Gin His Gin100 105 110

Gly Val Asn Ser Cys Asp Cys Giu Arg Giy Tyr Phe Gin Gly Ile Phe115 120 125

Met Gin Ala Ala Pro Trp Glu Gly Thr130 135

<210> <211> 510<212> PRT<213> Homo sapiens

<400>

62/105

00

00

Met1

Leu

Glu

Lys

Val

Leu

Arg

Leu

Val

Val145Glu

Pro

Ser

His

Va1225His

Asn

Glu

Leu

Leu305Phe

Glu

Val

Val

Lys385Leu

Gly

Cys

Thr

Leu

Leu

Glu

Pro

Trp

His

Glu

Arg115Thr

Val

Gln

Pro

Ser195Val

His

Ser

Trp

Gin275Ser

Thr

Ser

Ser

Val355Met

Glu

Ser

Arg

Val435Val

Ser

Leu

Thr

Cys

Ala

Ser

Gin100Asn

Phe

Pro

Gly

Ser180Phe

Pro

Pro

Phe

His260Pro

Gly

Glu

Arg

Gly340Ile

Ser

Glu

His

Ala420Met

Arg

Leu5

Leu

Ser

Phe

Arg

Lys

Pro

Ala

Pro

Pro

Leu165Val

Lys

Ser

Gly

Leu245Ile

Pro

Val

His

Asp325Lys

Ala

Arg

Glu

His405Glu

Ser

Glu

Glu

Gly

Leu

Asp

Tyr

Val70Tyr

Pro

Val

Ala

Leu150Thr

Thr

His

Arg

Leu230Ala

Gly

Pro

Arg

Ser310Ser

Gin

Ala

Tyr

Leu390Thr

Gly

Glu

Ile

Glu470

Ala

Ala

Val

Arg

Asp

Gly

Pro

Gin

Gly135Pro

Leu

Trp

Ser

Ser215Leu

Glu

Arg

Ser

Val295Gly

Gin

Val

Leu

His375Thr

Asp

His

Glu

Glu455Glu

Glu

Ser

Val40Gly

Ala

Leu

Pro

Ala120Ser

Ser

Ala

Asp

Arg200Met

Gin

Ala

Glu

Tyr280Asp

Ile

Va1

Asp

Leu360Arg

Leu

Pro

Pro

Pro440Thr

Glu

Met

Phe

Thr

Asp

Gly

His

Arg105Asp

Phe

Leu

Ala

Thr185Ser

Asn

Asp

Ser

Gly265Asn

Gly

Tyr

Thr

Leu345Phe

Arg

Thr

Arg

Asp425Glu

Gin

Asp

Pro Giu Ala

Arg

Leu

Glu

Ala

Pro

Leu

Glu

Arg140Gly

Thr

Lys

Val

Pro220Ile

Gly

Leu

Arg

Leu300His

Val

Ala

Leu

Gin380Asn

Pro

Lys

Ser

Leu460Glu

Cys

Gly

Gin

Gin

Ala

Asp

Tyr125Leu

Pro

Ala

Gly

Thr205Leu

Thr

Leu

Lye

Leu285Gly

Val

Leu

Ser

Val365Gin

Ser

Glu

Asp

Tyr445Leu

Gly

Trp

Ala

Asp

Gly

Leu

Glu

Ser

Cys

Leu

Leu

Gly175Thr

Glu

Cys

Ile

Asp255Leu

Gly

Pro

Asn

Pro335Val

Val

Thr

Arg

Ser415Ser

Thr

Pro

Lye

Leu

Gly

Ala

Gin

Ala

Gly

Vai

Arg

Arg

Glu160Ser

Ser

Phe

Val

Leu240Gin

Ser

Pro

Pro

Glu320Gin

Val

Val

Gin

Arg400Val

Ser

Leu

Gly

Gin480

Ser Gly Arg Ala

63/105

Ala Met Asn His Phe Val Gin Glu Asn Gly Thr Leu Arg Ala Lys Pro

485 490 495

00 Thr Gly Asn Gly Ile Tyr Ile Asn Gly Arg Gly His Leu Val

500 505 510

<210> 41<211> 510<212> PRT

<213> Homo sapiens

<400> 41

Met Pro Leu Ser Leu Gly Ala Glu Met Trp Gly Pro Glu Ala Trp Leu

1 5 10

S Leu Leu Leu Leu Leu Leu Ala Ser Phe Thr Gly Arg Cys Pro Ala Gly

25

Glu Leu Glu Thr Ser Asp Val Val Thr Val Val Leu Gly Gin Asp Ala

40

1 Lys Leu Pro Cys Phe Tyr Arg Gly Asp Ser Gly Glu Gin Val Gly Gin

00 50 55

Val Ala Trp Ala Arg Val Asp Ala Gly Glu Gly Ala Gin Glu Leu Ala

S 65 70 75

Leu Leu His Ser Lys Tyr Gly Leu His Val Ser Pro Ala Tyr Glu Gly90

Arg Val Glu Gin Pro Pro Pro Pro Arg Asn Pro Leu Asp Gly Ser Val

100 105 110

Leu Leu Arg Asn Ala Val Gin Ala Asp Glu Gly Glu Tyr Glu Cys Arg

115 120 125

Val Ser Thr Phe Pro Ala Gly Ser Phe Gin Ala Arg Leu Arg Leu Arg

130 135 140

Val Leu Val Pro Pro Leu Pro Ser Leu Asn Pro Gly Pro Ala Leu Glu

145 150 155 160

Glu Gly Gin Gly Leu Thr Leu Ala Ala Ser Cys Thr Ala Glu Gly Ser

165 170 175

Pro Ala Pro Ser Val Thr Trp Asp Thr Glu Val Lys Gly Thr Thr Ser

180 185 190

Ser Arg Ser Phe Lys His Ser Arg Ser Ala Ala Val Thr Ser Glu Phe

195 200 205

His Leu Val Pro Ser Arg Ser Met Asn Gly Gin Pro Leu Thr Cys Val

210 215 220

Val Ser His Pro Gly Leu Leu Gin Asp Gin Arg Ile Thr His Ile Leu

225 230 235 240

His Val Ser Phe Leu Ala Glu Ala Ser Val Arg Gly Leu Glu Asp Gin

245 250 255

Asn Leu Trp His Ile Gly Arg Glu Gly Ala Met Leu Lys Cys Leu Ser

260 265 270

Glu Gly Gin Pro Pro Pro Ser Tyr Asn Trp Thr Arg Leu Asp Gly Pro

275 280 285

Leu Pro Ser Gly Val Arg Val Asp Gly Asp Thr Leu Gly Phe Pro Pro

290 295 300

Leu Thr Thr Glu His Ser Gly Ile Tyr Val Cys His Val Ser Asn Glu

305 310 315 320

Phe Ser Ser Arg Asp Ser Gin Val Thr Val Asp Val Leu Asp Pro Gin

325 330 335

Glu Asp Ser Gly Lys Gin Val Asp Leu Val Ser Ala Ser Val Val Val

340 345 350

Val Gly Val Ile Ala Ala Leu Leu Phe Cys Leu Leu Val Val Val Val

355 360 365

Val Leu Met Ser Arg Tyr His Arg Arg Lys Ala Gin Gin Met Thr Gin

370 375 380

64/105

Lys Tyr Glu Glu Glu Leu Thr Leu Thr Arg Glu Asn Ser Ile Arg Arg

S 385 390 395 400S Leu His Ser His His Thr Asp Pro Arg Ser Gin Pro Glu Glu Ser Val

405 410 415

Gly Leu Arg Ala Glu Gly His Pro Asp Ser Leu Lys Asp Asn Ser Ser420 425 430

S Cys Ser Val Met Ser Glu Glu Pro Glu Gly Arg Ser Tyr Ser Thr Leu435 440 445

Thr Thr Val Arg Glu Ile Glu Thr Gin Thr Glu Leu Leu Ser Pro Gly450 455 460

Ser Gly Arg Ala Glu Glu Glu Glu Asp Gin Asp Glu Gly Ile Lys Gin465 470 475 480Ala Met Asn His Phe Val Gin Glu Asn Gly Thr Leu Arg Ala Lys Pro

485 490 495Thr Gly Asn Gly Ile Tyr Ile Asn Gly Arg Gly His Leu Val

500 505 510

00 <210> 42<211> 510<212> PRT

C <213> Homo sapiens

<400> 42Met Pro Leu Ser Leu Gly Ala Glu Met Trp Gly Pro Glu Ala Trp Leu1 5 10

Leu Leu Leu Leu Leu Leu Ala Ser Phe Thr Gly Arg Cys Pro Ala Gly25

Glu Leu Glu Thr Ser Asp Val Val Thr Val Val Leu Gly Gin Asp Ala40

.Lys Leu Pro Cys Phe Tyr Arg Gly Asp Ser Gly Glu Gin Val Gly Gin55

Val Ala Trp Ala Arg Val Asp Ala Gly Glu Gly Ala Gin Glu Leu Ala70 75

Leu Leu His Ser Lys Tyr Gly Leu His Val Ser Pro Ala Tyr Glu Gly90

Arg Val Glu Gin Pro Pro Pro Pro Arg Asn Pro Leu Asp Gly Ser Val100 105 110

Leu Leu Arg Asn Ala Val Gin Ala Asp Glu Gly Glu Tyr Glu Cys Arg115 120 125

Val Ser Thr Phe Pro Ala Gly Ser Phe Gin Ala Arg Leu Arg Leu Arg130 135 140

Val Leu Val Pro Pro Leu Pro Ser Leu Asn Pro Gly Pro Ala Leu Glu145 150 155 160Glu Gly Gin Gly Leu Thr Leu Ala Ala Ser Cys Thr Ala Glu Gly Ser

165 170 175Pro Ala Pro Ser Val Thr Trp Asp Thr Glu Val Lys Gly Thr Thr Ser

180 185 190Ser Arg Ser Phe Lys His Ser Arg Ser Ala Ala Val Thr Ser Glu Phe

195 200 205His Leu Val Pro Ser Arg Ser Met Asn Gly Gin Pro Leu Thr Cys Val

210 215 220Val Ser His Pro Gly Leu Leu Gin Asp Gin Arg Ile Thr His Ile Leu225 230 235 240His Val Ser Phe Leu Ala Glu Ala Ser Val Arg Gly Leu Glu Asp Gin

245 250 255Asn Leu Trp His Ile Gly Arg Glu Gly Ala Met Leu Lys Cys Leu Ser

260 265 270Glu Gly Gin Pro Pro Pro Ser Tyr Asn Trp Thr Arg Leu Asp Gly Pro

275 280 285

65/105

Leu Pro Ser Gly Val Arg Val Asp Gly Asp Thr Leu Gly Phe Pro Pro

290 295 300

00 Leu Thr Thr Glu His Ser Gly Ile Tyr Val Cys His Val Ser Asn Glu

S 305 310 315 320

0 Phe Ser Ser Arg Asp Ser Gin Val Thr Val Asp Val Leu Asp Pro Gin

C1 325 330 335

Glu Asp Ser Gly Lys Gin Val Asp Leu Val Ser Ala Ser Val Val Val

C 340 345 350

Val Gly Val Ile Ala Ala Leu Leu Phe Cys Leu Leu Val Val Val Val

355 360 365

Val Leu Met Ser Arg Tyr His Arg Arg Lys Ala Gin Gin Met Thr Gin

370 375 380

Lys Tyr Glu Glu Glu Leu Thr Leu Thr Arg Glu Asn Ser Ile Arg Arg

385 390 395 400

Leu His Ser His His Thr Asp Pro Arg Ser Gin Pro Glu Glu Ser Val

405 410 415

Gly Leu Arg Ala Glu Gly His Pro Asp Ser Leu Lys Asp Asn Ser Ser

420 425 430

Cys Ser Val Met Ser Glu Glu Pro Glu Gly Arg Ser Tyr Ser Thr Leu

00 435 440 445

Thr Thr Val Arg Glu Ile Glu Thr Gin Thr Glu Leu Leu Ser Pro Gly

450 455 460

Ser Gly Arg Ala Glu Glu Glu Glu Asp Gin Asp Glu Gly Ile Lys Gin

465 470 475 480

Ala Met Asn His Phe Val Gin Glu Asn Gly Thr Leu Arg Ala Lys Pro

485 490 495

Thr Gly Asn Gly Ile Tyr Ile Asn Gly Arg Gly His Leu Val

500 505 510

<210> 43<211> 508<212> PRT<213> Homo sapiens

<400> 43Met Pro Leu Ser Leu Gly Ala Glu Met Trp Gly Pro Glu Ala Trp Leu

1 5 10

Arg Leu Leu Phe Leu Ala Ser Phe Thr Gly Gin Tyr Ser Ala Gly Glu

25

Leu Glu Thr Ser Asp Val Val Thr Val Val Leu Gly Gin Asp Ala Lys

40

Leu Pro Cys Phe Tyr Arg Gly Asp Pro Asp Glu Gin Val Gly Gin Val

55

Ala Trp Ala Arg Val Asp Pro Asn Glu Gly Ile Arg Glu Leu Ala Leu

70 75

Leu His Ser Lys Tyr Gly Leu His Val Asn Pro Ala Tyr Glu Asp Arg

90

Val Glu Gin Pro Pro Pro Pro Arg Asp Pro Leu Asp Gly Ser Val Leu

100 105 110

Leu Arg Asn Ala Val Gin Ala Asp Glu Gly Glu Tyr Glu Cys Arg Val

115 120 125

Ser Thr Phe Pro Ala Gly Ser Phe Gin Ala Arg Met Arg Leu Arg Val

130 135 140

Leu Val Pro Pro Leu Pro Ser Leu Asn Pro Gly Pro Pro Leu Glu Glu

145 150 155 160

Gly Gin Gly Leu Thr Leu Ala Ala Ser Cys Thr Ala Glu Gly Ser Pro

165 170 175

Ala Pro Ser Val Thr Trp Asp Thr Glu Val Lys Gly Thr Gin Ser Ser

180 185 190

66/105

Arg Ser Phe Thr His Pro Arg Ser Ala Ala Val Thr Ser Glu Phe His195 200 20500

00

Leu Val210

Ser His225Val Ala

Leu Trp

Gly Gin

Pro Ser290

Thr Thr305Ser Ser

Pro Gly

Val Ile

Met Ser370

Glu Glu385Ser His

Arg Ala

Val Met

Val Arg450

Arg Thr465Asn His

Asn Gly

Pro

Pro

Phe

Gin

Pro275Gly

Giu

Arg

Lys

Ala355Arg

Glu

His

Glu

Ser435Glu

Glu

Phe

Ile

Ser

Gly

Leu

Val260Pro

Val1

His

Asp

Gin340Ala

Tyr

Leu

Ser

Gly420Glu

Ile

Giu

Val

Tyr500

Arg

Leu

Al a245Gly

Pro

Arg

Ser

Ser325Val1

Leu

His

Thr

Asp405His

Giu

Glu

Asp

Gin485Ile

Ser Met215

Leu Gin230Giu Ala

Arg Giu

Lys Tyr

Val Lys295

Gly Val310Gin Val

Asp Leu

Leu Phe

Arg Arg375

Leu Thr390Pro Arg

Pro Asp

Pro Giu

Thr Gin455

Asp Asp470Glu Asn

Asn Gly

Asn

Asp

Ser

Gly

As n280Gly

Tyr

Thr

Val1

Cys360Lys

Arg

Ser

Ser

Gly440Thr

Gin

Gly

Arg

Gin

Arg

Arg250Thr

Thr

Thr

Cys

Giu330Ala

Leu

Gin

Asn

Pro410Lys

Ser

Leu

Glu

Leu490His

Pro

Ile235Gly

Leu

Arg

Leu

His315Val1

Ser

Val1

Gin

Ser395Giu

Asp

Tyr

Leu

Gly475Arg

Leu

Leu220Thr

Leu

Lys

Leu

Gly300Val1

Leu

Val1

Val

Met380Ile

Glu

Asn

Ser

Ser460Ile

Al a

Val

Thr

His

Giu

Cys

Asp285Phe

Ser

Asp

Ile

Vai365Thr

Arg

Ser

Ser

Thr445Pro

Lys

Lys

Vai Val

Leu Gin240

Gin Asn255Ser Glu

Pro Leu

Pro Leu

Glu Leu320

Giu Asp335Vai Gly

Val Leu

Lys Tyr

Leu His400

Gly Leu415Cys Ser

Thr Thr

Ser Gly

Ala Met480

Thr Giy495

<210> 44<211> 14<212> PRT<213> Tetanus toxoid

<400> 44Gin Tyr Ile Lys Ala Asn Ser Lys Phe Ile Giy Ile Thr Glu1 5

<210> <211> 21<212> PRT<213> Piasmodium falciparum

<400> Asp Ile Giu. Lys Lys Ile Ala Lys Met Glu Lys Ala Ser Ser Val Phe1 5 10

67/105

Asn Val Val. Asn Ser

00

<210> 46C1 <211> 16

S <212> PRT<213> Streptococcus

<400> 46GyGlVa AlTrTr AaAa

Gly Ala Val Asp Ser Ile Leu Gly lVaAaThTyGyAaAa

1 510

<210> 47

<211> 13

(i <212> FRT<213> Artificial Sequence

00 <220>

<221> VARIANT

c~1 <222> 3<223> Xaa cyclohexylalanine, phenylalanine, or

tyrosifle.

