Program draft v21 20151026 for web

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Welcome Message

Dear Friends and Colleagues,

On behalf of the Organizing Committee, I would like to welcome you to “the fourth Antibody

Therapeutic Conference: Infectious Diseases, Oncology, and Immunology being held in

Academia Sinica on November 6, 2015

Looking at the application of antibody therapeutics, it remains a growing field today,

especially in the treatment of some cancer, many immune-mediated and infectious diseases,

such as breast cancer, leukemia, asthma, arthritis, psoriasis, Crohn's disease and transplant

rejection, all highlighting the critical pharmaceutical importance of antibody therapeutics.

This meeting covers a broad spectrum of topics on the new advances, as well as emerging

methods for effective discovery, production and application in antibody therapeutics; it aims to

provide young scientists an opportunity to face-to-face discuss the comprehensive scientific

knowledge and experiences on how to develop a therapeutic antibody from discovery,

development to commercialization.

Last but not least, we hope the meeting stimulates cross talks between senior experts and

young scientists working on antibody therapeutics. This meeting not only provides a forum

for sharing your insightful research but also a great opportunity to network with your fellow

professionals.

We look forward to welcoming you to Taiwan’s dynamic city, Taipei and hope that you will

find this meeting an informative, constructive and inspiring experience.

Andrew H.-J. Wang Ph. D Chairman, Organizing Committee

Distinguished Research Fellow

Institute of Biological Chemistry

Academia Sinica

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Chairman

Dr. Andrew H.-J. Wang Academia Sinica

Committee

Dr. Fu-Tong Liu Academia Sinica

Dr. An-Suei Yang Academia Sinica

Dr. Zhiqiang An University of Texas Health Science Center at Houston, USA

Dr. Wei-Kuan Chi Development Center for Biotechnology

Taiwan Antibody Association

National Research Program for Biopharmaceuticals

Biochemical Technology Education Foundation

Academia Sinica

Institute of Biological Chemistry, Academia Sinica

Institute of Biomedical Sciences, Academia Sinica

Steering Committee

Organizers

Co-Organizers

http://taa.tw/index.php/about

http://btef.org.tw/

http://www.sinica.edu.tw/

http://www.ibc.sinica.edu.tw/

http://www.ibms.sinica.edu.tw/

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Welcome Message P.1

Table of Contents P.3

Agenda P.4

Opening Remarks

Dr. Chien-Jen Chen P.8

Dr. Andrew H.-J. Wang P.10

Lectures

Keynote:

Moderator: Dr. Andrew H.-J. Wang P.10

Speaker: Dr. David Ho P.11

Session I: Perspectives on Current Trends and Future Opportunities

Moderator: Dr. Min-Liang Kuo P.14

Speaker: Dr. Zhiqiang An P.15

Speaker: Dr. Lawrence L. Gan P.17

Session II: Emerging Targets

Moderator: Dr. Chia-Lin Jeff Wang P.20

Speaker: Dr. Peter Kwong P.21

Speaker: Dr. Michael Jennings P.24

Speaker: Dr. Arun Kashyap P.26

Session III: Translation and Development of Antibody Therapeutics

Moderator: Dr. Fu-Tong Liu P.30

Speaker: Dr. Po-Jen Chen P.31

Speaker: Dr. Jeffrey J. Molldrem P.34

Speaker: Dr Alice Yu P.38

Session IV: Technologies for Antibody Discovery and Engineering

Moderator: Dr. Han-Chung Wu P.42

Speaker: Dr. An-Suei Yang P.43

Speaker: Dr. Tien-Lu Cheng P.45

Speaker: Dr. Hao-Chen P.48

Closing Remarks

Dr. Fu-Tong Liu P.50

Sponsors P.51

Table of Contents

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Antibody Therapeutics Conference 2015

Infectious Diseases, Oncology, and Immunology

Friday, November 6

Venue: The First Conference Room, 2F, Center for Academic Activities, Academia Sinica

08:30 - 09:00 Registration

09:00 - 09:05 Dr. Chien-Jen Chen

Vice President, Academia Sinica, Taiwan

09:05 - 09:10 Dr. Andrew H.-J. Wang

Distinguished Research Fellow, Institute of Biological Chemistry, Academia

Sinica, Taiwan

President, Taiwan Antibody Association, Taiwan

Moderator: Dr. Andrew H.-J. Wang

Distinguished Research Fellow, Institute of Biological Chemistry, Academia

Sinica, Taiwan President, Taiwan Antibody Association, Taiwan

09:10 - 09:55 Dr. David Ho

Scientific Director and CEO, Aaron Diamond AIDS Research Center

Irene Diamond Professor, the Rockefeller University, New York, NY, USA

Engineering Bispecific Antibodies to Treat and Prevent HIV Infection

Moderator: Dr. Min-Liang Kuo

Dean and Professor, College of Life Science, National Taiwan University,

Taiwan

10:00 - 10:35 Dr. Zhiqiang An

Director and Professor, Robert A. Welch Distinguished University Chair in

Chemistry

Director, Texas Therapeutics Institute, the University of Texas Health

Science Center at Houston, USA

The Current Landscape of Monoclonal Antibody Drug Discovery

10:35 - 10:55 Tea break

Opening Remarks

Keynote


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10:55 - 11:20 Dr. Lawrence L. Gan

President, Development Center for Biotechnology, Taiwan

Drug Delivery into the Brain – the Role of Transporters at the Blood

Brain Barrier and Convective Flows of Brain Interstitial Fluid (ISF)

and Cerebrospinal Fluid (CSF)

Moderator: Dr. Chia-Lin Jeff Wang

CEO, BioGate Medical Science Corp. Taiwan

11:25 – 12:00 Dr. Peter Kwong

Chief, Structural Biology Section and Structural Bioinformatics Core,

Vaccine Research Center, NIAID, National Institutes of Health, USA

HIV-1 Env as a Target of Neutralizing Antibodies

12:00 - 12:35 Dr. Michael Jennings

Deputy Director & Principal Research Leader, Institute for

Glycomics, Griffith University, Australia

Discovery and Exploitation of Host - Pathogen Interactions as New

Opportunities for Antibody Therapy

12:35 - 14:00 Lunch (Taiwan Antibody Association Members Meeting)

14:00 - 14:35 Dr. Arun Kashyap

Head of Research, Sea Lane Biotechnologies, USA

Surrobodies: A Novel Immune Scaffold for Immunotherapeutic

Applications

Moderator: Dr. Fu-Tong Liu

Director and Distinguished Research Fellow, Institute of Biomedical

Sciences, Academia Sinica, Taiwan

14:40 - 15:15 Dr. Po-Jen Chen

Professor, Department of Medicine, Rheumatology Division, UCLA, USA

From Autoantibodies to Potentially Therapeutic Antibodies against

HIV



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15:15 - 15:50 Dr. Jeffrey J Molldrem

Professor and Chief, Section of Transplantation Immunology, Department

of Stem Cell Transplantation and Cellular Therapy, Division of Cancer

Medicine, University of Texas, MD Anderson Cancer Center, Houston,

USA

T Cell Receptor-Like Antibody 8F4 Targets Leukemia and

Non-Hematopoietic Cancer

15:50 - 16:10 Tea break

16:10 - 16:35 Dr. Alice Yu

Distinguished Chair Professor and Co-Director, Institute of Stem Cell and

Translational Cancer Research, Chang Gung Memorial Hospital & Chang

Gung University, Taiwan

Development of Antibodies Directed against Cancer Associated

Glycans

Moderator: Dr. Han-Chung Wu

Research Fellow and Deputy Director, Institute of Cellular and Organismic

Biology, Academia Sinica, Taiwan

16:40 - 17:05 Dr. An-Suei Yang

Research Fellow and Deputy Director, Genomics Research Center,

Academia Sinica, Taiwan

A High Throughput Antibody Engineering Platform for Discovering

and Optimizing Antibodies in Antibody-Guided Drug Delivery Systems

17:05 - 17:30 Dr. Tien-Lu Cheng

Director of Graduate Institute of Medicine and Center for Biomarkers and

Biotech Drugs, Kaohsiung Medical University, Taiwan

Proteases (MMP2/9) Enhance the Affinity and Therapeutic Efficacy of

Targeted Antibody

17:30 - 18:05 Dr. Hao Chen

Director, BioProcess Development, Merck Research Laboratories,

Kenilworth, NJ, USA

Accelerated FIH (First-In-Human) for Mabs Enabled by Innovative

Bioprocess Strategy and Technologies


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18:05 - 18:10 Dr. Fu-Tong Liu

Director and Distinguished Research Fellow, Institute of Biomedical


18:10 Dinner & Taiwan Antibody Association Council Meeting (By Invitation)

Closing Remarks

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Opening Remarks

Chien-Jen CHEN Vice President,


([email protected])

Professor Chien-Jen Chen received his B.Sc. (1973) and M.P.H. (1977) from National Taiwan

University, and Sc.D. (1982) in epidemiology and human genetics from the Johns Hopkins

University. He then worked as a lecturer (1982-1983), associate professor (1983-1986), and

professor (since 1986) of National Taiwan University. He was appointed as the director of

Graduate Institute of Public Health (1993-1994), founding director of Graduate Institute of

Epidemiology (1994-1997), and dean of College of Public Health (1999-2002) in National

Taiwan University. He is now a distinguished research fellow of Genomics Research Center

(since 2006) and a Vice President (since 2011) of Academia Sinica.

Professor Chen has dedicated himself to molecular and genomic epidemiological researches on

chronic arsenic poisoning and virus-induced cancers for 30 years. His discoveries of multiple

health hazards of arsenic in drinking water has led to the global awareness and prevention of the

largest environmental calamity, and his researches on end-stage liver disease risk prediction of

chronic hepatitis B has pioneered the viral load paradigm in its clinical management. He has

published 12 books, 22 book chapters, 35 conference full articles, and over 640 original, review

and editorial articles in international journals, which have been cited for more than 27,000 times

in the SCI (Science Citation Index) journals with an h-index over 85. He has received

Outstanding Research Award (1986-1996) and Outstanding Research Fellow Award (2003) from

National Science Council; as well as Outstanding Teaching Award (1992), Academic Award

(1997) and National Chair Professor (1999-2002) from Ministry of Education in Taiwan. He was

elected as an academician of the Academia Sinica in 1998. He received the Presidential Science

Prize, the most prestigious science award in Taiwan, in 2005.

Professor Chen was elected as a fellow of American College of Epidemiology (1993), a member

of the World Academy of Sciences (2005), an honorary member of Mongolian Academy of

Science (2007), and a member of the Delta Omega Honorary Society in Public Health, Johns

Hopkins University (2010). He was elected as the Dr. D.V. Datta Memorial Orator by the Indian

National Association for Study of the Liver (2008), the Cutter Lecturer on Preventive Medicine

by Harvard University (2008) and Professor Vikit Viranuvatti Lecturer by the

Gastroenterological Association of Thailand (2011). He received the Science and Engineering

Achievement Award from Taiwanese- America Foundation in the USA (2009), the Outstanding

Academic Award from Wang Ming-Ning Memorial Foundation in Taiwan (2010), the

Knowledge for World Award from Johns Hopkins University (2012), the Outstanding

Contribution in Science and Technology Award from Executive Yuan in Taiwan (2013),

Professor Juei-Low Sung Award from Asia-Pacific Primary Liver Cancer Expert Meeting

(APPLE 2014).

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Professor Chen has served in several government positions including the Director General of

Division of Life Sciences (1997-1999) and Deputy Minister (2002-2003) of National Science

Council, Minister of Department of Health (2003-2005), and Minister of National Science

Council (2006-2008). After his outstanding leadership to control the outbreak of severe acute

respiratory syndrome successfully in 2003, he has made fundamental reforms of the organization

of Department of Health and Center for Disease Control, the Medical Care System for Infectious

Diseases and the Act of Infectious Disease Control in Taiwan. Under his significant leadership to

promote scientific research and technology development in Taiwan, he has successfully made the

reform of National Science Council and the promotion of international R&D collaboration. He

has won widespread praise as a successful academic administrator and government leader. He

received the Health Medal from Department of Health (2005), the Achievement Medal from

Executive Yuan (2005) and the Science Professional Medal from National Science Council (2012)

in Taiwan, the Officier dans l'Ordre des Palmes Academiques from the Ministry of Education,

France (2009), and the Knight of Pontifical Equestrian Order of St. Gregory the Great, Vatican

(2013).

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Opening Remarks & Keynote Moderator

Andrew H.-J. WANG Distinguished Research Fellow, Institute of Biological Chemistry,


President, Taiwan Antibody Association, Taiwan

([email protected])

Professor Andrew H.-J. Wang was educated in Taiwan with B.S. (1967) and M.S. (1970) degrees,

both from the Department of Chemistry, National Taiwan University. He obtained the Ph.D.

degree from the Department of Chemistry, University of Illinois in 1974. He was Professor of

Biochemistry, Biophysics and Chemistry at the University of Illinois (Urbana), during 1988-2000.

Dr. Wang served as Vice President of Academia Sinica and is currently Distinguished Research

Fellow of the Institute of Biological Chemistry, Academia Sinica, Taipei. He is an outstanding

research scholar, as evidenced by over 440 of his scientific papers in top international journals of

the field. He has made many seminal scientific contributions including the discovery of Z-DNA.

Dr. Wang has also actively been involved in the advancement of sciences. He served as Editor for

European J. Biochem., on Advisory Board of Nucleic Acids Research. He has been Council

Member of Human Proteomics Organization (HUPO). As the President of three societies (Taiwan

Society of Biochemistry and Molecular Biology (a member of IUBMB), Biophysical Society of

ROC (a member of IUPAB) and Taiwan Proteomics Society (a member of AOHUPO)), he has

successfully organized several major international conferences in Taipei, most recently the

2014_IUBMB/FAOBMB Joint Conference.

Dr. Wang’s numerous achievements were recognized by his election as Academician of

Academia Sinica (Taiwan), Fellow of American Association for the Advancement of Science,

Fellow of Third World Academy of Sciences and President of FAOBMB, President Elect of

IUBMB, etc. His research interests include structural proteomics, drug discovery including

therapeutic antibody development, synchrotron crystallography, structure-function relationship of

enzymes, membrane proteins and DNA-interacting proteins.

mailto:[email protected]

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Keynote Speaker

David HO Scientific Director and CEO, Aaron Diamond AIDS Research Center

Irene Diamond Professor, the Rockefeller University, New York, NY, USA

([email protected])

David D. Ho, M.D. is the founding Scientific Director and Chief Executive Officer of the Aaron

Diamond AIDS Research Center, a world-renowned biomedical research institute. He is also the Irene

Diamond Professor at The Rockefeller University.

Dr. Ho received his degrees from California Institute of Technology (1974) and Harvard Medical

School (1978). Subsequently, he did his clinical training in internal medicine and infectious diseases

at Cedars-Sinai Medical Center/UCLA School of Medicine (1978-1982) and Massachusetts General

Hospital/Harvard Medical School (1982-1985), respectively.

Dr. David Ho has been at the forefront of AIDS research for 34 years, publishing over 350 papers. His

elegant studies, beginning in 1994, unveiled the dynamic nature of HIV replication in vivo and

revolutionized our basic understanding of this horrific disease (Nature 1995; Science 1996). This

knowledge led Dr. Ho to champion combination antiretroviral therapy (N. Engl. J. Med. 1995;

Science 1996) that resulted in unprecedented control of HIV in patients (Nature 1997). AIDS

mortality in richer nations has declined 6-fold since 1996, and a massive international effort is now

underway to bring such life-saving treatment to millions in the developing world. Dr. Ho has been the

major driving force behind this major medical breakthrough in what is arguably the worst plague in

human history.

Dr. Ho’s research team is now devoting considerable efforts to develop vaccines to halt the spread of

the AIDS epidemic. Furthermore, he is now heading up a consortium of Chinese and American

organizations to help address the crisis of HIV/AIDS in China.

Dr. Ho has received numerous honors and awards for his scientific accomplishments. He is the

recipient of 12 honorary doctorates (including from Swarthmore, Tufts, Columbia, Tulane, University

of Natal, Tsinghua University and University of Hong Kong). He has been chosen as the

commencement speaker at Caltech, MIT, and Harvard School of Public Health. Additional accolades

include the Ernst Jung Prize in Medicine, Mayor’s Award for Excellence in Science & Technology,

the Squibb Award, and the Hoechst Marion Roussel Award. Dr. Ho has been elected as a member of

the American Academy of Arts and Sciences, Academia Sinica (Republic of China), Chinese

Academy of Engineering, and the Institute of Medicine, National Academy of Science in the United

States. He was inducted into the California Hall of Fame in 2006.

Dr. Ho is also an honorary professor at Peking Union Medical College, Chinese Academy of Medical

Sciences, Chinese Academy of Sciences, University of Hong Kong, Wuhan University, and Fudan

University. He was a member of the Board of Overseers of Harvard University and is a board member

of the Massachusetts Institute of Technology Corporation.

Dr. Ho was named Time Magazine’s Man of the Year in 1996, and was the recipient of a Presidential

Medal in 2001.


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Engineering Bispecific Antibodies to Treat and Prevent HIV Infection

David Ho

There is no effective vaccine to protect against HIV infection today, and none will be available

for the foreseeable future. The lack of an effective HIV vaccine is in part due to the structural

properties of the viral envelope glycoprotein, which possesses highly variable amino-acid

sequences along with extensive glycosylation that shield the virus from many anti-envelope

antibodies. As an alternative strategy, our group is pursuing the use of antibodies as agents for

passive administration to prevent HIV infection. We have engineered a number of bi-specific

monoclonal antibodies that have remarkable potency and breadth against the virus in vitro. We

have in hand a number of constructs with 100% breadth against a large panel of HIV strains with

potency in the nM range. Modifications to improve the pharmacokinetic properties of the

antibodies have also been made and evaluated. Several of the best antibody constructs are now

being assessed for their “developability” and two are now being advanced as candidates for

clinical development.

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Moderator: Dr. Min-Liang KUO

10:00 - 10:35 Dr. Zhiqiang AN

Director and Professor, Robert A. Welch Distinguished University Chair in

Chemistry




10:35 - 10:55 Tea break

10:55 - 11:20 Dr. Lawrence L. GAN

President, Development Center for Biotechnology, Taiwan

Drug Delivery into the Brain – the Role of Transporters at the Blood

Brain Barrier and Convective Flows of Brain Interstitial Fluid (ISF)

and Cerebrospinal Fluid (CSF)


Lectures

14

Session I Moderator

Min-Liang KUO Dean, National Taiwan University College of Life Science

Professor, Institute of Biochemical Science, National Taiwan University

College of Life Science

Co-hiring Professor, Graduate Institute of Toxicology, National Taiwan

University College of Medicine, Taiwan

([email protected])

Professional Experiences

1999 - 2005 Professor and Director, Institute of Toxicology College of Medicine

National Taiwan University

2005 - 2006 Professor, Institute of Toxicology College of Medicine National Taiwan

University

2006 - 2007 M.D., Department of Molecular Oncology MD Anderson Cancer Center

2007 - 2009 Distinguished Professor Associated Dean, Director of R&D, Institute of

Toxicology College of Medicine National Taiwan University

2009 - 2012 Director General, Department of Life Sciences, National Science Council

Republic of China

2010 - 2014 President, The Toxicology Society of Taiwan

2012 - Present Co-hiring Professor, Graduate Institute of Toxicology, National Taiwan

University College of Medicine

2012 - Present Professor, Institute of Biochemical Science, National Taiwan University

College of Life Science

2012 - Present Dean, National Taiwan University College of Life Science

Research Interests

Professor Kuo dedicate to the research of tumor progression and translational medicine for more

than 20 years in Taiwan. His works including discovery the molecular mechanism of cancer

malignance progression by epigenetic regulation and growth factor/cytokine response of cancer

cells. His mechanistical studies about epigenetic regulation, microRNA synthesis, protein

post-translational modification, growth factors and cytokines also give rise to serial discoveries of

novel tumor suppressors and oncogenes involve in tumor growth, invasiveness, metastasis, and

angiogenesis. These outstanding researches of Professor Kuo not only provide novel insights into

the underlying mechanisms but also translated into development of novel therapeutic strategies

for clinical application.