<221> VARIANT

<222> 1, 13<223> Xaa D-alanine or L-alanine

<223> Pan DR-binding Epitope

<400> 47

Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa

1 5

<210> 48<211> 14<212> DNA<213> Artificial Sequence

<220><223> Primer

<400> 48

ttttgatcaa gctt 14

<210> 49<211> 42<212> DNA<213> Artificial Sequence

<220><223> Primer

<400> 49

ctaatacgac tcactatagg gctcgagcgg ccgcccgggc ag 42

<210> <211> 12

68/105

<212> DNA

<213> Artificial Sequence

<220>

<223> Primer

S <400> gatcctgccc gg 12

0 <210> 51<211> <212> DNA<213> Artificial Sequence

<220><223> Primer

(<N<400> 51

00 gtaatacgac tcactatagg gcagcgtggt cgcggccgag

<210> 521 <211>

<212> DNA<213> Artificial Sequence

<220><223> Primer

<400> 52gatcctcggc

<210> 53<211> 22<212> DNA<213> Artificial Sequence

<220><223> Primer

<400> 53ctaatacgac tcactatagg gc 22

<210> 54<211> 22<212> DNA<213> Artificial Sequence

<220><223> Primer

<400> 54tcgagcggcc gcccgggcag ga 22

<210> <211> <212> DNA<213> Artificial Sequence

<220><223> Primer

69/105

<400>

00 agcgtggtcg cggccgagga

<210> 56<211>

<212> DNA

<213> Artificial Sequence

S <220><223> Primer

<400> 56atatcgccgc gctcgtcgtc gacaa

<210> 57<211> 26<212> DNA<213> Artificial Sequence

00<220><223> Primer

<400> 57agccacacgc agctcattgt agaagg 26

<210> 58<211> <212> DNA<213> Artificial Sequence

<220><223> Primer

<400> 58

ggctggagtt caatgaggtt tattt

<210> 59<211> <212> DNA<213> Artificial Sequence

<220><223> Primer

<400> 59tccagcagat ttcagactaa gaaga

<210> <211> 24<212> DNA<213> Artificial Sequence

<220>

<223> Epitope Tag

,<400> gattacaagg atgacgacga taag 24

<210> 61

70/105

<211> 4

00 <212> PRT

<213> Homo sapiens

C1 <400> 61Asn Trp Thr Arg1

<210> 62

C1 <211> 4<212> PRT<213> Homo sapiens

<400> 62Asn Ser Ser Cys1

00<210> 63<211> 4

<212> PRT<213> Homo sapiens

<400> 63Asn Gly Thr Leu

<210> 64<211> <212> PRT<213> Homo sapiens

<400> 64Val Gin Ala Asp Glu Gly Glu Tyr Glu Cys Arg Val Ser Thr Phe1 5 10

<210> <211> 4<212> PRT<213> Homo sapiens

<400> Thr Arg Leu Asp1

<210> 66<211> 4<212> PRT<213> HOMO sapiens

<400> 66Ser Ser Arg Asp1

<210> 67

71/105

00

00

<211> 4<212> PRT<213> Homo sapiens

<400> 67Ser Gin Pro Giu

<210> 68<211> 4<212> PRT<213> Homo sapiens

<400> 68Ser Leu Lys Asp1

<210> 69<211> 4<212> PRT<213> Homo sapiens

<400> 69Thr Val Arg Glu1

<210> <211> 4<212> PRT<213> Homo sapiens

<400> Thr Gin Thr Glu1

<210><211><212><213>

716PRTHomo sapiens

<400> 71Gly Ser Phe

IGin Ala Arg

<210> 72<211> 6<212> PRT<213> Homo sapiens

<400> 72Gly Gin Gly Leu Thr Leu

<210> 73

72/105

00

00

<211><212><213>

6PRTHomo sapiens

<400> 73Gly Leu Thr Lev Ala Ala

1

<210> 74<211> 6<212> PRT<213> Homno sapiens

<400> 74Gly Thr Thr Ser Ser Arg

<210> <211> 6<212> PRT<213> H-omo sapiens

<400> Gly Gin Pro Leu Thr Cys

<210> 76<211> 6<212> PRT<213> Homo sapiens

<400> 76Gly Ilie Tyr Val Cys His

1

<210> 77<211> 6<212> PRT<213> Homo sapiens

<400> 77Gly Val Ile Ala Ala Leu

<210> 78<211> 6<212> PRT<213> Homo sapiens

<400> 78Gly Ser Gly Arg Ala Glu

1

<210> 79

73/105

00

00

<211> 6<212> PRT<213> Homo sapiens

<400> 79Gly Ile Lys Gin Ala Met

<210> <211> 6<212> PRT<213> Homo sapiens

<400> Gly Thr Leu Arg Ala Lys

1

<210> 81<211> 6<212> PRT<213> Homo sapiens

<400> 81Gly Ile Tyr Ile Asn Gly

<210><211><212><213>

82510PRTHomo sapiens

<400> 82Met

Leu

Glu

Lys

Val

Leu

Arg

Leu

Val

Val145Giu

Pro

Pro

Leu

Leu

Leu

Al a

Leu

Val

Leu

Ser130Leu

Gly

Al a

Ser

Leu

Thr

Cys

Al a

Ser

Gin100Asn

Phe

Pro

Gly

Ser180

Leu

Leu

Ser

Phe

Arg

Lys

Pro

Ala

Pro

Pro

Leu165Val

Gly Ala Glu Met Trp Giy Pro Glu Ala Trp Leu

Ala

Val

Arg55Asp

Gly

Pro

Gin

Gly135Pro

Leu

Trp

Ser Phe25

Val Thr

Giy Asp

Ala Gly

Leu His

Pro Arg105

Ala Asp120Ser Phe

Ser Leu

Ala Ala

Asp Thr185

10Thr

Val

Ser

Giu

Val90Asn

Glu

Gin

Asn

Ser170Glu

Ala

Arg

Leu

Glu

Al a

Pro

Leu

Glu

Arg140Gly

Thr

Lys

Val

Cys

Gly

Gin

Gin

Ala

Asp

Tyr125Leu

Pro

Ala

Gly

Thr

Pro

Gin

Val1

Glu

Tyr

Gly110Glu

Arg

Al a

Glu

Thr190Ser

Al a

Asp

Gly

Leu

Glu

Ser

Cys

Leu

Leu

Gly175Thr

Glu

Gly

Ala

Gin

Ala

Gly

Val

Arg

Arg

Glu160Ser

Ser

PheSer Arg Ser Phe Lys His Ser Arg Ser

74/105

195 200 205

00 His Leu Val Pro Ser Arg Ser Met Asn Gly Gin Pro Leu Thr Cys Val210 215 220

Val Ser His Pro Gly Leu Leu Gin Asp Gin Arg Ile Thr His Ile Leu

225 230 235 240

His Val Ser Phe Leu Ala Giu Ala Ser Val Arg Gly Leu Glu Asp Gin

245 250 255

Asn Leu Trp, His Ile Gly Arg Giu Gly Ala Met Leu Lys Cys Leu Ser

260 265 270

Glu Giy Gln Pro Pro Pro Ser Tyr Asn Trp, Thr Arg Leu Asp Gly ProC1275 280 285

Leu Pro Ser Gly Val Arg Val Asp Gly Asp Thr Leu Gly Phe Pro Pro

290 295 '300Leu Thr Thr Giu His Ser Gly Ile Tyr Val Cys His Val Ser Asn Giu

35310 315 320Phe Ser Ser Arg Asp Ser Gin Val Thr Val Asp Val Leu Asp Pro Gin

rl325 330 335Giu Asp Ser Gly Lys Gin Val Asp Leu Val Ser Ala Ser Val Val Val

00 340 345 350Val Gly Val Ile Ala Ala Leu Leu Phe Cys Leu Leu Vai Val Val Val

355 360 365C1 Val Leu Met Ser Arg Tyr His Arg Arg Lys Ala Gin Gin Met Thr Gin

370 .375 380

Lys Tyr Giu Glu Glu Leu Thr Leu Thr Arg Glu Asn Ser Ile Arg Arg385 390 395 400Leu His Ser His His Thr Asp Pro Arg Ser Gin Pro Glu Glu Ser Val

405 410 415

Gly Leu Arg Ala Glu Gly His Pro Asp Ser Leu Lys Asp Asn Ser Ser420 425 430

Cys Ser Val Met Ser Glu Giu Pro Giu Gly Arg Ser Tyr Ser Thr Leu435 440 445

Thr Thr Val Arg Giu Ile Glu Thr Gin Thr Giu Leu Leu Ser Pro Gly450 455 460

Ser Gly Arg Ala Giu Giu Giu Glu Asp Gin Asp Giu Gly Ile Lys Gin465 470 475 480Ala Met Asn His Phe Val Gin Glu Asn Gly Thr Leu Arg Ala Lys Pro

485 490 495Thr Gly Asn Gly Ile Tyr Ile Asn Gly Arg Gly His Leu Val

500 505 510

<210> 83<211> 17<212> PRT<213> Homo sapiens

<400> 83Gly Gin Asp Ala Lys Leu Pro Cys Leu Tyr Arg Gly Asp Ser Gly Giu1 5 10

Gin

<210> 84<211> 19<212> PRT<213> Homo sapiens

<400> 84Leu Gly Gin Asp Ala Lys Leu Pro Cys Leu Tyr Arg Gly Asp Ser Gly

75/105

00

1 5 Giu Gin Val

<210> <211> 29<212> PRT<213> Homo sapiens

<400> Vai Val Thr Val Val Leu Gly Gin

1 5Arg Gly Asp Ser Gly Giu Gin Val

Asp Ala Lys Leu Pro Cys Leu Tyr10

Gly Gin Val Ala Trp

<210> 86<211> 16<212> PRT<213> Homo sapiens

<400> 86Ser His His Thr Asp Pro Arg Ser Gin Ser Glu Glu Pro Giu Gly Arg1 5 10

<210> 87<211> 18<212> PRT<213> Homo sapiens

<400> 87His Ser His His Thr Asp Pro Arg Ser Gin Ser Glu Glu Pro Glu Gly1 5 10

Arg Ser

<210> 88<211> 28<212> PRT<213> Homo sapiens

<400> 88Ser Ile Arg Arg Leu

1 5Giu Giu Pro Glu Gly

<210> 89<211> 137<212> PRT<213> Homio sapiens

His Ser His

Arg Ser Tyr

His Thr Asp Pro Arg Ser Gin Ser10

Ser Thr Leu Thr

<400> 89Met Arg Arg Giu Leu Leu Ala Gly Ile

1 5Phe Phe Leu Phe Phe Phe Leu Pro Phe

Leu Leu Arg Ile Thr Phe Asn10 Pro Leu Val Val Phe Phe Ile

76/105

25

0 -Tyr Phe Tyr Phe Tyr Phe Phe Leu Glu Met Glu Ser His Tyr Val Ala40

Gin Ala Gly Leu Giu Leu Leu Gly Ser Ser Asn Pro Pro Ala Ser Ala

55 Ser Leu Val Ala Gly Thr Leu Ser Val His His Cys Ala Cys Phe Glu

70 75 S Ser Phe Thr Lys Arg Lys Lys Lys Leu Lys Lys Ala Phe Arg Phe Ile

90 Gin Cys Leu Leu Leu Gly Leu Leu Lys Val Arg Pro Leu Gin His Gin

c-1100 105 110Gly Val Asn Ser Cys Asp Cys Giu Arg Gly Tyr Phe Gin Gly Ile Phe

115 120 125Met Gin Ala Ala Pro Trp Giu Gly Thr

130 135

<210>

00 <211> 17<212> PRT<213> Homo sapiens

<400> Gly Arg Cys Pro Ala Gly Glu Leu Gly Thr Ser Asp Val Val Thr Val

1 5 10 Val

<210> 91<211> 19<212> PRT<213> Homo sapiens

<400> 91Thr Gly Arg Cys Pro Ala Gly Glu Leu Gly Thr Ser Asp Val Val Thr1 5 10

Val Val Leu

<210> 92<211> 29<212> PRT<213> Homo sapiens

<400> 92Leu Leu Ala Ser Phe Thr Gly Arg Cys Pro Ala Gly Giu Leu Gly Thr1 5 10

Ser Asp Val Val Thr Val Val Leu Gly Gin Asp Ala Lys

<210> 93<211> 17<212> PRT,<213> Homo sapiens

<400> 93Gin Ala Arg Leu Arg Leu Arg Val Met Val Pro Pro Leu Pro Ser Leu

77/105

1 5 10 Asn

00

<210> 94

S <212> PRT<213> Homo sapiens

<400> 94

Phe Gin Ala Arg Leu Arg Leds Arg Val Met Val Pro Pro Leu Pro Ser

1 5 10

Leu Asn Pro

<210> C1 <211> 29

00 <212> PRT

<213> Homo sapiens

C1 <400>

Phe Pro Ala Gly Ser Phe Gin Ala Arg Leu Arg Leu Arg Val Met Val

1 5 10

Pro Pro Leu Pro Ser Leu Asn Pro Gly Pro Ala Leu Glu

<210> 96<211> 17<212> PRT<213> Homo sapiens

<400> 96

Val Met Ser Glu Glu Pro Glu Gly Cys Ser Tyr Ser Thr Leu Thr Thr

1 5 10

Val

<210> 97<211> <212> PRT<213> HOMO sapiens

<400> 97

Ser Val Met Ser Glu Giu Pro Giu Gly Cys Ser Tyr Ser Thr Leu Thr

1 5 10

Thr Val Arg Glu

<210> 98<211> 29<212> PRT<213> HOMO sapiens

<400> 98Asp Asn Ser Ser Cys Ser Val Met Ser Glu Glu Pro Glu Gly Cys Ser

78/105

000D

j?

1 5 10 Tyr Ser Thr Leu Thr Thr Val Arg Glu Ile Glu Thr Gin

20

<210> 99<211> 17<212> PRT<213> Homo sapiens

<400> 99Ser Gin Val Thr Val Asp Val Leu Ala Asp Pro Gin Glu Asp Ser Gly1 5 10

Lysr-

<210> 100<211> 19<212> PRT<213> Homo sapiens

<400> 100Asp Ser Gin Val Thr Val Asp Val Leu Ala Asp Pro Gin Glu Asp Ser1 5 10

Gly Lys Gin

<210> 101<211> 29<212> PRT<213> Homo sapiens

<400> 101Glu Phe Ser Ser Arg Asp Ser Gin1 5

Pro Gin Glu Asp Ser Gly Lys Gin

Val Thr Val Asp Val Leu Ala Asp10

Val Asp Leu Val Ser

<210> 102<211> 17<212> PRT<213> Homo sapiens

<400> 102Gly Ser Ser Asn Pro Pro Ala Ser Ala Ser Leu Val Ala Gly Thr Leu1 5 10

Ser

<210> 103<211> 19<212> PRT<213> Homo sapiens

<400> 103Leu Gly Ser Ser Asn Pro Pro Ala Ser Ala Ser Leu Val Ala Gly Thr

79/105

00

00

1 5 10 Leu Ser Val

<210> 104<211> 29<212> PRT<213> Homo sapiens

<400> 104Ala Gly Leu Glu Leu Leu Gly Ser Ser Asn Pro Pro Ala Ser Ala Ser

1 5 10

Leu Val Ala Gly Thr Leu Ser Val His His Cys Ala Cys

<210> 105<211> 3344<212> DNA<213> Homo sapiens

<400> 105ggccgtcgttacggcttctttcccctagtgcagttccttaagctggagactctaccgagggcgaaggcgccttacgagggtcctgcgcaaccgccggcagtgaatcctggctgagggcaggccgttccttgccgcagcataccaaaggatttgaagaccaaagggcagcctacgagtggaacgtctgccattgacccccatgggtgtgatgataccatCgccagggagaaaggagagtgtgctctgtgatagatagaaacatcaggatgagggccaagccggcctgcctcttgggggcCtcttgacctttcaccatgcattgtgtgtgtc-ctgtcatatcgggcaacactaaagcaggtEggtggagact

9ttggccacagggggtzagctgagacccaagtt caag t ctgctcagacgtgggactccggcccaggaactaccgcgtggagcgcagtgcagcttccaggcgtccagcactacccagccccccaagcactcgaatgggcagcacccacatcaaatctgtggccctccctcatggggacacttgtcagcaatggaagactctcgccgcactcgcgcaaggccctccatccggagggctgagagagtgaagagacagactgaa*aggcatcaaa*cacgggcaat*ccttccctac*ccttaaacac*acctccaaccgcaggtcactIgaggggtgacagagtcaagt

-gtcagggttt

ittttctcagigtggctcag

gcgtgggaagacggctgggttgcgagaggcctactgctgggtaactgtgggagcaagtgggcgctactgcc agc cgccgcgcggatgaggcggctgcggcgaagagggccagcgtgacctcgctctgctgccactgacttctccacgtgtc acattggcatacaactggattgggctttcgagt tctcctgggaagcaggttgttctgcccagcagatgaaggctgcattgccgagggcc*cccgagggcc*ctgctgtctccaggccatgaggcatctaceIgcctggctccccccatttctcttctgttczgtgtgtgtgctgtccgtggzgaactgtggtggcgtgtgt<

x. ccccagagcii cccaggtgt(

cagctctggggtgtagaacgaagaactctgcatcatttactgctgggccaggcaagtggcactccaaataccccacgcaagcgagtacgatccgagtgctagggcctgacgggacacggaccgtcacctcgtgtggtgtcccttccttgcgagaaggagccacggctggaccccactgaccaagggattctggacctagtttctggtggtcccagaaatacccatcacacaccctgataggcagttactccaggctctggLaccattttgtLtcaatgggcs_ttctgttgactgcggaagatLtcgggagggcatgtgtgcctggggtgact,-gtatgtgccz;tcatgtggct

cgggcatagc

ggagctcggagggccggggCcagcttcctgaggccggtgcggacgcaaaaatgggctcggcgggcttcatccccctggacgtgccgggtcggtgcctccccctggcagccggtcaaaggcagagttccacccatcctggctgaggcctcttatgctcaagtgggcctctgcactgagcactcaggtcactgtcagcctcgggtggtggtgtgaggaggagggacccaggtctcaaggaccacgctgacc

*gcgggccgagtcaggagaatgggacacctg*atgggagatt*gctccccatc*tccaccaatt*gtgtgagtgtItgtccgtggti cgggatttgagtgtgtgacc

i tgcagaggtttggagctgga

4ctcccgatc :ggggctggg 120ccttctgggt 180cccgcgggtg 240ctgccctgct 300gtggacgcgg 360gtgagcccgg 420ggctcagtgc 480agcaccttcc 540ctgccctcac 600tcctgcacag 660acaacgtcca 720ttggtgccta 780ctgctccagg 840gtgaggggcc 900tgcctgagtg 960cccagtgggg 1020agcggcatct 1080gtggatgttc 1140gtggtggtgg 1200ctcatgtccc 1260ctgaccctga 1320agccagccgg 1380aacagtagct 1440acggtgaggg 1500gaggaggaag 1560gggaccctac 1620gtctgaccca 1680ttagctcatc 1740ccactgactg 1800gagtctctcc 1860tgactgactg 1920gtgtattatg 1980gtggttgcgt 2040tctgcctgaa 2100ggaggagaga 2160atctgcctcc 2220

80/105

00

00

ggtgtgaggggt ccc tgggttgggcc tgctaatactgctctgtatttttttcaggctggctgggactttaattaaagaaacctccaacaccatgcaggcagagcctcgtggaattgcttggcagtgattaagaatgtcgctctgggttggagccagaataggcctaaggggcctgaagataaaatgatat

aacctgtctccagccagagggcatgtacatcgaatcacttatttatttttcttgaactccagtgtacaccgcctttagatcagggggttagccccttggggttactgagtgacctggtgatagaccgagactttccccctggctggagttcc taga tt taagaggctcccctaagatcct

ctaccacttccttgaactgtattttctgtattaattttttatttttattttgggctcaagactgtgcctgt tat cc aatgattcctgtgaagggcacctgaaggtaaaatcaagggctccgagtaggagtgggttttggacaatgaggttgtacccaaacatccttcgttaacatgtaca

ggagccatggtacagaagccaatatacatgtcttttttttttttttagagcaatcctcctctttgaatcctttactactgttgtgaaaggagagctggtatgcatccacctgttcaatagtgaggtgaggtcactaattctatttttagctcttcttagtccccagccagttttatgtaacaaaacttga

gggcaagtgtctctgccctccgccgggagcttcttgccctatggagtctcgcctcagccttttacgaagaggattgcttaggctacttccgagtctgaaaattgtttgtgtggtgt tgggtgaaggaggtaaggctcttctggcccacccctgaaatctgcctaggacttatatgtgcataaaa

gaagcagccatggtggcctcttcttgcaggttccattagtactatgttgcccctagtagcgaaaaaaaaaaagtgaggccaaggcatcttttagggatgtataccttagggagagagagagctgggggtgtggatgtttcagatacactcctggatttctcgaatgtggaatttgtacat

2280234024002460252025802640270027602820288029403000306031203180324033003344tctgttttta aataaacaga

<210> 106<211> 3464<212> DNA<213> Homo sapiens

<400> 106ggccgtcgttacggcttctttcccctagtgcagttccttagctgggcagtaggcctggctagctggagactctaccgagggcgaaggcgccttacgagggtcctgcgcaaccgccggcagtgaatcctggctgagggcaggccgttccttgccgcagcata cca aagga tttgaagaccaaagggcagcctacgagtggaacgtctgccattgacccccatgggtgtgatgataccatcgccagggagaaaggagagtgtgctctgtgatagatagaaacatcaggatgagggccaagccggcctgcctcttgggggcctcttgacctttcaccatgcat

gttggccacagggggtagctgagacccaagttcaagtctgctgcctttcagctgctgctgctcagacgtgggactccggcccaggaactaccgcgtggagcgcagtgcagcttccaggcgtccagcactacccagccccccaagcactccgaatgggcagcacccacatcaaatctgtggccctccctcatggggacacttgtcagcaatggaagactctcgccgcactcgcgcaaggccctccatccggagggctgagagagtgaagagacagactgaaaggcatcaaacacgggcaatccttccctagccttaaacacacctccaaccgcaggtcact

gcgtgggaagacggctgggttgcgagaggccagccggctcaccatgccccctactgctgggtaactgtgggagcaagtgggcgctactgccagccgccgcgcggatgaggcggctgcggcgaagagggccagcgtgacctcgctctgctgccactgacttctccacgtgtcac at tggcat acaac tggattgggctttcgagttctcctgggaagcaggttgttctgcccagcagatgaaggctgcattgccgagggcccccgagggccctgctgtctccaggccatgaggcatctacagcctggctccccccatttctcttctgttcagtgtgtgtgc

c agc t ctggggtgtagaacgaagaactctgccagggagattgtccctgggcatcatttactgctgggccaggcaagtggcactccaaataccccacgcaagcgagtacgatccgagtgctagggcctgacgggacacggaccgtcacctcgtgtggtgtcccttccttgcgagaaggagccacggctggaccccactgaccaagggattctggacctagtt tctggtggtcccagaaatacccatcacacaccctgataggcagttactccaggctctggaccattttgttcaatgggcgttctgttgactgcggaagattcgggagggcatgtgtgcct

ggagctcgga9ggCCggggccagcttcctgctcggtggaaagccgagatgaggccggtgcggacgcaaaaatgggctcggcgggcttcatccccctggacgtgccgggtcggtgcctccccctggcagccggtcaaaggcagagttccacccatcctggctgaggcctcttatgctcaagtgggcctctgcactgagcactcaggtcactgtcagcctcgggtggtggtgtgaggaggagggaccccaggtctcaaggaccacgctgaccgcgggccgagtcaggagaatgggacacctga tgggagattgctccccatctccaccaattgtgtgagtgt

gctcccgatctggggctgggccttctgggtcttcagaaactgggggcctgcccgcgggtgctgccctgctgtggacgcgggtgagcccggggctcagtgcagcaccttccctgccctcactcctgcacagacaacgtccattggtgcctac tgctccagggtgaggggcctgcctgagtgcccagtggggagcggcatctgtggatgttcgtggtggtggctcatgtcccctgaccctgaagccagccggaacagtagctacggtgaggggaggaggaaggggaccctacgtctgacccattagctcatcccactgactggagtctctcctgactgactg

120180240300360420480540600660720780840900960102010801140120012601320138014401500156016201680174018001860192019802040

81/105

00

00

tgtgtgtgtgctgtcatatcgggcaacactaaagcaggtaggtggagactggtgtgaggggtccctgggttgggcctgctaatactgctctgtatttttttcaggctggctgggactttaattaaagaaacctccaacaccatgcaggcagagcctcgtggaattgcttggcagtgattaagaatgtcgctc tgggttggagccagaataggcctaaggggcctgaagataaaatgatat

gaggggtgacagagtcaagtgtcagggtttttttctcagagtggctcagaaacctgtctccagccagagggcatgtacatcgaatcacttatttatttttcttgaactccagtgtacaccgcctttagatcagggggttagccccttggggttactgagtgacctggtgatagaccgagactttccccctggctggagttcctagatttaagaggctcccctaagatccttctgttttta

tgtccgtgga ggggtgactg tgtccgtggt gtgtattatg 2100gaactgtggt gtatgtgcca cgggatttga gtggttgcgt 2160

ggcgtgtgtg tcatgtggct gtgtgtgacc tctgcctgaa 2220ccccagagca gtattaatga tgcagaggtt ggaggagaga 2280

cccaggtgtg cgggcatagc tggagctgga atctgcctcc 2340ctaccacttc ggagccatgg gggcaagtgt gaagcagcca 2400

cttgaactgt tacagaagcc ctctgccctc tggtggcctc 2460

attttctgta aatatacatg cgccgggagc ttcttgcagg 2520

ttaatttttt tctttttttt ttcttgccct ttccattagt 2580

atttttattt ttttttagag atggagtctc actatgttgc 2640tgggctcaag caatcctcct gcctcagcct ccctagtagc 2700actgtgcctg ctttgaatcc tttacgaaga gaaaaaaaaa 2760

ttatccaatg tttactactg ggattgctta aagtgaggcc 2820

attcctgtga ttgtgaaagg ggctacttcc aaggcatctt 2880agggcacctg agagctggta gagtctgaaa ttagggatgt 2940

aaggtaaaat tgcatccacc attgtttgtg ataccttagg 3000caagggctcc tgttcaatag tggtgttggg gagagagaga 3060

gagtaggagt tgaggtgagg tgaaggaggt gctgggggtg 3120

gggttttgga tcactaattc aaggctcttc tggatgtttc 3180

caatgaggtt tatttttagc tggcccaccc agatacactc 3240

gtacccaaac tcttcttagt ctgaaatctg ctggatttct 3300atccttcgtt ccccagccag cctaggactt cgaatgtgga 3360aacatgtaca ttttatgtaa atatgtgcat atttgtacat 3420aataaacaga caaaacttga aaaa 3464

<210> 107<211> 3344<212> DNA<213> Homo sapiens

<400> 107ggccgtcgttacggcttctttcccctagtgcagttccttaagctggagactctaccgagggcgaaggcgccttacgagggtcctgcgcaaccgccggcagtgaatcctggctgagggcaggccgttccttgc cgc agcataccaaaggatttgaagaccaaagggcagcctacgagtggaacgtctgccattgacccccatgggtgtgatgataccatcgccagggagaaaggagagtgtgctctgtgatagatagaaacatcaggatgagggccaagcggcctgcctc

gttggccacagggggtagctgagacccaagttcaagtctgc tcagacgtgggactccggcccaggaactaccgcgtggagcgcagtgcagcttccaggcgt ccagc act acccagcCccccaagcactccgaatgggcagcacccacatcaaatctgtggccctccctcatggggacacttgtcagcaatggaagactctcgccgcactcgcgcaaggccctccatccggagggctgagagagtgaagagacagactgaaaggcatcaaacacgggcaatccttccctag

gcgtgggaagacggctgggttgcgagaggcctactgctgggtaactgtgggagcaagtgggcgctactgccagccgccgcgcggatgaggcggctgcggcgaagagggccagcgtgacc tcgctctgctgccactgacttctccacgtgtcacattggcatacaactggattgggctttcgagttctcctgggaagcaggttgttctgcccagcagatgaaggctgcattgccgagggcccccgagggccctgctgtctccaggccatgaggcatctacagcctggctcc

cagctctggggtgtagaacgaagaactctgcatcatttactgctgggccaggcaagtggcactccaaataccccacgcaagcgagtacgatccgagtgctagggcctgacgggacacggaccgtcacctcgtgtggtgtcccttccttgcgagaaggagccacggctggaccccactgaccaagggattctggacctagtttctggtggtcccagaaatacccatcacacac cctgat aggcagttactccaggctctggaccattttgttcaatgggcgttctgttgac

ggagctcgga9ggccggggCcagcttcctgaggccggtgcggacgcaaaaatgggctcggcgggcttcatccccctggacgtgccgggtcggtgcctccCcctggcagccggtcaaaggcagagttccacccatcctggctgaggcctcttatgctcaagtgggcctctgcactgagcactcaggtcactgtcagcc tcgggtggtggtgtgaggaggagggaccccaggtctcaaggaccacgctgaccgcgggccgagtcaggagaatgggacacctqatgggagatt

gctcccgatc tggggctggg 120ccttctgggt 180cccgcgggtg 240ctgccctgct 300gtggacgcgg 360gtgagcccgg 420ggctcagtgc 480agcaccttcc 540ctgccctcac 600tcctgcacag 660acaacgtcca 720ttggtgccta 780ctgctccagg 840gtgaggggcc 900tgcctgagtg 960cccagtgggg 1020agcggcatct 1080gtggatgttc 1140gtggtggtgg 1200ctcatgtccc 1260ctgaccctga 1320agccagccgg 1380aacagtagct 1440acggtgaggg 1500gaggaggaag 1560gggaccctac 1620gtctgaccca 1680ttagctcatc 1740

82/105

00

00

ttgggggcctcttgaccttt*caccatgcattgtgtgtgtgctgtcatatcgggcaacactaaagcaggtaggtggagactggtgtgaggggtccctgggttgggcctgctaatactgctctgtatttttttcaggctggctgggact t taattaaagaaacctccaacaccatgcaggcagagcctcgtggaattgcttggcagtgattaagaatgtcgctctgggttggagccagaataggcctaaggggcctgaagataaaatgatat

ccttaaacacacctccaaccgcaggtcactgaggggtgacagagtcaagtgtcagggtttttttctcagagtggctcagaaacctgtctccagccagagggcatgtacatcgaatcacttatttatttttcttgaactccagtgtacaccgcctttagatcagggggttagccccttggggttactgagtgacctggtgatagaccgagactttccccctggctggagttcctagatttaagaggctcccctaagatccttctgttttta

ccccatttctcttctgttcagtgtgtgtgctgtccgtggagaactgtggtggcgtgtgtgccccagagcacccaggtgtgctaccacttccttgaactgtattttctgtattaattttttatttttattttgggctcaagactgtgcctgttatccaatgattcctgtgaagggcacctgaaggtaaaatcaagggctccgagtaggagtgggttttggacaatgaggttgtacccaaacatccttcgttaacatgtacaaataaacaga

t9cggaagattcgggagggcatgtgtgcctggggtgactggtatgtgccatcatgtggctgtattaatgacgggcatagcggagccatggta cagaagc caatatacatgtcttttttttttttttagagcaatcctcctctttgaatcctttactactgttgtgaaaggagagctggtatgcatccacctgttcaatagtgaggtgaggtcactaattctatttttagctcttcttagtccccagccagttttatgtaacaaaacttga

gctccccatctccaccaattgtgtgagtgttgtccgtggtcgggatttgagtgtgtgacctgcagaggtttggagctggagggcaagtgtctctgccctccgccgggagcttcttgccctatggagtctcgcctcagccttttacgaagaggattgcttaggctacttccgagtctgaaaattgtttgtgtggtgttgggtgaaggaggtaaggctcttctggc ccac ccctgaaatctgcctaggacttatatgtgcataaaa

ccactgactggagtctctcctgactgactggtgtattatggtggttgcgttctgcctgaaggaggagagaatctgcctccgaagcagccatggtggcctcttcttgcaggttccattagtactatgttgcccctagtagcgaaaaaaaaaaagtgaggccaaggcatcttttagggatgtataccttagggagagagagagctgggggtgtggatgtttcagatacactcctggatttctcgaatgtggaatttgtacat

180018601920198020402100216022202280234024002460252025802640270027602820288029403000306031203180324033003344

<210> 108<211> 295<212> PRT<213> Homo sapiens

<400> 108Met Asn Gly Gin Pro Leu Thr Cys Val Val

His

Ser His Pro Gly Leu Leu

Gin Asp Gin

Ala Ser Val

Giu Gly Ala

Arg

Arg

Thr His Ile Val Ser Phe

Gly Leu Glu Asn Leu Trp

Leu Ala Giu

Ile Gly Arg

Pro Pro SerMet Leu Lys

Tyr Asn

Cys

Asp

Ser Glu Giy

Trp Thr Arg Gly Pro Leu

Asp

Pro

Thr

Gly Val Arg

Gly Asp Thr Phe Pro Pro Leu

Phe

Thr Glu His Ser Gly

Ile Tyr Val

Val Thr Val115

Asp Leu Val

Cys100Asp

Val Ser Asn Giu105Gin

Ser Ser Arg Asp Ser Gin110Lys Gin ValVal Leu Asp Glu Asp Ser Gly

125IleSer Ala Ser

130Leu Phe

Val135Val

Val Val Gly Val Ala Ala Leu

Cys Leu beu Val Vai Val Ser Arg Tyr145Arg Arg Lys Ala Gin

165Asn

Met Thr Gin Lys170Leu

Giu Giu Giu Leu175

Leu Thr Arg

Pro Arg Ser195

Giu180Gin

Ser Ile Arg Arg185

His Ser His

Leu Arg Ala205

His Thr Asp190Giu Gly HisPro Giu Glu Ser

200Val Gly

83/ 105

00

Pro

Pro225Thr

Giu

Giu

Asn

Asp210Giu

Gin

Asp

Asn

Gly290

Ser

Gly

Thr

Gin

Gly275Arg

Leu

Arg

Glu

Asp260Thr

Gly

Lys

Ser

Leu245Giu

Leu

His

Ser Ser Cys Ser Val220

Thr Leu Thr Thr Val235

Pro Gly Ser Gly Arg250

Lys Gin Ala Met Asn265

Lys Pro Thr Gly Asn

280

Met

Arg

Al a

His

Gly285

Ser Giu Giu

Giu Ile Giu240

Giu Giu Glu255

Phe Val Gin270Ile Tyr Ile

<210> 109<211> 295<212> PRT<213> Homno sapiens

<400> 109Met Asn Gly1

Gin Asp Gin

Ala Ser Val

Glu Gly Ala

Tyr Asn Trp

Asp Gly Asp

Ilie Tyr Val

Val Thr Val115

Asp Leu Val130

Leu Phe Cys145Arg Arg Lys

Leu Thr Arg

Pro Arg Ser195

Pro Asp Ser210

Pro Giu Gly225Thr Gin Thr

Giu Asp Gin

Giu Asn Gly275

Asn Gly Arg290

Gin

Arg

Arg

Met

Thr

Thr

Cys100Asp

Ser

Leu

Ala

Giu180Gin

Leu

Arg

Glu

Asp260Thr

Gly

Pro5Ile

Gly

Leu

Arg

Leu

His

Val1

Al a

Leu

Gin165Asn

Pro

Lys

Ser

Leu245Glu

Leu Thr Cys Val Val Ser His Pro Gly Leu Leu10

Thr

Leu

Lys

Leu70Gly

Val

Leu

Ser

Val150Gin

Ser

Giu

Asp

Tyr230Leu

Gly

His

Giu

Cys55Asp

Phe

Ser

Asp

Val135Val.