15

Session I Speaker

Zhiqiang AN Director and Professor, Robert A. Welch Distinguished University Chair in

Chemistry



([email protected])

Dr. Zhiqiang An is Professor of Molecular Medicine, the Robert A. Welch Distinguished

University Chair in Chemistry, and Director of the Texas Therapeutics Institute at the University

of Texas Health Science Center at Houston. His laboratory focuses on cancer antibody drug

resistance mechanisms, biomarkers for cancer therapeutic antibodies, and antibody drug

discovery targeting cancer and infectious diseases. Dr. An also directs the Therapeutic

Monoclonal Antibody Lead Optimization and Development Core Facility funded by the Cancer

Prevention and Research Institute of Texas (CPRIT). Previously, he served as Chief Scientific

Officer at Epitomics, Inc. and was Director of Biologics Research at Merck Research

Laboratories. He started his biotech career at Millennium Pharmaceuticals. Dr. An received his

Ph.D. degree from the University of Kentucky and his postdoctoral training at the University of

Wisconsin-Madison.


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Zhiqiang An

Antibody therapeutics represents a major breakthrough in combating human diseases and the

improvement of human health. At least 40 antibody therapies have been approved for the

treatment of cancer, immune disorders, and infectious diseases. A record six antibody therapies

were granted first marketing approval in 2014. Among the top 10 bestselling prescription

medicines in 2014, seven are recombinant proteins and antibodies. This trend will continue as

about 50% of the new drugs in various stages of clinical development are antibodies. Despite the

remarkable progress, many scientific, technological, and clinical challenges remain and

opportunities for innovation exist at every level: accessing difficult antibody targets, small

molecule and antibody combination therapies, immune check point therapies, antibody-drug

conjugation, novel antibody sources and formats, crossing the brain-blood-barrier and cell

membranes, modified effector functions, bispecific and poly-monoclonals, improved formulation

and delivery methods, and lower manufacturing cost, to name a few. This presentation will

review the current trend in therapeutic antibody discovery to fulfill the dream of personalized

medicine through basic scientific discovery and technological innovation.

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Session I Speaker

Lawrence L. GAN President, Development Center for Biotechnology, Taiwan

([email protected])

Accomplishments

1. Involved in four NDA and two BLA filings.

2. Participated in >25 IND filings.

Experience/Education

2007/07-2015/2/28 Senior Director, Drug Metabolism and Pharmacokinetics, Biogen Idec, Inc.

(now Biogen Inc.), Cambridge, MA, USA

2005/11-2007/07 Director (German Rank), Drug Metabolism and Pharmacokinetic, Drug

Discovery Support, Boehringer-Ingelheim Pharmaceuticals, Inc., Ridgefield,

CT, USA

2002/02-2005/11 Senior Director, Drug Metabolism and Pharmacokinetics, Millennium

Pharmaceuticals (now Takeda Pharmaceuticals), Cambridge, MA,

USA

1996/09-2002/02 Director, Drug Metabolism and Pharmacokinetics, DuPont Merck & then

DuPont Pharmaceuticals (now Bristol-Myers Squibb Co.), Wilmington, DE,

USA

1989/03-1996/09 Principal Investigator, Drug Metabolism and Pharmacokinetics, Glaxo Inc.,

then GlaxoWellcome Inc. (now GlaxoSmithKline, GSK), Research Triangle

Park, NC, USA

1986/02- 1989/03 Post-Doc Research Fellow, Chemical Toxicology, Massachusetts Institute of

Technology, Cambridge, MA, USA

1981/08-1986/02 Doctoral Research (Ph.D.), Department of Chemistry, Tulane Univ., New

Orleans, LA, USA

Adjunct Professorship

UNC, Chapel Hill, Northeastern Univ., West Virginia University, Massachusetts College of Pharmacy.

Supervised twelve doctoral and M.S. candidates.

Industry Representatives

Board of Director, International Consortium for Innovation and Quality (IQ) in Pharmaceutical

Development. IQ Drug Metabolism Leadership Group Representative. New England Drug

Metabolism Discussion Group Committee Member.

Editorial Roles

Editorial Advisory Board, Editor, and referee for more than 10 peer-reviewed journals.

Publications >80 peer-reviewed journal publications, 128 meeting abstracts, 6 book chapters, Associate Editor for

Drug Metabolism Handbooks, 32 invited presentations.

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Drug Delivery into the Brain

– the Role of Transporters at the Blood Brain Barrier and Convective

Flows of Brain Interstitial Fluid (ISF) and Cerebrospinal Fluid (CSF)

Lawrence L.-S. Gan1, and Qin Wang

2

1Development Center for Biotechnology, Xizhi District, New Taipei City, 22180, Taiwan, R.O.C. 2Department of Drug Metabolism and Pharmacokinetics, Biogen Inc., Cambridge, MA 02142,

USA

The brain is a privileged organ, sequestered from the general systemic circulation by the blood

brain barrier (BBB). BBB eliminates toxic substances from the endothelial compartment and

supplies the brain with nutrients and other endogenous compounds. It can be considered as an

organ protecting the brain and regulating its homeostasis. To date, many transport systems have

been discovered that play an important role in maintaining BBB integrity, brain homeostasis, and

drug uptake into the brain. The role of carrier-mediated transport systems (CMT, e.g. Pgp, BCRP,

MRPs, OATPs) and receptor-mediated transport systems (RMT, e.g. transferrin 1&2) at the BBB

will be reviewed first. The role that convective flows of brain interstitial fluid (ISF) and

cerebrospinal fluid (CSF) play in clearing wastes out of the central nervous system (CNS) and its

implications including the onset of β-amyloid accumulation in the brain will also be discussed.

The phenomenon that acetazolamide, a carbonic anhydrase inhibitor, reduces ISF and CSF

production and decreases the clearance of acetaminophen out of brain has been demonstrated via

microdialysis studies.

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Moderator: Dr. Chia-Lin Jeff WANG

CEO, BioGate Medical Science Corp. Taiwan

11:25 – 12:00 Dr. Peter KWONG

Chief, Structural Biology Section and Structural Bioinformatics Core,



12:00 - 12:35 Dr. Michael JENNINGS

Deputy Director & Principal Research Leader, Institute for




12:35 - 14:00 Lunch (Taiwan Antibody Association Members Meeting)

14:00 - 14:35 Dr. Arun KASHYAP

Head of Research, Sea Lane Biotechnologies, USA


Applications


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Session II Moderator

Chia-Lin Jeff WANG President, BioGate Medical Sciences Co, Taiwan

([email protected])

Education

1978-1979 Research Associate, Department of Chemistry, Harvard University (Advisor:

Professor Yoshito Kishi)

1977 Ph.D., Department of Chemistry, University of Pittsburgh, Pittsburgh, PA

(Thesis Advisor: Professor Paul A. Grieco)

1971 B.S., Department of Chemistry, National Taiwan University, Taipei, Taiwan

R.O.C.

Professional Experience

2/2015 Present: President, BioGate Medical Sciences Co.

8/2014 -2/2015 Senior VP, CHO Pharma

2008-8/2014 President, Development Center for Biotechnology

2007-2008 Chief Scientific Officer, Microbio Co.

2006-2007 Vice President, Development Center for Biotechnology

2000-2005 Director, U.S. East Coast Office Development Center for Biotechnology

1997-2000 Science Advisor (Biotechnology &Pharmaceutical) Department of Industrial

Technology, Ministry of Economic Affairs (Taiwan)

1992-1996 Director, Natural Product & Medicinal Chemistry Development Center for

Biotechnology (Taiwan)

1990-1992 Principal Research Scientist, The DuPont Merck Pharmaceutical Co. (US)

1985-1990 Senior Research Chemist, Du Pont Medical Products Department (US)

1979-1985 Research Chemist, Du Pont Central Research and Development Department

(US)

Accomplishments

1. Over 50 publications and 26 patents on the synthesis of medicinally interesting compounds

2. Help Taiwan Ministry of Economic Affairs (MOEA) formulate the R&D strategies for

promotion of the Taiwan biotech and pharmaceutical industries

3. Promote international cooperation for the development of Taiwan biotech and

pharmaceutical industries

4. Help form the “Five-year Herbal Medicine Industrial R&D Plans” for Taiwan

5. Transform DCB into a new drug translational research institute working closely with

academic institutes and industries.

21

Session II Speaker

Peter D. KWONG Chief, Structural Biology Section and Structural Bioinformatics Core,


([email protected])

Dr. Peter Kwong joined the Dale and Betty Bumpers Vaccine Research Center as chief of the

Structural Biology Section in the Laboratory of Virology. Dr. Kwong comes to the Washington

area from New York City, where he conducted research in the Department of Biochemistry and

Molecular Biophysics at Columbia University.

Dr. Kwong's research specialty is structural biology. Specifically, he has studied the atomic-level

structures of both the HIV protein, gp120, which resides on the outer surface of the virus as well as

the structure of the primary HIV receptor, CD4. HIV uses gp120 to find and latch onto special

CD4-containing immune cells in the first step of infection. Because of its exposed position on the

outer surface of the virus, gp120 is the primary target of antibodies, the body's first line of defense

against the invading virus. But, by mechanisms still not fully understood, gp120 is able to evade

most of these antibodies.

Because of its central role in evading the immune system, many investigators had previously

attempted to analyze the gp120 structure. However, these attempts were not successful due to

masking of the gp120 molecule. Dr. Kwong and his research collaborators constructed altered

forms of the gp120 protein until they found one that was suitable for analysis. By using X-ray

crystallography, Dr. Kwong elucidated the atomic-level structure of gp120 in complex with the

CD4 receptor and a neutralizing human antibody. The results of this seminal experiment and

discovery were published in the journals Nature and Science in 1998.

Although structural information has not played a large role in vaccine development thus far, Dr.

Kwong's research may change this. Since arriving at the VRC in 2001, Dr. Kwong and his research

team have focused on three areas of investigation: 1) Unveiling mechanisms used by the HIV-1

envelope to evade the humoral immune response; 2) The characterization of antibodies that

neutralize HIV-1, including their precise epitopes and mechanisms of neutralization; and 3) The

design of envelope-based vaccine immunogens that elicit an effective antibody immune response

against HIV-1.

The most dramatic advances have been in understanding mechanisms used by HIV-1 to disguise its

surface, thereby evading the immune system's attack of neutralizing antibodies. These involve

novel mechanisms of conformational masking and glycan shielding (published in the journal

Nature in 2002 and 2003). The investigations of antibodies have also revealed novel mechanisms

of binding, involving membrane interactions with the broadly neutralizing anti-HIV-1 antibody,

2F5, and of mimicry, involving antibody sulfation with the CD4i-class of gp120-reactive

antibodies.