Met

Ile

Giu

Asn215Ser

Ser

Ile

Ile

Asp40Leu

Gly

Pro

Asn

Pro120Val

Val

Thr

Arg

Ser200Ser

Thr

Pro

Lys

Leu25Gin

Ser

Pro

Pro

Giu105Gin

Val

Val

Gin

Arg185Val

Ser

Leu

Gly

Gin265Pro

His

Asn

Giu

Leu

Leu90Phe

Giu

Val

Val

Lys170Leu

Gly

Cys

Thr

Ser250Ala

Thr

Val

Leu

Gly

Pro

Thr

Ser

Asp

Gly

Leu

Tyr

His

Leu

Ser

Thr235Gly

Met

Gly

Ser

Trp

Gin

Ser

Thr

Ser

Ser

Val140Met

Gin

Ser

Arg

Val220Val

Arg

Asn

Asn

Phe

His

Pro

Gly

Giu

Arg

Gly125Ile

Ser

Giu

His

Al a205Met

Arg

Al a

His

Gly285

Leu

Ile

Pro

Vai

His

Asp110Lys

Al a

Arg

Giu

His190Giu

Ser

Glu

Giu

Phe270Ile

Ala

Gly

Pro

Arg

Ser

Ser

Gin

Ala

Tyr

Leu175Thr

Gly

Glu

Ile

Giu255Val

Tyr

Glu

Arg

Ser

Val1

Gly

Gin

Val

Leu

His160Thr

Asp

His

Giu

Giu240Giu

Gin

IleLeu Arg Ala Lys280

His Leu Val295

84/105

<210> 110<211> 295<212> PRT<213> Homo sapiens

<400> 110Met

Gin

Ala

Giu

Tyr

Asp

Ile

Val

Asp

Leu145Arg

Leu

Pro

Pro

Pro225Thr

Glu

Giu

Asn

Asn

Asp

Ser

Gly

Asn

Gly

Tyr

Thr

Leu130Phe

Arg

Thr

Arg

Asp210Giu

Gin

Asp

Asn

Gly290

Gdy

Gin

Val1

Ala

Trp

Asp

Val

Val1115Val

Cys

Lys

Arg

Ser195Ser

Gly

Thr

Gin

Gly275Arg

Gin

Arg

Arg

Met

Thr

Thr

Cys100Asp

Ser

Leu

Ala

Giu180Gin

Leu

Arg

Glu

Asp260Thr

Gly

Pro

Ile

Gly

Leu

Arg

Leu

His

Val1

Al a

Leu

Gin165Asn

Pro

Lys

Ser

Leu245Giu

Leu

His

Leu

Thr

ILeu

Lys

Leu70Gly

Val

Leu

Ser

Val150Gin

Ser

Giu

Asp

Tyr230Leu

Gly

Arg

Leu

Thr

His

Glu

Cys55Asp

Phe

Ser

Asp

Val135Val

Met

Ile

Glu

Asn215Ser

Ser

Ile

Ala

Val295

Cys

Ile

Asp40Leu

Gly

Pro

Asn

Pro120Val

Val

Thr

Arg

Ser200Ser

Thr

Pro

Lys

Lys280

Vali

Leu25Gin

Ser

Pro

Pro

Glu105Gin

Val

Vai

Gin

Arg185Val

Ser

Leu

Gly

Gin265Pro

Val

His

Asn

Giu

Leu

Leu90Phe

Giu

Val

Val1

Lys170Leu

Gly

Cys

Thr

Ser250Al a

Thr

Ser

Val1

Leu

Gly

Pro75Thr

Ser

Asp

Gly

Leu155Tyr

His

Leu

Ser

Thr235Gly

Met

Gly

H isr

Ser

Trp

Gin

Ser

Thr

Ser

Ser

Val140Met

Giu

Ser

Arg

Val220Val

Arg

Asn

Asn

Pro

Phe

His

Pro

Gly

Glu

Arg

Gly125Ile

Ser

Giu

His

Al a205Met

Arg

Ala

His

Gly285

Gly

Leu

Ile

Pro

Val

His

Asp110Lys

Ala

Arg

Glu

His190Giu

Ser

Giu

Giu

Phe270Ile

Leu

Ala

Gly

Pro

Arg

Ser

Ser

Gin

Ala

Tyr

Leu175Thr

Gly

Giu

Ile

Glu255Val1

Tyr

Leu

Giu

Arg

Ser

Val

Gly

Gin

Val

Leu

His160Thr

Asp

His

Giu

Glu240Giu

Gin

Ile

<210> Ill<21i> 3389<212> DNA<213> Homo sapiens

<400> I1*lggccgtcgtt gttggccaca gcgtgggaagacggcttctt gggggtagct acggctgggttcccctagtg gagacccaag tgcgagaggccagttcctta ttcaagtctg cagccggctcgctgggcagt ctgcctttca accatgccccaggcctggct gctgctgctg ctactgctggagctggagac ctcagacgtg gtaactgtggtctaccgagg ggactccggc gagcaagtgg

cagctctggg ggagctcgga gctcccgatc gtgtagaacg gggccggggc tggggctggg 120aagaactctg cagcttcctg ccttctgggt 180ccagggagat ctcggtggaa cttcagaaac 240tgtccctggg agccgagatg tgggggcctg 300catcatttac aggccggtgc cccgcgggtg 360tgctgggcca ggacgcaaaa ctgccctgct 420ggcaagtggc atgggctcgg gtggacgcgg 480

105

00

00

gcgaaggcgccttacgagggtcctgcgcaaccgccggcagtgaatcctggctgagggcaggccgttccttgccgcagcataccaaaggatt tgaagaccaaagggcagcctacgagtggaacgtctgccattgacccccatgggtgtgatgataccatcgccagggagaaaagagcCcgactgaaCtgCttcaaacaggcgcaatggcatcctaggcctgaacacccccacaacccttcttcactgtgtggtgactgtCCcaagtgaactggtttggCgttcagaccccatcagacccaggtctcctacagaggcttgatacatattttcacttttaattttttattttactcctgggcacaccactgttagatttatcggttaattccttgggagggctgagtaaggtggtgacaagEcgagagagtzcccctgggttgagttcaatca'zttagtacCtcc Cat cct

ccaggaactaccgcgtggagcgcagtgcagcttccaggcgtccagcactacccagccccccaagcactccgaatgggcagcacccacatcaaatctgtggccctccctcatggggacacttgtcagcaatggaagactctcgccgcactcgcgcaaggccctccatccgggggccgcagtgtctccaggccatgaaccatctacatcaatgctccttctgtttcttgcgggttcatcgggtgtgcatgtggtggaggggtgtggtgtatggtgtgtcatggagcagtattgtgtgcgggCacttcggagcactgttacagctgtaaatatttttttcttttatttttttttcaagcaatcgcctgctttc-caatgtttactgtgattgtcacctgagagcaaaattgcatIgctcctgttcLggagttgaqttggatcactaggtttattt

-caaactcttc

-tcgttccccz

gcgctactgccagccgccgcgcggatgaggcggctgcggcgaagagggc cagcgtgacctcgctctgctgccactgacttctccacgtgtcacattggcatacaactggattgggctttcgagt tct Octgggaagc aggttgttctgcccagcagatgaaggctgcatttactccacgctctgggcgggtttgttcagggggcggggacttgacatgggaagatgctccagggctccactgcctgtgtggactgtgtCCtgccacgggatggctgtgtgaatgatgcagatagctggagcatgggggcaaagcctctgacatgcgccgtttttttctttagagatggactcctgcctCaatcctttactactgggatt

jaaaggggctatggtagagtcccaccattgtaatagtggtcItgaggtgaac:aattcaaggc:ttagctggcttagtctgaE

i gccagcctacxtgtaaatatc

i cttgaaaaa

actccaaataccccacgcaagcgagtacgatccgagtgctagggcctgacgggacacggaccgtcacctcgtgtggtgtcccttccttgcgagaaggagccacggctggaccccactgaccaagggattctggacctagtttctggtggtcccagaaatacccatcacactgaccacggtccgaggaggaagaatgggacacctggtctgagattttagcccatcccactcaattgagtcagtgttgactgtggtgtgtatttgagtggttgacctctgcaggt tggaggctggaatctgagtgtgaagcccctctggtgggagcttcttgccctttccagtctcactatagcctccctagaagagaaaagcttaaagtg*cttccaaggctgaaattagg*ttgtgataCCIttggggagagIgaggtgctggtcttctggatcacccagatatatctgctgga;gacttcgaatItgcatatttS

cgggcttcatccccctggacgtgccgggtcggtgcctccccctggcagccggtcaaaggcagagttccacccatcctggctgaggcctcttatgctcaagtgggcctctgcactgagcactcaggtcactgtcagcctcgggtggtggtgtgaggaggagggaccccagggagggagataggaagatcagcctacgggccacccaggccttcatcttggggactgcttgatctcccaccagactgtgtgtttatgctgtctgcgtgggcaCt gaaaaagcagagaggtggcctccggtgtagccagtcccgcctctgggcgcaggaatacttagttgtatgttgctcagggtagctgggaaaaaaattaaaggcccctccatcttcatgcgatgtgagccttagggaattagagagcagtgggtgagaatgt tt ctCtggcactcagccat ttCtggcctgtggagcctgtacataaaat

gtgagcccgg 540ggctcagtgc 600agCaCCttCC 660ctgCCCtCaC 720tCCtgcaCag 780aCaacgtcca 840ttggtgccta 900CtgCtCCagg 960gtgaggggCC 1020tgcctgagtg 1080CCCagtgggg 1140agcggcatCt 1200gtggatgttc 1260gtggtggtgg 1320ctcatgtccc 1380Ctgaccctga 1440agCCagagtg 1500gaaacacaga 1560gatgaaggca 1620aagccacgg 1680gCCtcccttC 1740ggcctcctta 1800CctttaCctc 1860tgCatgCagg 1920gtgtggaggg 1980atatcagagt 2040aCactgtcag 2100aggtattttC 2160agaCtgtggC 2220gagggaacct 2280tgggtCagCC 2340ctgCtgCatg 2400tgctccgaat 2460tttttattta 2520ctggCCttga 2580Ctttaagtgt 2640agaaagCctt 2700aacaccaggg 2760aggcagCCCC 2820tCgtggttac 2880gcttggacct 2940gattatagac 3000gtCgCCtttC 3060gttggggctg 3120gaataCCtag 3180aagggagagg 3240aagatCtaag 3300gatattCtgt 3360

3389atCCtaaCat gtacattttttttaaataa acagacaaa~

<210> 112<211> 3464<212> DNA<213> Homo sapiens

<400> 112ggccgtcgttacggcttctttcccctagtgcagttcctta

gttggccaca gcgtgggaag cagctctggg ggagctcgga gctcccgatc gggggtagct acggctgggt gtgtagaacg gggCcggggC tggggctggg 120gagacccaag tgcgagaggc aagaactctg cagcttcctg ccttctgggt 180ttcaagtctg cagccggctc ccagggagat ctcggtggaa Cttcagaaac 240

86/105

00

00

gctgggcagtaggcctggctagctggagactctaccgagggcgaaggcgccttacgagggtcctgcgcaaccgccggcagtgaatcctggctgagggcaggccgttccttgccgcagcataccaaaggatttgaagaccaaagggcagcctacgagtggaacgtctgccattgacccccatgggtgtgatgataccatcgccagggagaaaggagagtgtgctctgtgatagatagaaacatcaggatgagggccaagccggcctgcctcttgggggcctcttgacctttcaccatgcattgtgtgtgtgctgtcatatcgggcaacactaaagcaggtaggtggagactggtgtgaggggtccctgggttgggcctgctaatactgctctgtatttttttcaggctggctgggactttaattaaagaaacctccaacaccatgcaggcagagcctcgtggaattgcttggcagtgattaagaatgtcgctctgggttggagccagaataggcctaaggggcctgaagataaaatgatat

ctgcctttcagctgctgctgctcagacgtgggactccggcccaggaactaccgcgtggagcgcagtgcagcttccaggcgtccagcactacccagccccccaagcactccgaatgggcagcacccacatcaaatctzgtggccctccctcatggggacacttgt cagcaatggaagactctcgccgcactcgcgcaaggccctccatccggagggctgagagagtgaagagacagactgaaaggcatcaaacacgggcaatccttccctagccttaaacacacctccaaccgcaggtcactgaggggtgacagagtcaagtgtcagggtttttttctcagagtggctcagaaacctgtctccagccagagggcatgtacatcgaatcacttatttatttttcttgaactccagtgtacaccgcctttagatcagggggttagccccttggggttactgagtgacctggtgatagaccgagactttccccctggctggagttcctagatttaagaggctcccctaagatccttctgttttta

accatgccccctactgctgggtaactgtgggagcaagtgggcgctactgccagccgccgcgcggatgaggcggctgcggcgaagagggccagcgtgacctcgctctgctgccactgacttctccacgtgtcacattggcatacaactggat tgggc ttt cgagttctcctgggaagcaggttgttctgcccagcagatgaaggctgcattgccgagggcccccgagggccctgctgtctccaggccatgaggcatctacagcctggctccccccatttctcttctgttcagtgtgtgtgctgtccgtggagaactgtggtggcgtgtgtgcc ccag agc acccaggtgtgctaccacttccttgaactgtattttctgtattaattttttatttttattttgggctcaagactgtgcctgttatccaatgattcctgtgaagggcacctgaaggtaaaatcaagggctccgagtaggagtgggttt tggacaatgaggttgtacccaaacatccttcgttaacatgtacaaataaacaga

tgtccctgggcatcatttactgctgggccaggcaagtggcactccaaataccccacgcaagcgagtacgatccgagtgctagggcctgacgggacacggaccgtcacctcgtgtggtgtcccttccttgcgagaaggagccacggctggaccccactgaccaagggattctggacctagtttctggtggtcccagaaatacccatcacacaccctgataggcagttactccaggctctggaccattttgttcaatgggcgttctgttgactgcggaagatt cgggagggcatgtgtgcctggggtgactggtatgtgccatcatgtggctgtattaatgacgggcatagcggagccatggtacagaagccaatatacatgtcttttttttt tt tt tagagcaatcctcctctttgaatcctttactactgttgtgaaaggagagctggtatgcatccacctgttcaatagtgaggtgaggtcactaattctatttttagctcttcttagtccccagccagttttatgtaacaaaacttga

agccgagatgaggccggtgcggacgcaaaaatgggctcggcgggcttcatccccctggacgtgccgggtcggtgcctccccctggcagccggtcaaaggcagagttccacccatcctggctgaggcctcttatgctcaagtgggcctctgcactgagcactcaggtcactgtcagcctcgggtggtggtgtgaggaggagggaccccaggtctcaaggaccacgctgaccgcgggccgagtcaggagaatgggacacctgatgggagattgctccccatctccaccaattgtgtgagtgttgtccgtggtcgggatttgagtgtgtgacctgcagaggt ttggagctggagggcaagtgtctctgccctccgccgggagcttcttgccctatggagtctcgcctcagccttttacgaagaggattgcttaggctacttccgagtctgaaaattgtttgtgtggtgttgggtgaaggaggtaaggctcttctggcccacccctgaaatctgcctaggacttatatgtgcataaaa

tgggggcctgcccgcgggtgctgccctgctgtggacgcgggtgagcccggggctcagtgcagcaccttccctgccctcactcctgcacagacaacgtccattggtgcctactgctccagggtgaggggcctgcctgagtgcccagtggggagcggcatctgtggatgttcgtggtggtggctcatgtcccctgaccctgaagccagccggaacagtagctacggtgaggggaggaggaaggggaccctacgtctgacccat tagctcatcccactgactggagtctctcctgactgactggtgtattatggtggttgcgttctgcctgaaggaggagagaatctgcctccgaagcagccatggtggcctcttcttgcaggttccattagtactatgttgcccctagtagcgaaaaaaaaaaagtgaggccaaggcatcttttagggatgtataccttagggagagagagagctgggggtgtggatgtttcaga ta cactcctggatttctcgaatgtggaatttgtacat

300360420480540600660720780840900960102010801140120012601320138014401500156016201680174018001860192019802040210021602220228023402400246025202580264027002760282028802940300030603120318032403300336034203464

<210> 113<211> 3389<212> DNA<213> Homo sapiens

87/1

00

00

<400> 113ggccgtcgttacggcttctttcccctagtgcagttccttagctgggcagtaggcctggctagctggagactctaccgagggcgaaggcgccttacgagggtcctgcgcaaccgccggcagtgaatcctggctgagggcaggccgttccttgccgcagcataccaaaggatttgaagaccaaag~ggcagcctacgagtggaacgtctgccattgacccccatgggtgtgatgataccatcgccagggagaaaagagcccgactgaactgcttcaaacaggcgcaatggcatcctaggcctgaacacccccacaacccttcttcactgtgtggtgactgtcccaagtgaactggtttggcgttcagaccccatcagacccasgtctcctaccagaggcttgatacatattttcacttttaattttttattttactcctgggcacaccactgttagatttatcggttaattccttgggagggctgagtaaggtggtgacaagcgagagagtzcccctgggttgagttcaatcatttagtac(ctcccatcclatcctaacalttttaaatai

<210> 114

gggggtagctgagacccaagttcaagtctgctgcctttcagctgctgctgctcagacgtgggactccggcccaggaactaccgcgtggagcgcagtgcagcttccaggcgtccagcactacccagccccccaagcactccgaatgggcagcacccacatcaaatctgtggccctccctcatggggacacttgtcagcaatggaagactctcgccgcactcgcgcaaggccctccatccgggggccgcagtgtctccaggccatgaaccatctacatcaatgctccttctgtttcttgcgggttcatcgggtgtgcatgtggtggaggggtgtggtgtatqgtgtgtcatg*gagcagtattIgtgtgcgggCacttcggagcactgttaeag

*ctgtaaatatttttttcttttatttttttttcaagcaatcgcctgctttccaatgtttactgtgattgtcacctgagagcaaaattgcat

Igctcctgttciggagttgag:ttggatcactI aggtttattt

caaactctt(tcgttccccz

-gtacatttti

a acagacaaa

acggctgggttgcgagaggccagccggctcaccatgccccctactgctgggtaactgtgggagcaagtgggcgctactgccagccgccgcgcggatgaggcggctgcggcgaagagggccagcgtgacctcgctctgctgccactgacttctccacgtgtcacattggcatacaactggattgggctttcgagttctcctgggaagcaggttgttctgcccagcagatgaaggctgcatttactccacgctctgggCgggtttgttcagggggcggggact tgacatgggaagatgctccagggctccactgcctgtgtggactgtgtcctgccacgggatggctgtgt~gaatgatgcagatagctggagcatgggggcaaagccctctgacatgcgccgtttttttctttagagatggactcctgcctcaatcctttactactgggatt

faaaggggctatggtagagtcccaccattgtaatagtggtc

Itgaggtgaacaattcaaggcttagctggccttagtctgaa

i gccagcctaci tgtaaatatci cttgaaaaa

gtgtagaacgaagaactctgccagggagattgtccctgggcatcatttactgctgggccaggcaagtggcactccaaataccccacgcaagcgagtacgatccgagtgctagggcctgacgggacacggaccgtcacctcgtgtggtgtcccttccttgcgagaaggagccacggctggaccccactgaccaagggattctggacctagtttctggtggtcccagaaatacccatcacactgaccacggtccgaggaggaagaatgggacacctggtctgagattttagcccatcccactcaattgagtcagtgttgactgtggtgtgtatttgagtggttgacctctgcaggt tggaggctggaatctgagtgtgaagcccctctggtgggagcttcttgccctttccagtctcactatagcctccctagaagagaaaagcttaaagtqLcttccaaggctgaaattagSttgtgatacc

fttggggagacfgaggtgctgstcttctggatcacccagatz

LatctgctggzIgacttcgaatItgcatatttc

gttggccaca gcgtgggaag cagctctggg ggagctcggagggCCggggCcagcttcctgctcggtggaaagccgagatgaggccggtgcggacgcaaaaatgggctcggcgggcttcatccccctggacgtgccgggtcggtgcctccccctggcagccggtcaaaggcagagttccacccatcctggctgaggcctcttatgctcaagtgggcctctgcactgagcactcaggtcactgt cagc ctcgggtggtggtgtgaggaggagggaccc cagggagggagataggaagatcagcctacgggccacccaggccttcatcttggggactgcttgatctcccaccagactgtgtgtttatgctgtctgcgtgggcabtgaaaaagcagagaggtggcctccggtgtagccagtcccgcctctgggCgcaggaatacttagttgtatgttgctcagg

*gtagctggga*aaaaaattaafaggcccctccatcttcatgc

Igatgtgagcc*ttagggaattagagagcagt

Igggtgagaat*gttttCtgicactcagcczLtttctggcctgtggagcctctacataaaat

gctcccgatc tggggctggg 120ccttctgggt 180cttcagaaac 240tgggggcctg 300cccgcgggtg 360ctgccctgct 420gtggacgcgg 480gtgagcccgg 540ggctcagtgc 600agcaccttcc 660ctgccctcac 720tcctgcacag 780acaacgtcca 840ttggtgccta 900ctgctccagg 960gtgaggggcc 1020tgcctgagtg 1080cccagtgggg 1140agcggcatct 1200gtggatgttc 1260gtggtggtgg 1320ctcatgtccc 1380ctgaccctga 1440agccagagtg 1500gaaacacaga 1560gatgaaggca 1620aagcccacgg 1680gcctcccttc 1740ggcctcctta 1800cctttacctc 1860tgcatgcagg 1920gtgtggaggg 1980atatcagagt 2040acactgtcag 2100aggtattttc 2160agactgtggc 2220gagggaacct 2280tgggtcagcc 2340ctgctgcatg 2400tgctccgaat 2460tttttattta 25201ctggccttga 2580ctttaagtgt 2640agaaagcctt 2700aacaccaggg 2760aggcagcccc 2820tcgtggttac 2880gcttggacct 2940gattatagac 300Dgtcgcctttc 3060

1gttggggctg 3120igaatacctag 3180:aagggagagg 3240i aagatctaag 3300

gatattctgt 33603389

88/105

<211> 485<212> PRT

00 S <213> Homo sapiens

<400> 114

Met Pro Leu Ser Leu Gly Ala Glu Met Trp Gly Pro Glu Ala Trp Leu1 5 10

Leu Leu Leu Leu Leu Leu Ala Ser Phe Thr Gly Arg Cys Pro Ala Gly25

Glu Leu Glu Thr Ser Asp Val Val Thr Val Val Leu Gly Gin Asp Ala40

Lys Leu Pro Cys Phe Tyr Arg Gly Asp Ser Gly Glu Gin Val Gly Gin55

Val Ala Trp Ala Arg Val Asp Ala Gly Glu Gly Ala Gin Glu Leu Ala65 70 75 Leu Leu His Ser Lys Tyr Gly Leu His Val Ser Pro Ala Tyr Glu Gly

90 Arg Val Glu Gin Pro Pro Pro Pro Arg Asn Pro Leu Asp Gly Ser Val

OO 100 105 110S Leu Leu Arg Asn Ala Val Gin Ala Asp Glu Gly Glu Tyr Glu Cys ArgS115 120 125

Val Ser Thr Phe Pro Ala Gly Ser Phe Gin Ala Arg Leu Arg Leu Arg130 135 140

Val Leu Val Pro Pro Leu Pro Ser Leu Asn Pro Gly Pro Ala Leu Glu145 150 155 160Glu Gly Gin Gly Leu Thr Leu Ala Ala Ser Cys Thr Ala Glu Gly Ser

165 170 175Pro Ala Pro Ser Val Thr Trp Asp Thr Glu Val Lys Gly Thr Thr Ser

180 185 190Ser Arg Ser Phe Lys His Ser Arg Ser Ala Ala Val Thr Ser Glu Phe

195 200 205His Leu Val Pro Ser Arg Ser Met Asn Gly Gin Pro Leu Thr Cys Val

210 215 220Val Ser His Pro Gly Leu Leu Gin Asp Gin Arg Ile Thr His Ile Leu225 230 235 240His Val Ser Phe Leu Ala Glu Ala Ser Val Arg Gly Leu Glu Asp Gin

245 250 255Asn Leu Trp His Ile Gly Arg Glu Gly Ala Met Leu Lys Cys Leu Ser

260 265 270Glu Gly Gin Pro Pro Pro Ser Tyr Asn Trp Thr Arg Leu Asp Gly Pro

275 280 285Leu Pro Ser Gly Val Arg Val Asp Gly Asp Thr Leu Gly Phe Pro Pro

290 295 300Leu Thr Thr Glu His Ser Gly Ile Tyr Val Cys His Val Ser Asn Glu305 310 315 320Phe Ser Ser Arg Asp Ser Gin Val Thr Val Asp Val Leu Asp Pro Gin

325 330 335Glu Asp Ser Gly Lys Gin Val Asp Leu Val Ser Ala Ser Val Val Val

340 345 350Val Gly Val Ile Ala Ala Leu Leu Phe Cys Leu Leu Val Val Val Val

355 360 365Val Leu Met Ser Arg Tyr His Arg Arg Lys Ala Gin Gin Met Thr Gin

370 375 380Lys Tyr Glu Glu Glu Leu Thr Leu Thr Arg Glu Asn Ser Ile Arg Arg385 390 395 400Leu His Ser His His Thr Asp Pro Arg Ser Gin Ser Glu Glu Pro Glu

405 410 415Gly Arg Ser Tyr Ser Thr Leu Thr Thr Val Arg Glu Ile Glu Thr Gin

420 425 430Thr Glu Leu Leu Ser Pro Gly Ser Gly Arg Ala Glu Glu Glu Glu Asp

89/105

00

00

435 440 445Gin Asp Glu Gly Ile Lys Gin Ala Met Asn His Phe Val Gin Giu Asn

450 455 460

Gly Thr Leu Arg Ala Lys Pro Thr Gly Asn Gly Ile Tyr Ile Asn Gly

465 470 475 480

Arg Gly His Leu Val

<210> 115<211> 510<212> PRT<213> Homo sapiens

<400> 115Met Pro Leu Ser Leu Gly Ala Giu Met Trp Gly Pro Glu Ala Trp Leu

1 5 10

Leu

Glu

Lys

Val

Leu

Arg

Leu

Val

Val145Glu

Pro

Ser

His

Val225His

Asn

Glu

Leu

Leu305Phe

GIl

Leu I

Leu

Leu I

Ala

Leu

Val

Leu

Ser130Leu

Gly

Ala

Arg

Leu210Ser

Val

Leu

Gly

Pro290Thr

Ser

Asp

ieu

3iu

?ro

rrp

His

31u

Arg115Thr

Val

Gln

Pro

Ser195Val

His

Ser

Trp

Gin275Ser

Thr

Ser

Ser

Leu

Thr

ys

Ala

Ser

Gin100Asn.

Phe

Pro

Gly

Ser180Phe

Pro

Pro

Phe

His260Pro

Gly

Glu

Arg

Gly

Leu

Ser

Phe

Arg

Lys

Pro

Ala

Pro

Pro

Leu165Val

Lys

Ser

Gly

Leu245Ile

Prc

Val

His

Asl32!LyC

Leu

Asp

Tyr

Val70Tyr

Pro

Val

Ala

Leu150Thr

Thr

His

Arg

Leu230Ala

Gly

Pro

Arg

Ser310Ser

Gin

kia

Jal

Arg55

Asp

Gly

Pro

Gin

Gly135Pro

Leu

Trp

Ser

Ser215Leu

Glu

Arg

Ser

Val295Gly

Gin

Val

Ser

Val40Gly

Ala

Leu

Pro

Ala120Ser

Ser

Ala

Asp

Arg200Met

Gin

Ala

Glu

Tyr280Asp

Ile

Val

AsI

Phe25Thr

Asp

Gly

His

Arg105Asp

Phe

Leu

Ala

Thr185Ser

Asn

Asp

Ser

Gly265Asn

Gly

Tyr

Thr

Leu

Chr

lal

Ser

31u

Val90Psn

Glu

Gin

Asn

Ser170Glu

Ala

Gly

Gin

Val250Ala

Trp

Asp

Val

Val330Val

Gly

Val

Gly

Gly75Ser

Pro

Gly

Ala

Pro155Cys

Val

Ala

Gin

Arg235Arg

Met

Thr

Thr

Cys315Asp

Ser

Arg

Leu

Glu

Ala

Pro

Leu

Glu

Arg140Gly

Thr

Lys

Val

Pro220Ile

Gly

Leu

Arg

Leu300His

Val

Ala

Cys

Gly

Gin

Gin

Ala

Asp

Tyr125Leu

Pro

Ala

Gly

Thr205Leu

Thr

Leu

Lys

Leu285Gly

Val

Leu

Ser

?ro

3ml

Ja1

Glu

Tyr

Gly110Glu

Arg

Ala

Glu

Thr190Ser

Thr

His

Glu

Cys270Asp

Phe

Ser

Asp

Val

Ala

Asp

Gly

Leu

Glu

Ser

Cys

Leu

Leu

Gly175Thr

Glu

Cys

Ile

Asp255Leu

Gly

Pro

Asn

Pro335Val

3iy

Ala

Gin

Ala

Gly

Val

Arg

Arg

Glu160Ser

Ser

Phe

Val

Leu240Gin

Ser

Pro

Pro

Glu320Gin

Val

340 345 350

Val Gly Val Ile Ala Ala Leu Leu Phe Cys Leu Leu Val Val Val Val

90/105

355 360 365Val Leu Met Ser Arg Tyr His Arg Arg Lys Ala Gin Gin Met Thr Gin

00 30375 380Lys Tyr Giu Glu Glu Leu Thr Leu Thr Arg Giu Asn Ser Ile Arg Arg385 390 395 400Leu His Ser His His Thr Asp Pro Arg Ser Gin Pro Giu Glu Ser Vai

405 410 415Giy Leu Arg Aia Glu Gly His Pro Asp Ser Leu Lys Asp Asn Ser Ser

420 425 430Cys Ser Val Met Ser Glu Glu Pro Giu Giy Arg Ser Tyr Ser Thr Leu

C1435 440 445Thr Thr Val Arg Glu Ile Giu Thr Gin Thr Glu Leu Leu Ser Pro Gly

450 455 460Ser Gly Arg Ala Glu Glu Giu Giu Asp Gin Asp Giu Gly Ile Lys Gin465 470 475 480Aia Met Asn His Phe Val Gin Glu Asn Gly Thr Leu Arg Ala Lys Pro

c1485 490 495Thr Giy Asn Gly Ile Tyr Ile Asn Gly Arg Gly His Leu Val

00500 505 510

<210> 116

<211> 485<212> PRT<213> Homo sapiens

<400> 116Met Pro Leu Ser Leu Gly Ala Giu Met Trp, Gly Pro Giu Ala Trp, Leu1 5 10

Leu Leu Leu Leu Leu Leu Ala Ser Phe Thr Gly Arg Cys Pro Ala Gly25

Giu Leu Giu Thr Ser Asp Vai Val Thr Val Vai Leu Gly Gin Asp Ala40

Lys Leu Pro Cys Phe Tyr Arg Gly Asp Ser Gly Glu Gin Val Gly Gin55

Val Ala Trp Ala Arg Val Asp Ala Gly Glu Gly Ala Gin Giu Leu Ala70 75

Leu Leu His Ser Lys Tyr Gly Leu His Val Ser Pro Ala Tyr Glu Gly90

Arg Val Giu Gin Pro Pro Pro Pro Arg Asn Pro Leu Asp Gly Ser Val100 105 110

Leu Leu Arg Asn Ala Val Gin Ala Asp Glu Gly Glu Tyr Giu Cys Arg115 120 125

Val Ser Thr Phe Pro Ala Gly Ser Phe Gin Ala Arg Leu Arg Leu Arg130 135 140

Val Leu Val Pro Pro Leu Pro Ser Leu Asn Pro Gly Pro Ala Leu Giu145 150 155 160Giu Gly Gin Gly Leu Thr Leu Ala Ala Ser Cys T)lr Ala Giu Gly Ser

165 170 175Pro Ala Pro Ser Val Thr Trp Asp Thr Giu Val Lys Gly Thr Thr Ser

180 185 190Ser Arg Ser Phe Lys His Ser Arg Ser Ala Ala Val Thr Ser Glu Phe

195 200 205His Leu Val Pro Ser Arg Ser Met Asn Gly Gin Pro Leu Thr Cys Val

210 215 220Val Ser His Pro Gly Leu Leu Gin Asp Gin Arg Ile Thr His Ile Leu225 230 235 240His Val Ser Phe Leu Ala Glu Ala Ser Val Arg Gly Leu Glu Asp Gin