22

By studying the mechanisms gp120 uses to evade the immune system, Dr. Kwong and his team

hope to find how to disable them and construct a modified HIV-1 envelope that will elicit an

immune response against HIV. Conversely, by understanding how the rare select antibodies from

HIV-1 infected individuals can neutralize HIV-1, Dr. Kwong and his team hope to understand how

they might be efficiently re-elicited. The success of this research may lead to new strategies for

developing vaccines against HIV as well as against other disease-causing viruses.

Dr. Kwong entered the University of Chicago at age 16 and earned a bachelor's degree in chemistry

and physics and a master's degree in biochemistry by age 20. He earned his second master's degree

and his doctoral degree in biochemistry and molecular biophysics from Columbia University in

New York.

23


Peter D. Kwong


Extraordinary antibodies capable of near pan-neutralization of HIV-1 have been identified (1). One

of the broadest is antibody 10E8, which recognizes the membrane-proximal external region of

HIV-1 and neutralizes over 95% of circulating HIV-1 strains (2). Antibody 10E8, however, suffers

from issues of solubility and, if dosed at 30 mg/kg, would require over ~2 g of antibody per dose for

a typical adult. Here, we describe the use of structural biology, somatic variation and

surface-matrix screening to identify optimized versions of 10E8 with substantially increased

solubility and potency. First we used both structural biology and somatic variants obtained by next

generation sequencing to identify 10E8-v4, with 26 amino acid changes, similar neutralization

potency, but more than 10-fold improved solubility relative to the parent 10E8. Second we used a

matrix-screening approach to analyze the surface of 10E8 with Arg, Phe/Trp, N-linked glycan and

poly-glycine alterations coupled to assessment of neutralization potency and solubility. By using

clues glean from this surface-matrix analysis, we developed modified versions of 10E8-v4 with

neutralization potency increased by over 30-fold. Delivery of these more potent versions of

10E8-v4, along with an extended half-life alteration (a “LS” change in the constant region), may

reduce dosing to ~0.1 g of optimized 10E8 every 3 months, a more practical target. The impact of

such optimized antibodies on treatment and prevention of HIV-1 will be discussed.

References

1. Kwong P.D. and Mascola J.R. Human antibodies that neutralize HIV-1: Identification,

structures and B cell ontogenies. Immunity 37, 412-425, 2012.

2. Huang J., Ofek G., Laub L., Louder M.K., Doria-Rose N.A., Longo N.S., Imamichi H., Bailer

R.T., Chakrabarti B., Sharma S.K., Alam S.M., Wang T., Yang Y., Zhang B., Migueles S.A.,

Wyatt R., Haynes B.F., Kwong P.D., Mascola J.R., Connors M. Broad and potent

neutralization of HIV-1 by a gp41-specific human antibody. Nature 491, 406-412, 2012.

24

Session II Speaker

Michael JENNINGS Deputy Director & Principal Research Leader, Institute for


([email protected])

Professor Michael Jennings works in the fields of glycobiology, bacterial genetics and bacterial

pathogenesis. His work has focused on bacterial pathogens, in particular the pathogenic Neisseria

(meningitis) and Haemophilus influenzae. He was awarded his PhD (1990) from Griffith

University. His post-doctoral training was in the laboratory of Professor Richard Moxon at the

University of Oxford 1992-1996 funded by the Beit Memorial Fellowship for Medical Research.

In 1997 he took up a faculty position at the University of Queensland. He remained at University

of Queensland until 2009, until he returned to Griffith University to take up the position of

Deputy Director at the Institute for Glycomics. His current research program is investigating the

molecular basis for interactions between a wide range of pathogens and the human host and the

application of this data to develop novel strategies for diagnostics, prevention and treatment of

disease.

25



Michael Jennings

Glycans are important structures in many host - pathogen interactions. Bacterial lectins such as

adhesins and toxins exploit host glycans as targets. Host lectins recognize bacterial glycans in

innate immune processes. The molecular details of many bacterial - host interactions remain to be

discovered. Understanding these processes is key for the development of novel strategies for

prevention and therapeutics. We have applied glycan array to discover novel interactions between

bacterial and human cells. Interfering with these processes may for the basis of therapeutic

approaches using antibody therapeutics.

26

Session II Speaker

Arun KASHYAP Head of Research, Sea Lane Biotechnologies, Atherton, CA, USA

([email protected])

Experience

Head of Research, Sea Lane Biotechnologies, 12/2014-present

Director of Biology, Sea Lane Biotechnologies, 2/2008 to 9/2012

Principal Scientist, Sea Lane Biotechnologies, 2/2006 to 2/2008

Bioprocess Engineer, BD Biosciences, 5/2004-2/2006

Scientist, Pharmagenesis, 9/2001-7/2003

Research Associate, Affymax Research Institute, 11/1992-10/1995

Scientist, Sandoz Agro, 4/1990-11/1992

Education

PhD, University of California, Santa Cruz, 2001

AB, University of California, Berkeley, 1989

Awards and Associations

University of California Regents Fellowship (1995)

Newcomb Cleveland Prize- AAAS (1997)

Member, American Society for Cell Biology (2003-present)

Qualifying Therapeutic Discovery Program- Awards for two programs (2011)

Publications

1. Milutinovic S., et al. Dual agonist SurrobodyTM simultaneously activates death receptors

DR4 and DR5 to induce cancer cell death. Mol Cancer Ther. Submitted.

2. Ekiert D.C., et al Cross-neutralization of influenza A viruses mediated by a single antibody

loop. Nature 489:526-532, 2012.

3. Kashyap A.K., et al. Protection from the 2009 H1N1 Pandemic Influenza by an Antibody

from Combinatorial Survivor-based Libraries PLoS Pathog 6(7):e1000990, 2010.

4. Xu L., et al, Surrobodies with functional tails. J Mol Biol 397(1):352–360, 2010.

5. Xu L., et al, Combinatorial surrobody libraries. Proc Natl Acad Sci USA 105(31):10756–

10761, 2008.

6. Kashyap A.K, et al. Combinatorial Antibody Libraries from Survivors of the Turkish H5N1

Avian Influenza Outbreak Reveal Virus Neutralization Strategies. Proc Natl Acad Sci USA

105(16):5986-91, 2008.

7. Kashyap A.K, et al. Biochemical and genetic characterization of Yra1p function in budding

yeast. Yeast 22:43-56, 2005.

8. Wrighton N.C., et al, Increased potency of an erythropoietin peptide mimetic through

covalent dimerization. Nat Biotech 15:1261-1265, 1997.

27

9. Wrighton N.C., et al Small peptides as potent mimetics of the protein hormone

erythropoietin. Science 273(5274):458-463, 1996.

28


Applications

Arun Kashyap

Surrobodies are heterotetrameric proteins that contain the surrogate light chain and a full

antibody heavy chain. The surrogate light chain is the fusion of two human immune proteins that

form the pre-B-cell receptor, namely VpreB and Lambda 5. Normally expressed during B-cell

development just after heavy chainV-DJ joining, the complex of VpreB and Lambda 5 pair with

all heavy chains in what is thought to be a quality control step to eliminate self reactive

combinations. We have adapted the surrogate light chain to the development of the Surrobody

scaffold that has highly desirable characteristics; high affinity and specificity, long serum

half-life, excellent stability, and developed manufacturing processes. In addition, since the

surrogate light chain is an undiversified and fixed component of all Surrobodies, it is uniquely

suited to the creation of bispecific molecules and drug conjugate applications. Sea Lane has

created a full discovery package including a 2.8 X1010 member phagemid library based on

proprietary ConCIRT diversity and transient production methods. Application of Surrobody

libraries to oncology targets ErbB3 and the death receptors DR4 and DR5 has produced highly

potent molecules with unique activity profiles in pre-clinical proof of concept studies.

29

Moderator: Dr. Fu-Tong LIU

Director and Distinguished Research Fellow, Institute for Biomedical


14:40 - 15:15 Dr. Po-Jen CHEN

Professor, Department of Medicine, Rheumatology Division, UCLA, USA

From Autoantibodies to Potentially Therapeutic Antibodies against

HIV

15:15 - 15:50 Dr. Jeffrey J MOLLDREM

Professor and Chief, Section of Transplantation Immunology, Department


Medicine, University of Texas, MD Anderson Cancer Center, Houston,

USA

T Cell Receptor-Like Antibody 8F4 Targets Leukemia and

Non-Hematopoietic Cancer

15:50 - 16:10 Tea break

16:10 - 16:35 Dr. Alice YU




Development of Antibodies Directed against Cancer Associated

Glycans


30

Session III Moderator

Fu-Tong LIU Distinguished Research Fellow and Director, Institute of Biomedical


([email protected])

Dr. Fu-Tong Liu is currently Distinguished Research Fellow and Director at Institute of

Biomedical Sciences, Academia Sinica and was previously Distinguished Professor and Chair at

Department of Dermatology, University of California-Davis. He is currently Associate Director

for the Academia Sinica Translational Medicine Degree Program, Co-Director for the

International Collaboration Program under the National Research Program for

Biopharmaceuticals (NRPB), Director for the National Glycoscience Program of the Ministry of

Science and Technology, and Principle Investigator of the Taiwan Biobank. He received his BS

in Chemistry from National Taiwan University, PhD in Chemistry from University of Chicago,

and MD from University of Miami. He has served as Head of the Allergy Research Section at the

Scripps Research Institute and Head of the Division of Allergy at La Jolla Institute for Allergy

and Immunology.

Dr. Liu is a pioneer and leading investigator in the studies of a family of animal lectins, galectins,

and his research is focused on the roles of these proteins in inflammation and immunity, as well

as cancer progression and adiposity. He has published over 310 original scientific papers and

review articles. He has served as an Associate Editor of Journal of Clinical Investigation and is

currently a member of the Editorial Boards of a number of scientific journals in dermatology and

allergy. He is a Fellow of American Association for the Advancement of Science (AAAS) and an

Academician of Academia Sinica. He was the Laureate of the 2015 Khwarizmi International

Award.