245 250 255Asn Leu Trp His Ile Gly Arg Glu Gly Ala Met Leu Lys Cys Leu Ser

91/105

260 265Glu Gly Gin

275Leu Pro Ser

Pro Pro Pro Ser Tyr280Asp

Asn Trp Thr Arg Leu Asp Gly Pro

00

285GlyGly Val Arg

290Leu Thr

Val295Gly

Gly Asp Thr Leu300His

Phe Pro Pro

Thr Glu His Ser310Ser

Ile Tyr Val Cys Val Ser Asn Giu320315

AspSer Ser Arg Gin Val Thr Val Val Leu Asp Pro Gin335

Glu Asp Ser

Val Giy Val355

Val Leu Met

Gly340Ile

Gin Val Asp Leu Ser Ala Ser345PheAla Ala Leu Leu

360Arg

Cys Leu Leu

Val Val Val350Val Val Vai

Met Thr GinSer Arg Tyr370

Lys Tyr

His375Thr

Arg Lys Ala

Glu Giu Giu385Leu

Leu390Thr

Leu Thr Arg Ser Ile Arg Arg400

His Ser His H-is405Ser

Asp Pro Arg Ser410Val

Ser Giu Giu Pro Giu415

Gly Arg Ser

Thr Glu Leu435

Gin Asp Glu

Tyr420Leu

Thr Leu Thr Thr425Gly

Arg Giu Ile

Ser Pro Gly Ser440Al a

Arg Ala Giu Glu

Giu Thr Gin430Giu Glu Asp

Gin Giu AsnGly Ile Lys450

Giv Thr

Gin455Pro

Met Asn His Phe460IleLeu Arg Ala Thr Gly Asn

465Arg

Gly475

Tyr Ile Asn

Gly His Leu Val485

<210> 117<211> 3401<212> DNA<213> Homo sapiens

<400> 117ggccgtcgttacggcttctttcccctagtgcagttccttagctgggcagtaggcctggctagctggagactctaccgagggcgaaggcgccttacgagggtcctgcgcaaccgccggcagtgaatcctggctgagggcaggccgttccttgccgcagcataccaaaggatttgaagaccaaagggcagcctacgagtggaacgtctgccattgacccccatgggtgtgat

gttggccacagggggtagctgagaccczaagttcaagtctgctgcctttcagctgctgctgctcagacgtgggactccggcccaggaactaccgcgtggagcgcagtgcagcttccaggcgtccagcactacccagccccccaagcactccgaatgggcagcacccacatcaaatctgtggccctccctcatggggacacttgtcagcaatggaagactctcgccgcactc

gcgtgggaagacggctgggttgcgagaggccagccggctcaccatgccccctactgctgggtaactgtgggagcaagtgggcgctactgccagccgccgcgcggatgaggcggctgcggcgaagagggccagcgtgacctcgctctgctgccactgacttctccacgtgtcacattggcatacaactggattgggctttcgagtt ctC ctgggaagcaggttgttctgcc

cagctctggggtgtagaacgaagaactctgccagggagattgtccctgggcatcatttactgctgggccaggcaagtggcactccaaataccccacgcaagcgagtacgatCCgagtgctagggcctgacgggacacggaccgtcacctcgtgtggtgtcccttccttgcgagaaggagcCacggctggaCCCCactgaCcaagggattctggacctagtttctggtggt

ggagctcggagggccggggccagcttcctgctcggtggaaagccgagatgaggccggtgcggacgCaaaaatgggCtCggcgggcttcatccccctggaCgtgccgggtCggtgcctccccctggcagccggtcaaaggCagagttccacccatcctggctgaggcctcttatgctcaagtgggcctctgcactgagcactcaggtcactgtcagcctcgggtggtggtg

gctcccgatc tggggctggg 120ccttctgggt 180cttcagaaaC 240tgggggcctg 300cccgcgggtg 360ctgccctgct 420gtggacgcgg 480gtgagCCCgg 540ggctcagtgc 600agcacCttCC 660ctgccctCac 720tcctgCaCag 780acaacgtcca 840ttggtgCcta 900ctgctccagg 960gtgaggggCC 1020tgcctgagtg 1080cccagtgggg 1140agcggcatct 1200gtggatgttc 1260gtggtggtgg 1320ctcatgtCCC 1380

92/105

00

00

gataccatcgccagggagaaaggagagtgtgctctgtgatagatagaaacatcaggatgagggccaagccggCCtgcctcttgggggcctcttgacctttcaccatgcattgtgtgtgtgctgtcatatcgggcaacactaaagcaggtaggtggagactggtgtgaggggtccctgggttgggcctgetaatactgctctgtatttttttcaggctggctgggactttaattaaagaaa.cctccaacaccatgcaggcagagcctcgtggtgattatagatgtcgccttgggttggggccagaatacctctaagggagatgaagatctaatgatattct

gcgcaaggccctccatccggagggctgagagagtgaagagacagactgaa.aggcatcaaa.cacgggcaatccttccctagccttaaacacacetccaaccgcaggtcactgaggggtgacagagtcaagtgtcagggtttttttctcagagtggctcagaaacctgtctccagccagagggcatgtacatcgaatcacttatttatttttcttgaactccag tgt a ca ccgcctttagatcagggggtta.gccccttgggctggtgacaaaccgagagagtccccctgggtggagttcaaagatttagta9 ct ccc ate

agatcctaacgtttttaaat

cagcagatgaaggctgcattgccgagggcccccgagggccctgctgtctccaggccatgaggcatctaca.gcctggctccccccatttctcttctgttca.gtgtgtgtgctgtccgtggagaactgtggtggcgtgtgtgccccagageacccaggtgtgctaccacttccttgaactgtattttctgtattaattttttatttttattttgggctcaagactgtgcctgttatccaatgattcctgtgaagggcacctggggctcctgttaggagttgattttggatcatgaggtttatcccaaactctcttcgttcecatgtacatttaaacagacaa.

cccagaaata.cccatcacacaccctgataggcagttactccaggctctggaccattttgttcaatgggcgttctgttgactgcggaagattcgggagggcatgtgtgcctggggtgactggtatgtgccatcatgtggctgtattaatgacgggcatagcggagccatggtacagaagccaatatacatgtcttttttttttttttagagcaatcctcctctttgaatcctttactactgttgtgaaaggagagctggtatcaatagtggggtgaggtgaetaattcaagttttagctggtcttagtctgcagccagccttatgtaaataaaettgaaaa

tgaggaggagggaeeecaggtctcaaggaccacgctgaccgcgggccgagtcaggagaatgggacacctgatgggagattgctccccatctecaccaattgtgtgagtgttgtccgtggtcgggatttgagtgtgtgacctgcagaggtttggagctggagggcaagtgtctctgccctccgccgggagcttcttgccctatggagtctcgcctcagccttttacgaagaggattgcttaggctacttccgagtctgaaatgttggggagaggaggtgctgetet t ctggeccacccagaaaatctgctgaggacttcgatgtgcatatta

ctgaccctgaagccagccggaaeagtagctacggtgaggggaggaggaaggggaccctacgtctgacccattagctcatcccactgactggagtctctcctgactgactggtgtattatggtggttgcgttctgcctgaaggaggagagaatctgcctccgaagcagccatggtggcctcttcttgcaggttccattagtactatgttgcccctagtagcgaaaaaaaaaaagtgaggccaaggcatcttttagggatgtagagagagcagggggtgagaatgtttctcttacactcagcgatttctggcatgtggagcctgtacataaa

1440150015601620168017401800186019201980204021002160222022802340240024602520258026402700276028202880294030003060312031803240330033603401

<210> 118<211> 3464<212> DNA<213> Homo sapiens

<400> 118ggccgtcgttacggcttctttec c tag tgcagttccttagctgggcagtaggcctggctagctggagact ctae cgagggcgaaggcgccttacgagggtcctgcgcaaccgccggeagtgaatcctggctgagggcaggccgttccttgccgcagcatace aaagga tttgaagaccaaagggcagec

gttggccacagggggtagctgagacccaagttcaagtctgctgcctttcagctgctgctgctcagaegtgggactccggceeaggaac taccgcgtggagcgeagtgcagcttceaggcgtecagcactacccagcceeaageacteegaatgggcagcacceacateaaatctgtggccctccetca

gegtgggaagacggctgggttgcgagaggccagccggctcaccatgcccectactgctgggtaactgtgggageaagtgggcgctactgccagccgccgcgcggatgaggeggctgeggegaagagggccagcgtgaeetcgctetgctgceactgacttctccacgtgtcacattggeatacaactgga.

cagctctggggtgtagaacgaagaactctgccagggagattgteeetgggcatcatttactgctgggeeaggeaagtggeacteeaaata.ccceaegeaagegagtacgatccgagtgctagggcctgaegggaeacggaeegtcacctcgtgtggtgteccttccttgcgagaaggagccacggctgga

ggageteggaggecggggceagcttectgetcggtggaaageegagatgaggccggtgcggaegcaaaaatgggctcggcgggcttcatecce tgga egtgccgggtcg gtgectcccectggcagccggtcaaaggeagagttccacccatcetggctgaggcctettatgctcaagtgggcctctg

gctcccgatetgggge tgggccttctgggtcttcagaaactgggggcctgcccgcgggtgctgccctgctgtggacgcgggtgagceeggggetcagtgcag cace tteectgecetcactcctgcacagacaacgtccattggtgectactgctccagggtgaggggectgcctgagtgcccagtgggg

120180240300360420480540600660720780840900960102010801140

93/105

00

00

tacgagtggaacgtctgccattgacccccatgggtgt gatgataccatcgccagggagaaaggagagtgtgctctgtgatagatagaaacatcaggatgagggccaagcggcctgcctcttgggggcctcttgacctttcaccatgcattgtgtgtgtgctgtcatatcgggcaacactaaagcaggtaggtggagactggtgtgaggggtccctgggttgggcctgctaatactgctctgtatttttttcaggctggctgggactttaattaaagaaacctccaacaccatgcaggczgagcctcgtgaattgcttgcagtgattEagaatgtcg(tctgggt tg~agccagaatggcctaagggcctgaagalaaaatgatal

tggggacact ttgggctttc ctgtcagcaat gagttctcct cggaagactct gggaagcagg tcgccgcactc ttgttctgcctgcgcaaggcc cagcagatgactccatccgg aggctgcattagggctgaga gccgagggccgagtgaagag cccgagggccacagactgaa ctgctgtctcaggcatcaaa caggccatgacacgggcaat ggcatctacaccttccctag gcctggctccccttaaacac ccccatttctacctccaacc cttctgttcagcaggtcact gtgtgtgtgcgaggggtgac tgtccgtggaagagtcaagt gaactgtggtgtcagggttt ggcgtgtgtgttttctcaga ccccagagcagtggctcaga cccaggtgtgaacctgtctc ctaccacttccagccagagg cttgaactgtgcatgtacat attttctgtacgaatcactt ttaatttttt

cttgaactcc tgggctcaagagtgtacacc actgtgcctggcctttagat ttatccaatgcagggggtta attcctgtgagccccttggg agggcacctggttactgagt aaggtaaaatgacctggtga caagggctcctagaccgaga gagtaggagtctttccccct gggttttgga

3 ggctggagtt caatgaggtti cctagattta gtacccaaac3 agaggctccc atccttcgttt ctaagatcct aacatgtacat tctgttttta aataaacaga

~cccactgac~aagggat tc:ggacctagt:tctggtggt:ccagaaata:ccatcacacaccctgatag3cagttactccaggctctggaccattttgttcaatgggcgttctgttgactgcggaagattcgggagggcatgtgtgcctggggtgactggtatgtgccatcatgtggctgtattaatgacgggcatagcggagccatggtacagaagccaatatacatgtcttttttttttttttagagcaatcctcctctttgaatcctttactactqttgtgaaagsagagctggtatgcatccacctgttcaatactgaggtgagtcactaattctatttttagctcttcttagtccccagccacttttatgtazcaaaacttgz

cactgagcactcaggtcactgtcagcctcgggtggtggtgtgaggaggagggaccccaggtctcaaggaccacgctgaccgcgggccgagtcaggagaatgggacacctgatgggagattgctccccatctccaccaattgtgtgagtgttgtccgtggtcgggatttgagtgtgtgacctgcagaggtttggagctggagggcaagtgtctctgccctccgccgggagcttcttgccctatggagtctcgcctcagccttttacgaagaggattgcttaggctacttcgagtctgaaaattgtttgtgItggtgttgggItgaaggaggtaaggctcttctggcccacccctgaaatctgIcctaggacttxatatgtgcatiaaaa

agcggcatct 1200gtggatgttc 1260gtggtggtgg 1320ctcatgtccc 1380ctgaccctga 1440agccagccgg 1500aacagtagct 1560acggtgaggg 1620gaggaggaag 1680gggaccctac 1740gtctgaccca 1800ttagctcatc 1860ccactgactg 1920gagtctctcc 1980tgactgactg 2040gtgtattatg 2100gtggttgcgt 2160tctgcctgaa 2220ggaggagaga 2280atctgcctcc 2340gaagcagcca 2400tggtggcctc 2460ttcttgcagg 2520ttccattagt 2580actatgttyc 2640ccctagtagc 2700gaaaaaaaaa 2760aagtgaggcc 2820aaggcatctt 2880ttagggatgt 2940ataccttagg 3000gagagagaga 3060gctgggggtg 3120tggatgtttc 3180agatacactc 3240ctggatttct 3300cgaatgtgga 3360atttgtacat 3420

3464

<210> 119<211> 3401<212> DNA<213> Homo sapiens

<400> 119ggccgtcgttacggcttctttcccctagtgcagttccttagctgggcagtaggcctggctagctggagactctaccgagggcgaaggcgccttacgagggtcctgcgcaaccgccggcagtgaatcctggctgagggcag

gttggccacagggggtagctgagacccaagttcaagtctgctgcctttcagctgctgctgctcagacgtgggactccggcccaggaactaccgcgtggagcgcagtgcagcttccaggcgtccagcactacccagcccc c

gcgtgggaagacggctgggttgcgagaggccagccggctcaccatgccccctactgctgggtaactgtgggagcaagtgggcgctactgccagccgccgcgcggatgaggcggctgcggcgaagagggccagcgtgacct

cagctctggggtgtagaacgaagaactctgccagggagattgt ccc tgggcatcatttactgctgggccaggcaagtggcactccaaataccccacgcaagcgagtacgatccgagtgctagggcctgacgggacacgga

ggagctcggagggccggggccagcttcctgctcggtggaaagccgagatgaggccggtgcggacgcaaaaatgggctcggcgggcttcatccccctggacgtgccgggtcggtgcctccccctggcagccggtcaaaggc

gctcccgatctggggctgggccttctgggtcttcagaaactgggggcctgcccgcgggtgctgccctgctgtggacgcgggtgagcccggggctcagtgcagcaccttccctgccctcactcctgcacagacaacgtcca

120180240300360420480540600660720780840

94/105

00

00

gccgttcctt.gccgcagcataccaaaggatttgaagaccaaagggcagcctacgagtggaacgtctgccattgacccccatgggtgtgatgataccatcgccagggagaaaggagagtgt.gctctgtgatagatagaaacatcaggatgaggg cc aagc cggcctgcctcttgggggcctcttgacctttcaccatgcat.tgtgtgtgtgctgtcatatcgggcaacactaaagcaggtaggtggagac tggtgtgaggggtccctgggttgggcctgctaatactgctctgtatttttttcaggctggctgggactttaattaaagaaacctccaacaccatgcaggcagagcctcgtggtgattatagatgtcgccttgggttggggccagaatacctctaagggagatgaagatctaatgatattct

caagcactccgaatgggcagcacccacatcaaatctgtggccctccctcatggggacacttgtcagcaatggaagactctcgccgcactcgcgcaaggccctccatccggagggc tgagagagtgaagagacagactgaaaggcatcaaacacgggcaatccttccctagccttaaacacacctccaaccgcaggtcactgaggggtgacagagtcaagtgtcagggtttttttctcagagtggctcagaaacctgtctccagccagagggcatgtacatcgaatcacttatttatttttcttgaactccagtgtacaccgcctttagatcagggggttagccccttgggctggtgacaaaccgagagagtccccctgggtggagttcaaagatttagtaggctcccatcagatcctaacgtttttaaat

cgCtctgctgccactgacttctccacgtgtcacattggcatacaactggattgggctttcgagttctcctgggaagcaggttgttctgcccagcagatgaaggctgcattgccgagggcccccgagggccctgctgtctccaggccatgaggcatctacagcctggctccccccatttctcttctgttcagtgtgtgtgctgtccgtggagaactgtggtggcgtgtgtgccccagagcacccaggtgtgctaccacttccttgaactgtattttctgtattaattttttatttttattttgggctcaagactgtgcctgttatccaatgattcctgtgaagggcacctggggctcctgttaggagttgattttggatcatgaggtttatcccaaactctcttcgttcccatgtacatttaaacagacaa

ccgtcacctcgtgtggtgtcccttccttgcgagaaggagccacggctggaccccactgaccaagggattctggacctagtttctggtggt.cccagaaatacccatcacacaccctgataggcagttactccaggctctggaccattttgttcaatgggcgttctgttgactgcggaagattcgggagggcatgtgtgcct.ggggtgactggtatgtgccatcatgtggctgtattaatgacgggcatagcggagccatggtacagaagccaatatacatgtctttttttt.ttttttagagcaatcctcctctttgaatcctttactactgttgtgaaaggagagctggtatcaatagtggggtgaggtgactaattcaagttttagctggtct tagt ctgcagccagccttatgtaaataaacttgaaaa

agagttccacccatcctggctgaggcctcttatgctcaagtgggcctctgcactgagcactcaggtcactgtcagcctcgggtggtggtgtgaggaggagggaccccaggtctcaaggaccacgctgaccgcgggccgagtcaggagaatgggacacctgatgggagatt.gctccccatctccaccaattgtgtgagtgttgtccgtggt,cgggat ttgagtgtgtgacctgcagaggtttggagctggagggcaagtgt,ctctgccctccgccgggagcttcttgccctatggagtctcgcctcagccttttacgaagaggattgcttaggc tact tccgagtctgaaatgttggggagaggaggtgc tgCtcttctggcccacccagaaaatctgctgaggacttcgatgtgcatatta

ttggtgcctactgctccagggtgaggggcctgcctgagtgcccagtggggagcggcatctgtggatgt tcgtggtggtggctcatgtcccctgaccctgaagccagccggaacagtagctacggtgaggggaggaggaaggggaccctacgtctgacccattagctcatcccactgactggagtctctcctgactgactggtgtattatggtggttgcgttctgcctgaaggaggagagaatctgcctccgaagcagccatggtggcCtcttcttgcaggttccattagtactatgttgcccctagtagcgaaaaaaaaaaagtgaggccaaggcatcttttagggatgtagagagagcagggggtgagaatgtttctcttacactcagcgatttctggcatgtggagcctgtacataaa

90096010201080114012001260132013801440150015601620168017401800186019201980204021002160222022802340240024602520258026402700276028202880294030003060312031803240330033603401

<210> 120<211> 510<212> PRT<213> H-omo sapiens

<400> 120Met Pro Leu Ser Leu Gly Ala Glu

1 5Leu Leu Leu Leu Leu Leu Ala Ser

Glu Leu Glu Thr Ser Asp Val Val

Lys Leu Pro Cys Phe Tyr Arg Gly55

Val Ala Trp Ala Arg Val Asp Ala70

Met Trp Gly Pro Glu Ala Trp Leu

Phe25Thr

Gly Arg Cys

Val Val Leu

Pro Ala Gly

Gin Asp Ala

Val Gly GinAsp Ser Gly Glu

AlaGly Glu Gly Gln Glu Leu

95/105

Leu Leu His Ser Lys Tyr Gly Leu His Val Ser Pro Ala Tyr Glu Gly90

00

00

Arg

Leu

Val

Val145Glu

Pro

Ser

His

Val225His

Asn

Glu

Leu

Leu305Phe

Glu

Val

Val

Lye385Lei

Gi]

CY

Th

Se~46!Al

Th

Val G

Leu A1

Ser T130Leu V

Gly G

Ala P

Arg S

Leu N210Ser I

Val

Leu

Gly

Pro290Thr

Ser

Asp

Gly

Leu370Tyr

1 His

Leu

Ser

f Thr

450r Gly5

a Met

r Gly

lu

rg15hr

'al

lIn

ro

er

Tal

{is

3er

rrp

Gin275Ser

Thr

Ser

Sex

Val355Met

G1

Se

Ar

Va43!Va.