31

Session III Speaker

Po-Jen CHEN Professor, Department of Medicine, Rheumatology Division, UCLA, USA

([email protected])

Experience

Professor Emeritus, Department of Medicine, Division of Rheumatology, UCLA, 2014-date

Member, International Advisory Committee for the International Congress of

Antiphospholipid Antibodies, 2010-2012

Scientific Consultant, PEREGRINE PHARMACEUTICALS, INC., Tustin, California, United

States, 2007-2009

Professor, Department of Medicine, Division of Rheumatology, University of California Los

Angeles (UCLA), Los Angeles, California, United States, 1997-2014

Member, General Medicine A Study Section, NIH, 1996-2000

Professor, Departments of Medicine and Pathology, UCSD, 1995-1997

Member, General Medicine A Study Section, National Institutes of Health (NIH), USA,

1991-1995

Scientific Consultant, CIBA-GEIGY Corp., Summit, New Jersey, 1990-1996

Associate Professor, Departments of Medicine and Pathology, University of California San

Diego (UCSD), 1990-1995

Assistant and Associate Professor, Department of Basic and Clinical Research, the Scripps

Research Institute, La Jolla, California, USA, 1985-1990

PhD, University of California, San Francisco, 1980

BS, Tunghai University, Taiwan, 1973

Selected Invited Lectures

1. Invited speaker, Jiangsu provincial Rheumatology conference, Yangzhou, Jiangsu, China,

2013.

2. Invited seminar, Department of Rheumatology, Peking Union Medical College Hospital,

Chinese Academy of Medical Sciences, Beijing, China, 2010.

3. Invited Speaker, the 13th International Congress of Antiphospholipid Antibodies (APLA

2010), Galveston, Texas, United States, 2010.

4. Invited Speaker, The 8th International Congress on SLE, Shanghai, China, 2007.

5. Invited keynote speaker, the joint annual meeting of the Taiwanese society of Immunology

and the Taiwanese Rheumatology Association, November 22-23, 2003, Taichung, Taiwan,

2003.

6. Invited Speaker, the 9th Asian Pacific League Against Rheumatism, Beijing, China, 2000.

7. Plenary Lecturer, the Major Histocompatibility Complex in Medicine, Australasian and

South East Asian Tissue Typing Association (ASEATTA), Adelaide, Australasia, 1994.

32

8. Plenary Lecturer, First International Workshop on: "Platelets, Endothelial Cells: from

Autoimmunity to Immunomodulation", Annecy, France, 1993.

9. Plenary Lecturer, XXIst Annual Meeting of the Society of Immunology, Aachen, Germany,

1990.

10. Invited Speaker, XVIIth International Congress of Rheumatology-ILAR '89, Rio de Janeiro,

Brazil, 1989.

11. Plenary Lecturer, the Third Mediterranean Congress of Rheumatology, Tunis, Tunisia,

1986.

Selected Publications

1. Moody M.A., Liao H.X., Alam S.M., Scearce R.M., Plonk M.K., Kozink D.M., Drinker

M.S., Zhang R., Xia S.M., Sutherland L.L., Tomaras G.D., Giles I.P., Kappes J.C.,

Ochsenbauer-Jambor C., Edmonds T.G., Soares M., Barbero G., Forthal D.N., Landucci G.,

Chang C., King S.W., Kavlie A., Denny T.N., Hwang K.K., Chen P.P, Thorpe P.E.,

Montefiori D.C., Haynes B.F. Anti-phospholipid human monoclonal antibodies inhibit

CCR5-tropic HIV-1 and induce beta-chemokines. J Exp Med 207:763-776, 2010.

2. Zhu M., Olee T., Le D.T., Roubey R.A.S., Hahn B.H., Woods Jr. V.L., Chen P.P.

Characterization of IgG monoclonal anti-cardiolipn/anti-2GP1 antibodies from two patients

with antiphospholipid syndrome reveals three species of antibodies. Brit. J. Haematology

105:102-109, 1999.

3. Olee T., Pierangeli S.S., Handley H.H., Le D.T., Wei X., Lai C.J., En J., Novotny W., Harris

E.N., Woods V.L., Chen P.P. A monoclonal IgG anticardiolipin antibody from a patient with

the antiphospholipid syndrome is thrombogenic in mice. Proc Natl Acad Sci USA

93:8606-8611, 1996.

4. Lu E.W., Deftos M., Tighe H., Carson D.A., Chen P.P.. Generation and characterization of

two monoclonal self-associating IgG rheumatoid factors from a rheumatoid synovium.

Arthritis Rheum 35:101-105, 1992.

5. Chen P.P., Houghten R.A., Fong S., Rhodes G.H., Gilbertson T.A., Vaughan J.H., Lerner

R.A., Carson D.A. Anti-hypervariable region antibody induced by a defined peptide. A new

approach for studying the structural correlates of idiotypes. Proc Natl Acad Sci USA

81:1784-1788, 1984.

6. Chen P.P., Nitecki D.E., Lewis G.K., Goodman J.W. Antigen structural requirements for

immunoglobulin isotype switching in mice. J Exp Med 152:1670-1683, 1980.

http://www.ncbi.nlm.nih.gov/pubmed/20368576


33

From Autoantibodies to Potentially Therapeutic Antibodies against HIV

Po-Jen Chen

In 2005, Haynes et al. showed that two broadly neutralizing human monoclonal antibodies (mAbs)

against HIV-1 envelope glycoprotein 41 (gp41; 2F5 and 4E10) were polyspecific autoantibodies.

In particular, both reacted with the phospholipid cardiolipin [1]. Subsequently, it was found that

four human anti-phospholipid mAbs (PGN632, P1, IS4, and CL1, including three from patients

with the antiphodpholipid syndrome) inhibited HIV-1 CCR5-tropic (R5) primary isolate infection

of peripheral blood mononuclear cells (PBMCs) with 80% inhibitory concentrations of <0.02 to

approximately 10 microgram/ml [2]. Anti-phospholipid mAbs inhibited PBMC HIV-1 infection

in vitro by mechanisms involving binding to monocytes and triggering the release of MIP-1alpha

and MIP-1beta. Recently, a patient with systemic lupus erythematosus (SLE) and

HIV-1-infection was found to have controlled viral load (<5,000 copies/ml). Serological analysis

revealed that this patient’s plasma neutralized 41/42 (97.6%) HIV-1 strains tested [3]. When the

memory B cells from this individual were used to generate mAbs, a broadly neutralizing mAb

(bnmAb), CH98, was obtained. The mAb targeted the CD4 binding site (CD4bs) of HIV-1

envelope gp120. CH98 also bound to human antigens including double-stranded DNA (dsDNA),

a hallmark autoantibody of SLE. Taken together, these findings show that broadly neutralizing

anti-HIV mAb may be more readily obtained from HIV-1-infected individuals with autoimmune

diseases.

1. Bonsignori et al. An autoreactive antibody from an SLE/HIV-1 individual broadly neutralizes

HIV-1. J Clin Invest 124:1835, 2014.

2. Moddy et al. Anti-phospholipid human monoclonal antibodies inhibit CCR5-tropic HIV-1 and

induce beta-chemokines. J Exp Med 207:763, 2010.

3. Haynes et al. Cardiolipin polyspecific autoreactivity in two broadly neutralizing HIV-1

antibodies. Science 308:1906, 2005.

34

Session III Speaker

Jeffrey J MOLLDREM Professor and Chief, Section of Transplantation Immunology, Department


Medicine, University of Texas, MD Anderson Cancer Center, Houston, USA

([email protected])

Experience

7/1993-7/1997 BMT Fellowship, National Heart, Lung & Blood Institute, National

Institutes of Health (NIH), Bethesda, MD, USA

7/1993-7/1996 Clinical Associate and Post-doctoral Fellow, National Heart, Lung and

Blood Institute and National Cancer Institute, Bethesda, MD, USA

6/1990-5/1993 Internal Medicine Residency, University of California, Los Angeles, CA,

USA

3/1990 M.D., Univ. of Minnesota, Minneapolis-St. Paul, MN, USA

3/1986 B.A., Moorhead State University, Moorhead, MN, USA

Personal Statement

The long-term goals of my lab are to understand how immunity to hematopoietic cells is mediated

and regulated, and to develop novel immunotherapies that target hematological malignancies. We

found T cells suppress effective hematopoiesis in patients with myelodysplastic syndrome, and

showed ATG restored cytopenia in patients by reducing autoreactive T cells. We identified PR1 as

an HLA-A2-restricted leukemia-associated self-antigen and determined that self-renewing

PR1-specific CD8+ memory T cells contribute to long-term cytogenetic remission of CML.

Conversely, high PR1-expressing leukemia shapes host immunity by deleting high avidity

PR1-specific T cells, enabling leukemia outgrowth. Recently, peptide vaccine-induced immunity

to PR1 with objective clinical response was observed in low leukemia burden patients. To treat

high leukemia burden, we developed a T cell receptor-like monoclonal antibody that binds a

conformational epitope of PR1/HLA-A2 on the cell surface, which mediates specific lysis of AML

blasts and leukemia stem cells.

Positions and Employment

2014-present Scientific Director, Oncology Research for Biologics and Immunotherapy

Translation (ORBIT), UT MD Anderson Cancer Center, Houston, TX

2011-present Program Co-Leader, Cancer Center Support Grant (CCSG),

Clinical/Translational Thematic Programs, Stem Cell Transplantation and

Cellular Therapy, UT MD Anderson Cancer Center, Houston, TX

2011-present Program Co-leader, Cancer Center Support Grant (CCSG), Basic Science

Programs, Immunology, UT MD Anderson Cancer Center, Houston, TX

2006-present Virginia H. Cockrell Distinguished Professorship in Immunology, UT MD

Anderson Cancer Center, Houston, TX

2005-present Professor (tenured), Department of Stem Cell Transplantation and Cellular

Therapy, Division of Cancer Medicine, UT MD Anderson Cancer Center,

35

Houston, TX

2003-present Co-Director, Center for Cancer Immunology Research (CCIR), Department of

Stem Cell Transplantation and Cellular Therapy, UT MD Anderson Cancer

Center, Houston, TX

2001-2005 Associate Professor (tenured), Department of Stem Cell Transplantation and

Cellular Therapy, Division of Cancer Medicine, UT MD Anderson Cancer

Center, Houston, TX

1998-present Associate Medical Director, Bone Marrow Transplant Lab, Department of Stem

Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, UT

MD Anderson Cancer Center, Houston, TX

1998-present Faculty (tenure track), UT Graduate School for Biomedical Sciences, Program in

Immunology, Houston, TX

1997-2001 Assistant Professor (tenure track), Department of Stem Cell Transplantation and

Cellular Therapy, Division of Cancer Medicine, UT MD Anderson Cancer

Center, Houston, TX

1996-1997 Attending Physician, Hematology Branch, NHLBI, NIH, Bethesda, MD

Other Experience and Professional Memberships

2012-present Scientific Advisory Board, Texas Cancer Vaccine, Dallas

2012-present Scientific Advisory Board, Baylor Institute for Immunology Research (BIIR),

Houston, TX

2010-present Scientific Advisory Board, Gabrielle's Angel Foundation for Cancer Research,

New York, NY

2004-2009 Founder and Director, Scientific Advisory Board, The Vaccine Company,

Houston, TX

2003-2014 International Scientific Advisory Committee, Jose Carreras International

Leukaemia Foundation, Barcelona, Spain

2002-2007 Medical Advisory Board, Aplastic Anemia and Myelodysplasia Foundation, Inc.

(AA&MDSIF), Annapolis, MD

Honors

2015 Robert M. Chamberlain Distinguished Mentor Award Nominee, MD Anderson

Cancer Center

2015 President's Recognition for Faculty Excellence, MD Anderson Cancer Center

2014 Fellow, American Association for the Advancement of Science

2013 Robert M. Chamberlain Distinguished Mentor Award Nominee, MD Anderson

Cancer Center

2009 American Society of Clinical Investigators

2007 Division of Cancer Medicine Mentor Award, Fellowship Program, MD Anderson

Cancer Center

2003 Julie and Ben Rogers Award for Excellence, MD Anderson Cancer Center

2001 Faculty Scholar Award, The University of Texas MD Anderson Cancer Center

Contribution to Science

1. Reported the discovery of PR1 as the first leukemia-associated antigen, which is targeted by

CD8+ T lymphocytes that preferentially kill leukemia, but not normal bone marrow cells.

Established biological and clinical validation of the PR1 leukemia-associated antigen by

showing that CD8+ T lymphocyte immunity to PR1 induces complete cytogenetic remission

by chronic myelogenous leukemia. Determined an important mechanism of how leukemia

36

escapes immune surveillance through the deletion of high-avidity leukemia-reactive CD8+ T

lymphocytes by leukemia that over-expresses leukemia-associated antigens, which results in

unchecked growth of leukemia. Blood 88(7):2450-7, 1996; PubMed PMID:8839835; Nat Med.

6(9):1018-23, 2000; PubMed PMID:10973322; J Clin Invest. 111(5):639-47, 2003; PubMed

PMID:12618518; PubMed Central PMCID:PMC151894.

2. Demonstrated that adoptive cell transfer of a limited number of PR1-specific CD8+ T

lymphocytes reduces or eliminates human AML cells in xenograft models. Further, a small,

circulating population of memory leukemia-specific T lymphocytes that self-renew mediate

long-term cytogenetic and molecular remission of CML after treatment. This study showed the

critical role of a long-lived specific anti-leukemia immune response in maintaining sustained

molecular remission of leukemia. PLoS One 5(7):e11770, 2010; PubMed PMID:20668669;

PubMed Central PMCID:PMC2909896; Cytotherapy 12(8):1056-62, 2010; PubMed


3. Initial report of our development of a T cell receptor-like monoclonal antibody (8F4)

recognizes PR1 in the context of HLA-A2 and is highly active against Acute Myeloid

Leukemia (AML) and leukemia-initiating cells. 8F4 is currently in development as a

first-in-class antibody for clinical use. Blood 117(16):4262-72, 2011; PubMed


4. Established that hematopoietic antigens derived from tumor-associated neutrophils are

cross-presented on non-hematopoietic solid tumors as novel target antigens that induce

susceptibility to antigen-specific immunotherapies. Cancer Res. 72(13):3153-62, 2012;

PubMed PMID:22564522; PubMed Central PMCID:PMC3397251; J Immunol.

189(11):5476-84, 2012; PubMed PMID:23105141; PubMed Central PMCID:PMC3504175.

http://www.ncbi.nlm.nih.gov/pubmed/8839835/



http://www.ncbi.nlm.nih.gov/pmc/articles/PMC151894/










37

T Cell Receptor-Like Antibody 8F4 Targets Leukemia

and Non-Hematopoietic Cancer

Jeffrey Molldrem, Anna Sergeeva, Helen He, Amanda Herrmann, Tian-Hui Yang, Celine

Kerros, Haley Peters, Jin Im, Sapna Parshottam, Sijie Lu, Qing Ma, Karen Dwyer, Elizabeth

Mittendorf, and Gheath Alatrash.

Section of Transplantation Immunology, Department of Stem Cell Transplantation and

Cellular Therapy, the University of Texas M. D. Anderson Cancer Center, Houston, TX,

USA.

Adaptive anti-tumor immune surveillance of leukemia, called the graft-versus-leukemia (GVL)

effect in the setting of allogeneic stem cell transplantation (alloSCT), is responsible for inducing

and maintaining long term remission. However, although donor T cells mediate GVL, they also

mediate graft-versus-host disease (GVHD), which results in significant morbidity and can be fatal,

and is thus a substantial barrier to the more widespread application of alloSCT for many patients

with hematological malignancies. CD8 T cells are activated by cognate peptide/MHC-I target cell

antigens through binding of clonally unique αß-heterodimer T cell receptors (TCRs) on the cell

surface. Thus, because GVL and GVHD target antigens can be unique, immunotherapy strategies

that target GVL antigens such as adoptively transferred T cells could be developed to mediate

GVL without GVHD. Likewise, TCR-like monoclonal antibodies (mAbs) that similarly bind to

peptide/MHC-I also could be useful as novel immunotherapeutic agents to mediate GVL in the

absence of cellular therapies. Moreover, if potent anti-tumor activity was mediated by such

TCR-like mAbs, they could have advantages over adoptively transferred donor T cells, including

easier standardized manufacturing, ease of dose and scheduled administration, and they could be

given to patients in the absence of an alloSCT. We identified PR1, an HLA-A2-restricted 9-mer

peptide a peptide derived from aberrantly expressed proteinase 3 (P3) and neutrophil elastase (NE)

in myeloid leukemia, as a leukemia-associated target antigen for CD8 T cells that mediate GVL.

PR1-specific CD8 T cells target HLA-A2+ AML, CML and MDS but not normal hematopoietic

cells and they contribute to cytogenetic and molecular remission of myeloid leukemia. We

developed a murine TCR-like mAb that binds to PR1/HLA-A2 (8F4) and showed that 8F4

mediated complement-dependent cytotoxicity (CDC) of AML, CML and MDS progenitor cells

and blasts, but not normal bone marrow cells. Because 8F4 did not eliminate normal human

hematopoietic cells in a xenograft model, we humanized 8F4 to an IgG1 isotype (h8F4). In AML

PDX models, 8F4 and h8F4 eliminated HLA-A2+ AML and leukemia stem cells (LSCs). In

preclinical safety models, only mild reversible blood cytopenia was observed after multiple-dose

IV administration of high-dose 8F4. Based on these findings, h8F4 is being developed for a

first-in-human phase I safety study in HLA-A2+ patients with high-risk AML. In addition, 8F4

also mediated lysis of many non-hematopoietic cancers due to PR1 cross-presentation on surface

HLA-A2, which increased cancer cells susceptibility to 8F4-mediated lysis. Therefore, 8F4 also

could be tested for the treatment of non-hematopoietic HLA-A2+ cancers such as breast cancer,

non-small cell lung cancer, and colon cancer.

38

Session III Speaker

Alice YU




([email protected])

Dr. Alice Yu is a Distinguished Professor & Co-Director of the Institute of Stem Cell & Cancer

Translational Research in Chang Gung Memorial Hospital at Linko, Taiwan, and a Professor

Emeritus at the University of California in San Diego. Formerly she was the Chief of Pediatric

Hematology/Oncology at the University of California in San Diego, and Distinguished Research

Fellow and Deputy Director of the Genomics Research Center of Academia Sinica in Taiwan.

Dr. Yu received her MD at the National Taiwan University Medical College, and a PhD in

microbiology/ immunology at University of Chicago. She had received “Key to Life” Award from

the Leukemia & Lymphoma Society, the 19th Wang Min-Ning Memorial Award for Outstanding

Contribution to the Development Mediccal Sciene and Technology, National Health and Society,

and the 55th Academic Award from the Ministry of Education, Taiwan. She is a pioneer in

GD2-targeted immunotherapy of neuroblastoma who led the development of a monoclonal

anti-GD2 antibody, ch14.18, from preclinical studies to IND, phase I through phase III studies. It

culminated in a remarkable improvement in the event free survival leading to approval by FDA

and European Commission. This is the first antibody targeting a glycolipid shown to be effective

for cancer immunotherapy. Her recent research focused on other glycan-targeted cancer

immunotherapy in breast cancer, the biology of breast cancer stem cells and identification new

markers for breast cancer.

Relevant publications in past 5 years

1. Lin H.H, Lee H.W, Lin R.J., Huang C.W., Liao Y.C., Chen Y.T., Fang J.M., Lee T.C., Yu A.

L., and Chang H.C. Tracking and finding slow-proliferating/quiescent cancer stem cells with

fluorescent nanodiamonds. Small 2015, (In press).

2. Cheng J.Y., Wang S.H., Lin J., Tsai Y.C., Yu J., Wu J.C., Hung J.T., Lin J.J., Wu Y.Y., Yeh

K.T., and Yu A.L.* Globo-H ceramide shed from cancer cells triggers translin-associated

factor X-dependent angiogenesis. Cancer Research 74:6856-66, 2014.

3. Lin J.J., Huang C.S., Yu J., Liao G.S., Lien H.C., Hung J.T., Lin R.J., Chou F.P., Yeh K.T., Yu

A.L.* Malignant phyllodes tumors display mesenchymal stem cell features and aldehyde

dehydrogenase/disialoganglioside identify their tumor stem cells. Breast Cancer Research

16(2): R29, 2014.