Ar

As

As

Gin100Asn

Phe

Pro

Gly

Ser180Phe

Pro

Pro

Phe

His260Pro

Gly

Glu

Arc

G1334(I2A

Se

I Gl

SHit

g Al42

1 Me'51 Ar

g Al

n Hi

Pro I

Ala

Pro I

Pro I

Leu165Val

Lys

Ser

Gly

Leu245Ile

Pro

Val

i His

Asp325

r Lys

i Ala

c Arg

1 Glu

s His405

a Glu0t Ser

g Glu

a Glu

s Phe485

'ro

Ta1

kla

eu150rhr

rhr

His

Arg

Leu230Ala

Gly

Pro

Arg

Ser310Ser

Gir

Alz

Ty2

Let39(Th

Gb

G1

Ill

G1r47Va

Pro P

Giln P1

Gly E135Pro c

Leu I

Trp

Ser

Ser I215Leu

Glu

Arg

Ser

Val295Gly

Gin

Val

Leu

His375

i Thr

c Asp

His

Glu

Glu455

u Glu01 Gin

~ro

la.20

er

ier

kla

ksp

krg200Met

Gln

Ala

Glu

Tyr280Asp

Ile

Val

Asy

Let36(Arc

Let

Pr

Pr

Pr44Th:

Gi,

Gi

Arg I105Asp C

Phe C

Leu I

Ala

Thr185Ser

Asn

Asp

Ser

Gly.265Asn

Gly

Tyr

Thr

Leu345Phe

3 Arg

a Thr

Arg

Asp425Glu

0r Gin

u Asp

u Asn

Sn

flu

in

Isn

3erL70lu

k1a

Gly

3Gl

Va1250Ala

Trp

Asp

Val

Val330Val

ys

Lys

Arc

Sei41(Se

GI1

Th~

G1

G149'

Pro L

Gly G

Ala

Pro C155Cys I

Val I

Ala

Gin

Arg235Arg

Met

Thr

Thr

Cys315Asp

Ser

Leu

Ala

Glu395Gin

Leu

Arg

r Glu

n Asp475

y Thr0

ieu

flu

Lrg I

fly I

Thr I

.ys

7al

?ro220lie

31y

Leu

Arg

Leu300His

Val

Ala

Leu

Gln380Asn

Pro

Lys

Ser

Leu460Glu

Leu

~sp

Eyr

aeu

?ro

kla

3iy

rhr205Leu

Thr

Leu

Lys

Leu285Gly

Val

Leu

Sex

Val365Gir

Sex

Glt

Asl

Tyl44!Let

Gb

Ar

Gly S110Glu C

Arg I

Ala I

Glu

Thr190Ser

Thr

His

Glu

Cys270Asp

Phe

Ser

Asp

Val350Val

Met

lie

1 Glu

Asn430Ser

a Ser

Ile

g Ala

er

:ys

Jeu

.eu

fly175rhr

3lu

Cys

lie

Asp255Leu

Gly

Pro

Asn

Pro335Val

Val

Thr

Arg

Ser415Sex

Thi

Prc

Lye

Ly49!

Val

Arg

Arg

Glu160Ser

Ser

Phe

Val

Leu240Gin

Ser

Pro

Pro

Glu320Gin

Val

Val

Gin

Arg400Val

Ser

Leu

Gly

s Gin480

s Pro

n Gly500

Ile Tyr Ile Asn Gly Arg Gly His Leu Vai505 510

<210> 121<211> 510<212> PRT<213> Homo sapiens

96/105

00

00

<400> 121Met Pro Leu Ser Leu Gly Ala Giu Met Trp Gly Pro Glu Ala Trp Leu

1Leu I

Glu I

Lys I

Val 2

Leu

Arg

Leu

Val

Val145Glu

Pro

Ser

His

Va1225His

Asn

Glu

Leu

Leu305Phe

Glu

Val

Val

Lys385Leu

Gly

Cys

Thr

~eu

eu

ieu

%la

Leu

ial

Leu

Ser130Leu

ly

Ala

Arg

Leu210Ser

Va1

Leu

Gly

Pro290Thr

Sex

Asp

Gl

Leu370Tyi

Hi

Let

Se

Th

Leu

Glu

Pro

Trp

His

Glu

Arg115Thr

Val

Gin

Pro

Ser195Va1

His

Ser

Trp

Gin275Ser

Thr

Ser

Ser

Val355Met

Glu

Ser

i Arg

Val435

r Val

Leu

Thr

Cys

Ala

Ser

Gin100Asn

Phe

Pro

Gly

Ser180Phe

Pro

Pro

Phe

His260Pro

Gly

Glu

Arg

Gly340Ile

Sex

Glu

His

Al42(Met

Arc

5Leu

Ser

Phe

Arg

Lys

Pro

Ala

Pro

Pro

Leu165Val

Lys

Ser

Gly

Leu245Ile

Pro

Val

His

Asp325Lys

Ala

Arg

Glu

His405

I Glu

Ser

Glu

Leu

sp

yr

Val70

Tyr

Pro

Val

Ala

Leu150Thr

Thr

His

Arg

Leu230Ala

Gly

Pro

Arg

Ser310Ser

Gin

Ala

Tyr

Leu390Thr

Gl

Glt

Ile

Ala

Val

Arg55Asp 2

Gly i

Pro

Gin

Gly135Pro

Leu

Trp

Ser

Ser215Leu

Glu

Arg

Ser

Vai295Gly

Gin

Val

Leu

His375Thr

Asp

His

Glu

Glu455

3er 1

Jai40

.ly

.la

Leu I

Pro 2

4la l120Ser

Ser

Ala

Asp

Arg200Met

Gin

Ala

Glu

Tyr280Asp

Ile

Val

Asp

Leu360Arg

Leu

Pro

Pro

Pro440Thr

?he55

rhr

ksp

31y

iIis

krg105Asp

Phe

Leu

Ala

Thr185Ser

Asn

Asp

Ser

Gly265Asn

Gly

Tyr

Thr

Leu345Phe

Arg

Thr

Arg

Asp425Glu

Gin

10Thr

Val

Ser

Glu

Val90Asn

Glu

Gin

Asn

Ser170Glu

Ala

Gly

Gin

Val250Ala

Trp

Asp

Val

Val330Val

Cys

Lys

Arg

Ser410Sex

Gly

Thr

Gly

Val I

Gly

Gly 2

Ser

Pro I

Gly

Ala 2

Pro155Cys

Val

Ala

Gin

Arg235Arg

Met

Thr

Thr

Cys315Asp

Ser

Leu

Ala

Glu395Gln

Leu

Arg

Glu

~rg

jeu

iu

kla

?ro

4eu

31u

Drg140Gly

rhr

Lys

Val

Pro220Ile

Gly

Leu

Arg

Leu300His

Val

Ala

Leu

Gin380Asn

Pro

Lys

Sex

Leu460

Cys

Gly

Gin

Gin

Ala

Asp

Tyr125Leu

Pro

Ala

Gly

Thr205Leu

Thr

Leu

Lys

Leu285Gly

Val

Leu

Ser

Val365Gin

Ser

Glu

Asp

Tyr445Leu

Pro

3Gl

Val

31u

Tyr

Gly110Glu

Arg

Ala

Glu

Thr190Ser

Thr

His

Glu

Cys270Asp

Phe

Ser

Asp

Val350Val

Met

Ile

Glu

Asn430Ser

Ser

Ala

Asp 2

Gly

Leu

Glu

Ser

Cys

Leu

Leu

Gly175Thr

Glu

Cys

Ile

Asp255Leu

Gly

Pro

Asn

Pro335Val

Val

Thr

Arg

Ser415Ser

Thr

Pro

3ly

Ala

Gln

Ala

3ly

Val

Arg

Arg

Glu160Ser

Ser

Phe

Val

Leu240Gin

Ser

Pro

Pro

Glu320Gin

Val

Val

Gin

Arg400Val

Ser

Leu

Gly0

97/105

Ser Gly Arg Ala Giu Giu Glu Giu Asp Gin Asp Glu Gly Ile Lys Gin

465 470 475 480

00 Ala Met Asn His Phe Val Gin Giu Asn Gly Thr Leu Arg Ala Lys Pro

485 490 495

S Thr Gly Asn Gly Ile Tyr Ile Asn Giy Arg Gly His Leu Val

C1500 505 510

S <210> 122<211> 510<212> PRT

<213> Homo sapiens

<400> 122

Met Pro Leu Ser Leu Gly Ala Glu Met Trp Gly Pro Giu Ala Trp Leu

1 5 10

Leu Leu Leu Leu Leu Leu Ala Ser Phe Thr Gly Arg Cys Pro Ala Gly

25

Giu Leu Giu Thr Ser Asp Val Val Thr Val Val Leu Gly Gin Asp Ala

00 35 40

Lys Leu Pro Cys Phe Tyr Arg Giy Asp Ser Gly Giu Gin Val Gly Gin

55

Val Ala Trp Ala Arg Val Asp Ala Gly Giu Gly Ala Gin Giu Leu Ala

70 75

Leu Leu His Ser Lys Tyr Gly Leu His Val Ser Pro Ala Tyr Glu Gly

90

Arg Val Giu Gin Pro Pro Pro Pro Arg Asn Pro Leu Asp Giy Ser Val

100 105 110

Leu Leu Arg Asn Ala Val Gin Ala Asp Giu Gly Giu Tyr Giu Cys Arg

115 120 125

Vai Ser Thr Phe Pro Ala cGiy Ser Phe Gin Ala Ary Leu Arg Leu Arg

130 135 140

Val Leu Val Pro Pro Leu Pro Ser Leu Asn Pro Gly Pro Ala Leu Giu

145 150 155 160

Giu Gly Gin Gly Leu Thr Leu Ala Ala Ser Cys Thr Ala Giu Giy Ser

165 170 175

Pro Ala Pro Ser Val Thr Trp Asp Thr Giu Val Lys Giy Thr Thr Ser

180 185 190

Ser Arg Ser Phe Lys His Ser Arg Ser Ala Ala Val Thr Ser Giu Phe

195 200 205

His Leu Vai Pro Ser Arg Ser Met Asn Gly Gin Pro Leu Thr Cys Vai

210 215 220

Val Ser His Pro Giy Leu Leu Gin Asp Gin Arg Ile Thr His Ile Leu

225 230 235 240

His Val Ser Phe Leu Ala Giu Ala Ser Val Arg Gly Leu Giu Asp Gin

245 250 255

Asfl Leu Trp His Ile Gly Arg Giu Gly Ala Met Leu Lys Cys Leu Ser

260 265 270

Giu Gly Gin Pro Pro Pro Ser Tyr Asn Trp Thr Arg Leu Asp Gly Pro

275 280 285

Leu Pro Ser Gly Val Arg Val Asp Gly Asp Thr Leu Gly Phe Pro Pro

290 295 300

Leu Thr Thr Giu His Ser Gly Ile Tyr Val Cys His Val Ser Asn Giu

305 310 315 320

Phe Ser Ser Arg Asp Ser Gin Val Thr Val Asp Val Leu Asp Pro Gin

325 330 335

Giu Asp Ser Gly Lys Gin Val Asp Leu Val Ser Ala Ser Val Vai Val

340 345 350

Val Gly Val Ile Ala Ala Leu Leu Phe Cys Leu Leu Val Val Val Val

355 360 365

98/105

Val Leu Met Ser Arg Tyr

00

00

370Tyr

His375Thr

Val eu Mt Se ArgTyr Arg Arg Lys Ala Gin Gin Met Thr Gin

Glu Glu Giu Leu390Thr

Leu Thr Arg Glu395Gin

Ser Ile Arg

His Ser His His405Giu

Asp Pro Arg Ser410Ser

Pro Giu Giu Ser

Gly Leu Arg

Cys Ser Val435

Thr Thr Val

Gly His Pro Asp425Glu

Leu Lys Asp

Ser Giu Glu Pro440Thr

Gly Arg Ser

415Asn Ser Ser430Ser Thr Leu

Ser Pro Giy

Tyr445LeuArg Glu Ile Gin Thr Giu

450Ser Gly Arg Ala Giu Glu Asp Gin

Met Asn His Phe485TIP

Gin Giu Asn Gly490Arg

Asp Giu Gly Ile Lys475Thr Leu Arg Ala Lys

495Gly His Leu Val

510Thr Gly Asn

<210> 123<2ii> 1669<212> DNA

GlyS00

Tyr Ile Asn GlySOS

<213> Homo sapiens

<400> 123gtctgacccattagctcatcccactgactggagtctctcctgactgactggtgtattatggtggttgcgttctgcctgaaggaggagagaatctgcctccgaagcagccatggtggcctcttcttgcaggttccattagtactatgttgcccctagtagcgaaaaaaaaaaagtgaggccaaggcatcttttagggatgtataccttagggagagagagagctgggggtgtggatgtttcagatacactcctggatttctcgaatgtggaatttgtacat

ggcctgcctct tgggggcctcttgacctttcaccatgcattgtgtgtgtgctgtcatatcgggcaacactaaagcaggta.ggtggagactggtgtgaggggtCcctgggttgggcctgctaatactgctctgtatttttttcaggctggctgggacttta.attaaagaaacctccaacaccatgcaggcagagcctcgtggaattgcttggcagtgattaagaatgtcgctctgggttggagccagaata.ggcctaaggggcctgaagataaaatgatat

ccttccctagccttaaacacacctccaaccgcaggtcactgaggggtgacagagtcaagtgtcagggtttttttctcagagtggct cagaaacctgtctccagccagagggcatgtacatcgaatcacttatttatttttcttgaactccagtgtacaccgcctttagatcagggggtta.gccccttggggttactgagtgacctggtgatagaccgaga.ctttccccctggctggagt tcctagatttaagaggctcccctaagatccttctgttttta

gcctggctccccccatttctcttctgttcagtgtgtgtgctgtccgtggagaactgtggtggcgtgtgtgccccagagcacccaggtgtgctaccacttccttgaactgtattttctgta.ttaattttttatttttattttgggctcaagactgtgcctgttatccaatgattcctgtgaagggcacctgaaggtaaaatcaagggctccgagtaggagtgggttttggacaatgaggttgtacccaaacatccttcgttaacatgtacaaataaacaga

ttctgttgactgcggaagatt cgggagggcatgtgtgcctggggtgactggtatgtgccatcatgtggc tgtattaatgacgggcatagcggagccatggtacagaagccaatatacatgtcttttttttttttttagagcaatcctcctctttgaatcctttactactgttgtgaaaggagagctggtatgcatccacctgttcaatagtgaggtgaggtcactaattctatttttagctcttcttagtccccagccagttttatgtaa.caaaacttg

atgggagattgctccccatctccaccaattgtgtgagtgttgtccgtggtcgggatttgagtgtgtgacctgcagaggtttggagctggagggcaagtgtctctgccctccgccgggagcttcttgccctatgg agt ct cgcct cagc cttttacgaagaggattgcttaggctacttcegagtctgaaaattgtttgtgtggtgttgggtgaaggaggtaaggctcttctggcccacccctgaaatctgcctaggacttatatgtgcat