4. Huang J.R., Tsai Y.C., Chang Y.J., Wu J.C., Hung J.T., Lin K.H., Wong C.H., Yu A.L.*

alpha-Galactosylceramide but not phenyl-glycolipids induced NKT cell anergy and

IL-33-mediated myeloid-derived suppressor cell accumulation via upregulation of egr2/3. J

Immunol 192(4): 1972-1981, 2014.

5. Tsai Y.C., Huang J.R., Cheng J.Y., Lin J.J., Hung J.T., Wu Y.Y., Yeh K.T., Yu A.L. A

Prevalent Cancer Associated Glycan, Globo H Ceramide, Induces Immunosuppression by

Reducing Notch1 Signaling. Journal of Cancer Science & Therapy 5:264-270, 2013.

39

6. Huang Y.L., Hung J.T., Cheung S.K., Lee H.Y., Chu K.C., Li S.T., Lin Y.C., Ren C.T., Cheng

T.J., Hsu T.L., Yu A.L.*, Wu C.Y.*, Wong C.H.* Carbohydrate-based vaccines with a

glycolipid adjuvant for breast cancer. Proc Natl Acad Sci USA 110(7):2517-2522, 2013.

7. Matthay K.K.*, George R.E., Yu A.L. Promising therapeutic targets in neuroblastoma. Clin

Cancer Res 18(10):2740-2753, 2012.

8. Wu T.N., Lin K.H., Chang Y.J., Huang J.R., Cheng J.Y., Yu A.L.*, Wong C.H.* Avidity of

CD1d-ligand-receptor ternary complex contributes to T-helper 1 (Th1) polarization and

anticancer efficacy. Proc Natl Acad Sci USA 108(42):17275-17280, 2011.

9. Yu A.L.*, Gilman A.L., Ozkaynak M.F., London W.B., Kreissman S.G., Chen H.X., Smith M.,

Anderson B., Villablanca J.G., Matthay K.K., Shimada H., Grupp S.A., Seeger R., Reynolds

C.P., Buxton A., Reisfeld R.A., Gillies S.D., Cohn S.L., Maris J.M., Sondel P.M. Anti-GD2

antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med

363(14) :1324-1334, 2010.

40

Development of Antibodies Directed against Cancer Associated Glycans

Alice Yu

Although aberrant glycosylation is a feature of cancer cells, all approved cancer immunotherapeutics

target proteins but not glycans, until recently. The approval of Unituxin (dinutuximab), a chimeric

monoclonal antibody targeting GD2, ch14.18, for the treatment of patients with high-risk

neuroblastoma by US FDA on March 10, 2015 and European Commission on August 17, 2015,

marks the first new agent targeting a non-protein glycolipid molecule, thereby widening the net of

potential pharmaceutical targets. It is also the first agent approved for therapy aimed specifically for

neuroblastoma. In fact, there had been only two initial FDA approvals for drugs to treat any pediatric

cancer - Erwinase and clofarabine. The remaining new drugs were first approved for adult cancers

and then trickled down to children. The development history of Unituxin is also quite unique.

Usually, after the initial discovery of a new drug, it is steered by pharmaceutical companies, which

drive the development and execution of clinical trials. In the case of Unituxin, Dr. Yu had to take it

from the initial investigational new drug (IND) application all the way through the final randomized

phase III clinical trial. It started out as collaboration between Dr. Ralph Reisfeld at the Scripps

Research and Dr. Yu at UC San Diego, in the mid-1980s. The initial investigational new drug (IND)

for ch14.18 was submitted in 1989, 3 years before rituxan and Herceptin. In spite of promising

results in phase I and II clinical trials, no pharmaceutical company was willing to manufacture the

anti-GD2 antibody for the pivotal phase III clinical trial, because of the rarity of neuroblastoma. NCI

began producing the antibody for a randomized national phase III clinical trial, led by Dr. Yu under

the auspice of the NCI sponsored multicenter Children’s Oncology Group. This trial showed an

event-free survival at two years of 66% with Unituxin plus isotretinoin compared with 46% in

patients treated with isotretinoin alone (NEJM 2010). Overall survival was improved from 75% to

86% with the immunotherapy. After the announcement of the impressive phase III results, many

biotech companies competed and United Therapeutics Corporation obtained the rights and was

awarded a Rare Pediatric Priority Review Voucher. This was the second time such a voucher was

awarded, under the Creating Hope Act which was included in the FDA Reform Bill in 2011. These

vouchers allow the companies to expedite the review process for their more profitable drugs if

researching and developing drugs for rare diseases, such as childhood cancers. The strategies to

improve the efficacy and reduce the side effects of Unituxin and development of other

immunotherapeutics targeting potentially promising glycans, such as O-acetyl GD2 and Globo H will

be discussed.

41

Moderator: Dr. Han-Chung WU

Research Fellow and Deputy Director, Institute of Cellular and Organismic


16:40 - 17:05 Dr. An-Suei YANG

Research Fellow and Deputy Director, Genomics Research Center,


A High Throughput Antibody Engineering Platform for Discovering

and Optimizing Antibodies in Antibody-Guided Drug Delivery Systems

17:05 - 17:30 Dr. Tien-Lu CHENG



Proteases (MMP2/9) Enhance the Affinity and Therapeutic Efficacy of

Targeted Antibody

17:30 - 18:05 Dr. Hao CHEN

Director, BioProcess Development, Merck Research Laboratories,

Kenilworth, NJ, USA

Accelerated FIH (First-In-Human) for Mabs Enabled by Innovative

Bioprocess Strategy and Technologies


42

Session IV Moderator

Han-Chung WU

Research Fellows and Vice Director Institute of Cellular and Organismic


([email protected])

Dr. Wu is currently a Professor and the Vice Director of the Institute of Cellular and Organismic

Biology at Academia Sinica, Taiwan. He is also a Professor at the College of Medicine of the

National Taiwan University. His research interest focuses on the development of targeting drug

delivery systems for cancer therapy and targeting imaging. He has developed phage display

methods for the generation of fully human monoclonal antibodies and the identification of

peptides for a variety of target molecules; including neutralizing epitopes of dengue viruses,

disease-specific antigens from serum samples of dengue or SARS patients, surface markers for

cancer stem cells and stem cells, as well as liver, lung, breast and colon cancer cell-specific

peptide ligands for the development of ligand-targeted cancer therapy. His lab has also leveraged

this technology platform to select tumor homing peptide ligands for the development of

anti-angiogenic therapy.

Dr. Wu has published over 72 original articles, 45 patents, 8 Invited review articles or books, and

over 130 plenary, invited or conference contributions. He frequently serves as the reviewer for

the international journals and has received numerous awards; including Academia Sinica Young

Investigator award (中央研究院年輕學者研究著作獎) in 2008, Yung-Shing Investigator Award

(永信李天德醫藥科技獎) in 2010, Outstanding Research Award, National Science Council (國

科會傑出研究獎) in 2011, three times of National Innovation Awards (國家新創獎) in 2011,

2012 and 2013, and Taiwan Healthcare and Agricultural Biotech Industries Innovation and

Excellence Awards (生醫暨生農產業選秀大賽生醫組潛力新秀獎) in 2013. He is also the

editor for a number of journals; such as PLoS ONE, International Journal of Oncology, Clinical

Cancer Drugs, and The Open Breast Cancer Journal.

Dr. Wu is actively involved in basic and translational research in the areas of lung cancer, breast

cancer, colon cancer and hepatocellular carcinoma. During the course of his research, forty-five

patents have been filed as the results of our research. Twenty-three patents were successfully

granted and 8 of them were licensed out to the biotech/pharmaceutical companies for drug

development.

43

Session IV Speaker

An-Suei YANG Research Fellow and Deputy Director, Genomics Research Center,


([email protected])

Dr. Yang’s lab has implemented phage-based protein display systems in connection with

computational and bioinformatics methodologies harnessing the power of rapidly expanding

computing capabilities and high throughput experimental technologies for antibody/protein

engineering and antibody/protein design. The research directions are aiming at innovating

antibody/protein design and engineering technologies and understanding the biological function

of natural antibody repertoires with synthetic phage-displayed antibody libraries and

bioinformatics; the goal is to develop antibody-based molecules for important biomedical

applications. The works from

Dr. Yang’s group can be found in https://scholar.google.com.tw/citations?user=YBoSfnAAAAAJ&hl=en

https://scholar.google.com.tw/citations?user=YBoSfnAAAAAJ&hl=en

44

A High Throughput Antibody Engineering Platform for Discovering and

Optimizing Antibodies in Antibody-Guided Drug Delivery Systems

An-Suei Yang

Medicinal payloads effective in treating human diseases are frequently guided to specific sites

with antibodies conjugated to the payloads, but engineering antibodies with optimal capability in

guiding drug delivery is not trivial. In addition to the antibodies’ specificity and affinity to the

target antigens, the antibodies’ epitopes on the antigens are critical to the capability of the

antibodies in guiding the payloads to the desired sites. Attaining a wide variety of antibody

candidates targeting diverse epitopes on a target antigen has been difficult with conventional

monoclonal antibody technologies. Moreover, each of the antibody candidates has to be evaluated

at low throughput rate on the efficiency to deliver a medicinal payload. Consequently,

engineering optimal antibodies for the antibody-guided drug delivery systems has been

resource-intensive. Synthetic antibody repertoires can be advantageous over natural antibody

repertoires in generating antibodies suitable for antibody-guided drug delivery systems. We used

HER2 as a model antigen, for which antibodies selected in vitro from a phage-displayed synthetic

antibody library bound to the model antigen on diverse epitopes with high affinity and specificity.

To select the most effective antibody candidates to deliver a biological toxin to cells with

over-expressed HER2 on the cell surfaces, we have established adaptor systems specifically

coupled with the synthetic antibody repertoires; antibody candidates suitable for delivering the

biological toxin to the HER2-positive cancer cells can be readily screened with cell-based assay

in high throughput format. The results demonstrate that the synthetic antibody libraries and the

coupled adaptor systems constitute an effective technological platform capable of engineering

optimal antibodies for medicinal payload delivery.