120180240300360420480540600660720780

900960102010801140120012601320138014401500156016201669

<210> 124<211> 1669<212> DNA<213> Homo sapiens

99/105

<400> 124gtctgaccca ggcctgcctc ccttccctag gcctggctcc ttctgttgac

00

00

ttagctcatcccactgactggagtct ctcctgactgactggtgtattatggtggttgcgttctgcctgaaggaggagagaatctgcctccgaagcagccatggtggcctcttcttgcaggttccattagtactatgttgcccctagtagcgaaaaaaaaaaagtgaggccaaggcatcttttagggatgtataccttagggagagagagagctgggggtgtggatgtttcagatacactcctggatttctcgaatgtggaatttgtacat

ttgggggcctcttgacctttcaccatgcattgtgtgtgtgctgtcatatcgggcaacactaaagcaggtaggtggagactggtgtgaggggtccctgggttgggcctgctaatactgctctgtatttttttcaggctggctgggactttaat taaagaaacctccaacaccatgcaggcagagcctcgtggaattgcttggcagtgattaagaatgtcgctctgggttggagccagaataggcctaaggggcctgaagataaaatgatat

ccttaaacacacctccaaccgcaggtcactgaggggtgacagagtcaagtgtcagggtttttttctcagagtggctcagaaacctgtctccagccagagggcatgtacatcgaatcacttatttatttttcttgaactccagtgtacaccgcctttagatcagggggttagccccttggggttactgagtgacctggtgatagaccgagactttccccctggctggagttcctagatttaagaggctcccc taag atcc ttctgttttta

ccccatttctcttctgttcagtgtgtgtgctgtccgtggagaactgtggtggcgtgtgtgccccagagcacccaggtgtgctaccacttccttgaactgtattttctgtattaattttttatttttattttgggctcaagactgtgcctgttatccaatgattcctgtgaagggcacctgaaggtaaaatcaagggctccgagtaggagtgggttttggacaatgaggttgtacccaaacatccttcgttaacatgtacaaataaacaga

tgcggaagattcgggagggcatgtgtgcctggggtgactggtatgtgcca.tcatgtggctgtattaatgacgggcatagcggagccatggtacagaagccaatatacatgtcttttttttttttttagagcaatcctcctctttgaatcctttactactgttgtgaaaggagagctggtatgcatccacctgttcaatagtgaggtgaggtcactaattct att ttt agctcttcttagtccc cagccagttttatgtaacaaaacttg

atgggagatt gctccccatc 120tccaccaatt 180gtgtgagtgt 240tgtccgtggt 300cgggatttga 360gtgtgtgacc 420tgcagaggtt 480tggagctgga 540gggcaagtgt 600ctctgccctc 660cgccgggagc 720ttcttgccct 780atggagtctc 840gcctcagcct 900tttacgaaga 960ggattgctta 1020ggctacttcc 1080gagtctgaaa 1140attgtttgtg 1200tggtgttggg 1260tgaaggaggt 1320aaggctcttc 1380tggcccaccc 1440ctgaaatctg 1500cctaggactt 1560atatgtgcat 1620

1669

<210> 125<211> 1669<212> DNA<213> Homo sapiens

<400> 125gtctgacccat tagctcatcccac tgactggagtc tct cctgactgactggtgtattatggtggttgcgttctgcctgaaggaggagagaatctgcctccgaagc agccatggtggcctcttcttgcaggttccattagtactatgttgcccctagtagcgaaaaaaaaaaagtgaggccaaggcatcttttagggatgtataccttagggagagagagagctgggggtgtggatgtttc

ggcctgcctcttgggggcctcttgacctttcaccatgcattgtgtgtgtgctgtcatatcgggcaacactaaagcaggtaggtggagactggtgtgaggggtccctgggttgggcctgctaatactgctctgtatttttttcaggctggctgggactttaattaaagaaacctccaacaccatgcaggcagagcctcgtggaattgcttggcagtgattaagaatgtcgctctgggttgg

ccttccctagccttaaacacacctccaaccgcaggtcactgaggggtgacagagtcaagtgtcagggtttttttctcagagtggctcagaaacctgtctccagccagagggcatgtacatcgaatcacttatttatttttcttgaactccagtgtacacgcctttagatcagggggttagccccttggggttactgagtgacctggtgatagaccgagactttccccctggctggagtt

gcctggctccccccatttctcttctgttcagtgtgtgtgctgtccgtggagaactgtggtqgcgtgtgtgccccagagcacccaggtgtgctaccacttccttgaactgtattttctgtattaattttttatt t ttatt ttgggctcaagactgtgcctgttatccaatgattcctgtgaagggcacctgaaggtaaaatcaagggctccgagtaggagtgggttttggacaatgaggtt

ttctgttgactgcggaagattcgggagggcatgtgtgcctggggtgactggtatgtgccatcatgtggctgtattaatgacgggcatagcggagccatggtacagaagccaatatacatgtcttttttttttttttagagcaatcctcctctttgaatcctttactactgttgtgaaaggagagctggtatgcatccacctgttcaatagtgaggtgaggtcactaattctatttttagc

atgggagattgctccccatctccaccaattgtgtgagtgttgtccgtggtcgggatttgagtgtgtgacctgcagaggtttggagctggagggcaagtgtctctgccctccgccgggagcttcttgccctatggagtctcgcctcagccttttacgaagaggattgcttaggctacttccgagtctgaaaattgtttgtgtggtgttgggtgaaggaggtaaggctcttctggc ccac cc

12018024030036042048054060066072078084090096010201080114012001260132013801440

100/ 105

agatacactc agccagaata cctagattta gtacccaaac tcttcttagt ctgaaatctg 1500ctggatttct ggcctaaggg agaggctccc atccttcgtt ccccagccag cctaggactt 1560

00 cgaatgtgga gcctgaagat ctaagatcct aacatgtaca ttttatgtaa atatgtgcat 1620atttgtacat aaaatgatat tctgttttta aataaacaga caaaacttg 1669

<210> 126

S <211> 137<212> PRT<213> Homo sapiens

<400> 126Met Arg Arg Glu Leu Leu Ala Gly Ile Leu Leu Arg Ile Thr Phe Asn1 5 10

Phe Phe Leu Phe Phe Phe Leu Pro Phe Pro Leu Val Val Phe Phe Ile25

Tyr Phe Tyr Phe Tyr Phe Phe Leu Glu Met Giu Ser His Tyr Val AlaC135 40

Gin Ala Gly Leu Glu Leu Leu Gly Ser Ser Asn Pro Pro Ala Ser AlaC150 55 00 Ser Leu Val Ala Gly Thr Leu Ser Val His His Cys Ala Cys Phe Giu

70 75 Ser Phe Thr Lys Arg Lys Lys Lys Leu Lys Lys Ala Phe Arg Phe Ile

90 Gin Cys Leu Leu Leu Gly Leu Leu Lys Vai Arg Pro Leu Gin His Gin

100 105 110Gly Val Asn Ser Cys Asp Cys Giu Arg Gly Tyr Phe Gin Gly Ile Phe

115 120 125Met Gin Aia Ala Pro Trp Giu Giy Thr

130 135

<210> 127<211> 510<212> PRT<213> Homo sapiens

<400> 127Met Pro Leu Ser Leu Gly Ala Giu Met Trp Gly Pro Giu Ala Trp, Leu1 5 10

Leu Leu Leu Leu Leu Leu Ala Ser Phe Thr Gly Arg Cys Pro Ala Gly25

Giu Leu Giu Thr Ser Asp Val Val Thr Val Val Leu Gly Gin Asp Ala40

Lys Leu Pro Cys Phe Tyr Arg Gly Asp Ser Gly Giu Gin Val Gly Gin55

Val Ala Trp Ala Arg Vai Asp Ala Gly Glu Gly Ala Gin Glu Leu Ala70 75

Leu Leu His Ser Lys Tyr Giy Leu His Val Ser Pro Ala Tyr Glu Gly90

Arg Val Giu Gin Pro Pro Pro Pro Arg Asn Pro Leu Asp Gly Ser Val100 105 110

Leu Leu Arg Asn Ala Val Gin Ala Asp Giu Gly Giu Tyr Giu Cys Arg115 120 125

Val Ser Thr Phe Pro Ala Gly Ser Phe Gin Ala Arg Leu Arg Leu Arg130 135 140

Vai Leu Val Pro Pro Leu Pro Ser Leu Asn Pro Gly Pro Ala Leu Glu145 150 155 160Glu Giy Gln Gly Leu Thr Leu Ala Ala Ser Cys Thr Ala Giu Giy Ser

165 170 175Pro Aia Pro Ser Val Thr Trp, Asp Thr Giu Val Lys Gly Thr Thr Ser

101/105

180 185 190Ser Arg Ser Phe Lys His Ser Arg Ser Ala Ala Val Thr Ser Giu Phe

00

00

His

Val225His

Asn

Giu

Leu

Leu305Phe

Glu

Val

Val

Lys385Leu

Gly

Cys

Thr

Ser465Ala

Thr

Leu210Ser

Val

Leu

Gly

Pro290Thr

Ser

Asp

Gly

Leu370Tyr

His

Leu

Ser

Thr450Gly

Met

Gly

195VTal

His

Ser

Trp

Gin275Ser

Thr

Ser

Ser

Val355Met

Giu

Ser

Arg

Vai435Val

Arg

Asn

Asn

Pro Ser

Pro Gly

Phe Leu245

His Ile260Pro Pro

Gly Val

Glu His

Arg Asp325

Gly Lys340Ile Ala

Ser Arg

Giu Glu

His His405

Ala Giu420Met Ser

Arg Glu

Ala Glu

His Phe485

Arg

Leu230Al a

Gly

Pro

Arg

Ser310Ser

Gin

Ala

Tyr

Leu390Thr

Gly

Giu

Ile

Glu470Val

200Ser Met215Leu Gin

Giu Ala

Arg Giu

Ser Tyr280

Val Asp295Gly Ile

Gin Val

Val Asp

Leu Leu360

His Arg375Thr Leu

Asp Pro

His Pro

Giu Pro440

Giu Thr455Giu Giu

Gin Giu

Asn

Asp

Ser

Gly265Asn

Gly

Tyr

Thr

Leu345Phe

Arg

Thr

Arg

Asp425Giu

Gin

Asp

Asn

Gly505

Gly Gin

Gin Arg235

Val Arg250Ala Met

Trp Thr

Asp Thr

Vai Cys315

Val Asp330Val Ser

Cys Leu

Lys Ala

Arg Giu395

Ser Gin410Ser Leu

Gly Arg

Thr Giu

Gin Asp475

Gly Thr490Arg Gly

Pro220Ile

Giy

Leu

Arg

Leu300His

Vai

Ala

Leu

Gin380Asn

Pro

Lys

Ser

Leu460Glu

Leu

His

205Leu

Thr

Leu

Lys

Leu285Gly

Val

Leu

Ser

Val365Gin

Ser

Giu

Asp

Tyr445Leu

Giy

Arg

Leu

Thr

His

Giu

Cys270Asp

Phe

Ser

Asp

Val350Val

Met

Ile

Giu

As n430Ser

Ser

Ile

Ala

Val510

Cys

Ile

Asp255Leu

Gly

Pro

Asn

Pro335Val

Val

Thr

Arg

Ser415Ser

Thr

Pro

Lys

Lys495

Val

Leu240Gin

Ser

Pro

Pro

Giu320Gin

Val

Val1

Gin

Arg400Val

Ser

Leu

Gly

Gin480Pro

Ilie Tyr Ile Asn

<210> 128<211> 295<212> PRT<213> Homo sapiens

<400> 128Met Asn Gly Gin Pri

1 Gin Asp Gin Arg Ill

Ala Ser Vai Arg Gi,

Glu Gly Ala met Le,

Tyr Asn Trp Thr Ar.

Asp Gly Asp Thr Le

Leu

Thr

Leu

Lys

Leu70Gly

Thr

His

Giu

Cys55Asp

Phe

Ser

Val

Leu

Gly

Pro

Thr

His

Ser

Trp

Gin

Ser

Thr

Gly

Leu

Ile

Pro

Vai

His

102/105

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00

Ile

Val1

Asp

Leu145Arg

Leu

Pro

Pro

Pro225Thr

Glu

Giu

Asn

Val1

Val1

115Val1

Cys

Lys

Arg

Ser195Ser

Gly

Thr

Gin

Gly275Arg

Cys100Asp

Ser

Leu

Al a

Glu180Gin

Leu

Arg

Giu

Asp260Thr

Gly

His

Val

Al a

Leu

Gin165Asn

Pro

Lys

Ser

Leu245Glu

Leu

His

Val1

Leu

Ser

Val150Gin

Ser

Glu

Asp

Tyr230Leu

Gly

Arg

Leu

Ser

Asp

Val135Val

Met

Ile

Giu

Asn215Ser

Ser

Ile

Ala

Vai295

Giu

105Gin

Val

Val1

Gin

Arg185Val

Ser

Leu

Gly

Gin265Pro

90Phe

Giu

Val1

Val1

Lys170Leu

Gly

Cys

Thr

Ser250Al a

Thr

Ser

Asp

Gly

Leu155Tyr

His

Leu

Ser

Thr235Gly

Met

Gly

Her

Ser

Val140Met

Giu

Ser

Arg

Vai220Val

Arg

Asn

Asn

Arg

Gly125Ile

Ser

Giu

His

Ala205Met

Arg

Al a

His

Gly285

Ser

Gin

Al a

Tyr

Leu175Thr

Gly

Giu

Ile

Giu255Val

Tyr

Gin

Val1

Leu

His160Thr

Asp

His

Glu

Glu240Glu

Gin

Ile

<210> 129<2i1> 485<212> PRT<213> Homo sapiens

<400> 129Met Pro Leu Her Leu

1 5Leu Leu Leu Leu Leu

Giu Leu Giu Thr Ser

Lys Leu Pro Cys Phe

Val Ala Trp Ala Arg

Leu Leu His Her Lys

Arg Val Glu Gin Pro100

Leu Leu Arg Asn Ala115

Val Ser Thr Phe Pro130

Val Leu Val Pro Pro145Glu Gly Gin Gly Leu

165Pro Ala Pro Her Val

180Ser Arg Ser Phe Lys

Gly Ala Giu Met Trp Gly Pro Giu Ala Trp Leu10

Leu

Asp

Tyr

Vai

Tyr

Pro

Val

Al a

Leu150Thr

Thr

His

Ala

Val

Arg5

Asp

Gly

Pro

Gin

Gly135Pro

Leu

Trp

Ser

Phe25Thr

Asp

Gly

His

Arg105Asp

Phe

Leu

Ala

Thr185Ser

Thr

Val1

Ser

Glu

Val90Asn

Glu

Gin

Asn

Ser170Glu

Al a

Arg

Leu

GiuG0Ala

Pro

Leu

Glu

Arg140Gly

Thr

Lys

Val

Cys

Gly

Gin

Gin

Ala

Asp

Tyr125Leu

Pro

Ala

Gly

Thr

Pro

Gin

Val

Giu

Tyr

Gly110Giu

Arg

Ala

Giu

Thr190Ser

Ala

Asp

Gly

Leu

Glu

Her

Cys

Leu

Leu

Gly175Thr

Glu

103/1105

1

His Leu Val Pro Ser Arg Ser Met Asn Gly Gin Pro Leu Thr Cys Vai

00

00

Val225His

Asn

Glu

Leu

Leu305Phe

Glu

Va1

Val

Lys385Leu

Gly

Thr

Gin

Gly465Arg

10er

lal

Leu

31y

Pro290Thr

Ser

Asp

Gly

Leu370Tyr

His

Arg

Glu

Asp450Thr

His I

Ser I

Trp I

Gin275Ser

Thr

Ser

Ser

Val355Met

Glu

Ser

Ser

Leu435Glu

Leu

?ro

?he

lis

260Pro

3ly

Glu

Arg

Gly340Ile

Ser

Glu

His

Tyr420Leu

Gly

Arg

Gly

Leu245Ile

Pro

Val

His

Asp325Lye

Ala

Arg

Glu

His405Ser

Ser

Ile

Leu230Ala

Gly

Pro

Arg

Ser310Ser

Gin

Ala

Tyr

Leu390Thr

Thr

Prc

LyE

215Leu

Glu

Arg

Ser

Val295Gly

Gin

Va1

Leu

His375Thr

Asp

Leu

Gly

Gin455

G1n

Ala

lu

Tyr280Asp

Ile

Vai

Asp

Leu360Arg

Leu

Pro

Thr

Ser440Ala

Asp

Ser

Gly265Asn

Gly

Tyr

Thr

Leu345Phe

Arg

Thr

Arg

Thr425Gly

Met

Gin

Val250Ala

Trp

Asp

Val

Val330Val

ys

Lys

Arg

Ser410Val

Arg

Asn

Arg235Arg

Met

Thr

Thr

cys315Asp

Ser

Leu

Ala

Glu395Gin

Arg

Ala

His

220Ile

Gly

Leu

Arg

Leu300His

Val

Ala

Leu

Gin380Asn

Ser

Glu

Glu

Phe460

rhr

Leu

Lys

Leu285Giy

Val

Leu

Ser

Val365Gin

Ser

Glu

Ile

Glu445Val

His

Glu

Cys270Asp

Phe

Ser

Asp

Val350Val

Met

Ile

Glu

Glu430Glu

Gin

Ile

ksp255Leu

2 1y

Pro

Asn

Pro335Val

Vai

Thr

Arg

Pro415Thr

Glu

Glu

Leu240Gin

Ser

Pro

Pro

Glu320Gin

Val

Val

Gin

Arg400Glu

Gln

Asp

Asn

I Ala Lys Pro Thr Giy Asn Gly470 475

Val485

Ile Tyr Ile Asn Gly480

Gly His Leu

<210> 130<211> 137<212> PRT<213> Homo sapiens

<400> 130Met Arg Arg Glu Leu

1 5Phe Phe Leu Phe Phe

Tyr Ple Tyr Phe Tyr

Gin Ala Gly Leu lu

Ser Leu Val Ala Gly

Ser Phe Thr Lys Arg

Gin Cys Leu Leu Leu100

Gly Val Asn Ser Cys

Leu Ala

Phe Leu

Phe Phe

Leu Leu55

Thr Leu70Lys Lye

Gly Leu

Asp Cys

Gly Ile

Pro Phe25

Leu Glu40Gly Ser

Ser Val

Lys Leu

Leu Lys105

Glu Arg

Leu Leu10Pro Leu

Met Glu

Ser Asn

His His75

Lye Lys90Val Arg

Gly Tyr

Arg Ile

Val Val

Ser His

Pro Pro

Cys Ala

Ala Phe

Pro Leu

Phe Gin

Thr

Phe

Tyr

Ala

Cys

Arg

Gin110Gly

PheisPhe

Val

Ser

Phe

Phe

His

Ile

Asn

Ile

Ala

Ala

Glu

Ile

Gin

Phe

104/105

115 120 125Met Gin Ala Ala Pro Trp Glu Gly Thr

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