45

Session IV Speaker

Tien-Lu CHENG



([email protected])

Job Titles

Distinguished Professor

Vice Dean, College of Medicine

Director of Graduate Institute of Medicine and Center for Biomarkers and Biotech Drugs,

Kaohsiung Medical University, Kaohsiung, Taiwan

Department of Biomedical Science and Environmental Biology, Kaohsiung Medical

University, Kaohsiung, Taiwan

Education

1995/8-1999/7 Ph.D. Graduate Institute of Life Science, Academia Sinica and National

Defense Medical Center, Taiwan

1991/8-1993/7 M.S. Institute of Microbiology and Immunology, National Defense Medical

Center, Taiwan

1987/9-1991/6 B.S. Department of Medical Technology, Kaohsiung Medical College,

Taiwan

Professional Experience

2013/03~2014/7, Chairman, Office for Operation of Industry-University Cooperation,

Kaohsiung Medical University

2011/08~2013/2, Chairman, Center for Promotion of Industry-University Cooperation,


2009/08~2011/07, Chairman, Department of Biomedical Science and Environmental

Biology , Kaohsiung Medical University

2008/08~, Professor, Department of Biomedical Science and Environmental Biology ,


Honors

2013 annual excellent research project funding, Kaohsiung Medical University, 2013 Award of

Excellent Paper, Kaohsiung Medical University, 2013 annual excellent technique transfer award,

Kaohsiung Medical University, 2013 annual excellent patent award, Kaohsiung Medical

University, the Second Prize of the 10th National Innovation Award- Student Research Contest by

the Institute for Biotechnology and Medicine Industry, the third Prize of the 10th National

Innovation Award- Student Research Contest by the Institute for Biotechnology and Medicine

Industry, the Third Prize of 9th 戰國策 Entrepreneurial Competition. The award of the 11th

National Innovation Award in the Academic Research Category by the Institute for

46

Biotechnology and Medicine Industry. 2014 Ministry of Science and Technology, Outstanding

Research Award

Selective publications in past 5 years

1. Kao C.H., Wang J.Y., Chuang K.H., Chuang C.H., Cheng T.C., Hsieh Y.C., Tseng Y.L.,

Chen B.M., Roffler S.R. *, Cheng T.L.*

One-step mixing with humanized antimPEG bispecific antibody enhances tumor accumulatio

n andtherapeutic efficacy of mPEGylated nanoparticles. Biomaterials 35(37):9930-40, 2014.

2. Chuang K.H., Kao C.H., Roffler S.R., Lu S.J., Cheng T.C., Wang Y.M., Chuang C.H., Hsieh

Y.C., Wang Y.T., Wang J.Y., Weng K.Y., Cheng T.L. Development of an Anti-Methoxy

Poly(ethylene glycol) (α-mPEG) Cell-Based Capture System to Measure mPEG and

mPEGylated Molecules. Macromolecules 47:6880-6888, 2014.

3. Su Y.C., Cheng T.C., Leu Y.L., Roffler S.R., Wang J.Y., Chuang C.H., Kao C.H., Chen K.C.,

Wang H.E., Cheng T.L.* PET Imaging of β-Glucuronidase Activity by an Activity-Based

124I-Trapping Probe for the Personalized Glucuronide Prodrug Targeted Therapy. Mol

Cancer Ther. 13(12):2852-63, 2014.

4. Cheng T.C., Roffler S.R., Tzou S.C., Chuang K.H., Su Y.C., Chuang, C.H., Kao C.H., Chen

C.S., Harn I.H., Liu K.Yi., Cheng T.L.*, Leu Y.L.* An Activity-Based Infrared Glucuronide

Trapping Probe for Imaging b-Glucuronidase Expression in Deep Tissues. J. Am. Chem. Soc.

134:3103−3110, 2012.

5. Chuang C.H., Chuang K.H., Wang H.E., Roffler S.R., Tzou S.C., Cheng T.C., Kao C.H., Wu

S.Y., Tseng W.L., Shiea J., Wang J.M.*, Cheng T.L.* In vivo PET Imaging of protease

activity by hydrophilic-to-hydrophobic conversion of a protease substrate. Clin Cancer Res.

18(1):238-247, 2012.

6. Chuang C.H., Wang W.J., Li C.F., Ko C.Y., Chou Y.H., Chuu C.P., Cheng T.L.*, Wang

J.M.*. The combination of the prodrugs perforin-CEBPD and perforin-granzyme B efficiently

enhances the activation of caspase signaling and kills prostate cancer. Cell Death Dis. 5:e1220,

2014.

7. Chuang K.H., Wang H.E., Cheng T.C., Tzou S.C., Cheng C.M., Kao C.H., Chuang C.H.,

Tseng W.L., Hung W.C., Tai M.H., Chang T.K., Chen B.M., Roffler S.R., Cheng T.L.*

Development of an Universal Anti-Polyethylene Glycol Reporter Gene for Noninvasive

Imaging of PEGylated Probes. Journal of Nuclear Medicine 51:933-941, 2010.

8. Chuang K.H., Tzou S.C., Chang Y.C, Kao C.H., Liao K.W., Cheng T.C., Huang B.J., Wu C.J.,

Tseng W.L., Shiea J., Chu P.Y., Roffler S.R., Cheng T.L.* Measurement of Free Polyethylene

Glycolby a Novel Cell-Based Anti-Polyethylene Glycol ELISA. Anal Chem. 82(6):2355-62,

2010.

9. Cheng T.L., Chuang K.H., Chen B.M., Roffler S.R. Analytical Measurement of PEGylated

Molecules. Bioconjug Chem. 23:81-899, 2012.

10. Chuang K.H., Wang H.E., Chen F.M., Tzou S.C., Cheng C.M., Chang Y.C., Tseng W.L.,

Shiea J., Lin S.R., Wang J.Y., Chen B.M., Roffler S.R., Cheng T.L.* Endocytosis of

PEGylated agents enhances cancer imaging and anti-cancer efficacy. Molecular cancer

therapeutics 9(6):1903-1912, 2010.

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Cheng%20TL%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Chuang%20KH%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Chen%20BM%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Roffler%20SR%22%5BAuthor%5D


47

Proteases (MMP2/9) Enhance the Affinity and Therapeutic Efficacy

of Targeted Antibody

Tien-Lu Cheng

Monoclonal antibody therapies apply to cancer, autoimmune diseases, inflammation and many

infectious diseases, etc. Based on monoclonal antibodies market statistics show that in 2010 the

global antibody labeled drugs total sales up to $ 43 billion, and the antibody will become most

potential biotech drugs. Its therapeutic mechanism of many anti-cancer antibody drugs for the

clinical use of high affinity antibody antigen, thereby blocking the growth of cancer cells

metabolic pathways. Therefore, we can improve antibody affinity binding force, the monoclonal

antibody drug treatment to achieve a breakthrough. Here, we provide the novel invention to

enhance the affinity of antibody to antigens, which improves the therapeutic effects and lower the

dosage used. Protease was used to cleavage the antibody for the enhancement its affinity, which

is attributed to the conformational changes at antibody-antigen interacting site. The methods we

used to enhance the antibody affinity included: 1. Antibody was treated with soluble protease. 2.

Antibody was digested by using protease conjugated column. 3. Recombinant antibody was

produced by genetic engineering. These methods not only enhance the binding affinity of tested

antibodies, improve the therapeutic efficacy, but also lower the dosage use. Based on the highly

conserve sequence among antibodies, we suggest that this invention is applicable to all of the

antibodies (antibody drugs) in markets for the affinity enhancement. This protease activation

technology could be applied to many clinical antibodies to enhance the affinity of antibodies to

antigens via ELIAS, for example: Erbitux, Herceptin, Humira, Remicade, Prolia, Yervoy,

Rituxan and Ilaris antibody. Based on a database included one thousand more sequence of

antibody, we calculated the specific substrate of protease almost 90% on antibody, and has high

conservation of sequence. We use MALDI-TOF MS to detect the substrate of protease cleavage

on antibody. So we initially found that protease enhanced antibody affinity and binding force due

to the cleavage on the antibody. Importantly, we also proved that the protease treatment can

enhance the in vitro and in vivo anti-tumor efficacy of Erbitux. In addition, this novel invention

has advanced global patent deployment and has applied for US provisional patent application and

through the Defense by Ministry of Science and Technology, committee of the bridge plan in

addition to promotes global Patent Cooperation Treaty (PCT).This innovative invention can apply

in enhancing mAb affinity of nowadays therapeutic antibodies, and provide more effective

treatment for patients. The novel method will not increase excessive pharmaceutical costs, and

only one simple step for treatment. This invention is most significantly applied in enhancing mAb

affinity of nowadays therapeutic antibodies, and is believed to possess immense commercial

value.

48

Session IV Speaker

Hao CHEN Director, BioProcess Development, Merck Research Laboratories,

Kenilworth, NJ, USA

([email protected])

Dr. Hao Chen is a Director in BioProcess Development at Merck Research Laboratories

(Kenilworth, NJ, USA). He currently manages the Upstream & Recovery Process Development

group, responsible for process development and scale-up, tech transfer, and initial process

characterization. His group supports both mammalian cell culture and microbial fermentation

projects from preclinical to commercial stage, including regulatory filings. Prior to Merck, he

worked on upstream process development and tech transfer for cell culture and fermentation in

various companies including Becton Dickinson (BD) and Amylin Pharmaceuticals.

Dr. Chen received his Ph.D. degree in Chemical Engineering from Purdue University. He also

holds an MS in Biochemical Engineering and a BS in Fine Chemical Engineering, from Zhejiang

University.

49

Accelerated First-In-Human for Mabs

Enabled by Innovative Bioprocess Strategy and Technologies

Hao Chen

Biologics including monoclonal antibodies is becoming the fastest growing area in

pharmaceutical industry due to their efficacy and safety profiles for unmet medical needs such as

oncology and autoimmune disease. Along with more competition, the new biologics development

is under more pressure to accelerate First in Human (FIH) trials. Traditionally, it takes 2 years or

even longer for CMC development from final cDNA to FIH. This timeline is reduced

significantly with recent progress in innovative technologies, such as high throughput automation,

single use technology, new medium, and perfusion based processes. Thoughtfully crafted strategy

to integrate these technologies and different functional areas can further reduce the development

timeline.

50

Closing Remarks

Fu-Tong LIU Distinguished Research Fellow and Director, Institute of Biomedical


([email protected])

51

香港分子儀器公司 Molecular Devices (Hong Kong) Limited

進階生物科技股份有限公司

Level Biotechnology Inc.

PALL Corporation

GE Healthcare Life Sciences

List of Sponsors

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Documents

Program draft v21 20151026 for web