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Dr. Sawsan Harfouch Andalus University
Annual Scientific Harvest 14/4/2015
Immunologic drugs
Immunotherapy is treatment that uses certain parts of a person‘s immune system to
fight diseases such as cancer. This can be done in a couple of ways.
Stimulating your own immune system to work harder or smarter to attack
cancer cells
Giving you immune system components, such as man-made immune system
proteins
In real, the recent advances in immunology and in the immuno-physiopathology have
led to better understanding of different mechanisms involved in various pathological
states such as the autoimmune diseases, tumor and graft rejection. Since then, doctors
have learned a great deal about how the immune system might be used to treat these
cases. This chapter describes the most important treatment mechanisms involved in
immunosuppression or immunostimulation.
Immunostimulants:
The most important immunostimulants used in therapy are cytokines. Cytokines are
used in the case of immunodeficiency, chronic infections, and cancer. The
disadvantage of these agents is the lack of specificity. They lead to a generalized
stimulation of the immune system which could be responsible for losing tolerance.
Cytokines are regulatory proteins or glycoproteins secreted by white blood cells.
These proteins assist in regulating the development of immune effector cells.
Cytokines are involved in a staggeringly broad array of biological activities including
innate immunity, adaptive immunity, inflammation, and hematopoiesis. They are
regulated by the presence of cytokine antagonists, which either bind directly to a
cytokine receptor but fail to activate the cell, or bind directly to a cytokine, inhibiting
its activity. This is the principle of most therapeutic monoclonal antibodies as we will
see.
The key therapeutic cytokines are:
- Hematopoietic factor: This cytokine causes the bone marrow to make more of
certain types of immune system cells and blood cells. A man-made version, known as
Dr. Sawsan Harfouch Andalus University
Annual Scientific Harvest 14/4/2015
sargramostim (Leukine®), is often used to boost white blood cell counts after
chemotherapy.
GM-CSF is also being tested against cancer as a non-specific immunotherapy and as
an adjuvant given with other types of immunotherapies. Clinical trials of GM-CSF,
alone or with other immunotherapies, are being done in people with many different
types of cancer.
Common side effects of GM-CSF include flu-like symptoms (fever, headaches,
muscle aches), rashes, facial flushing, and bone pain.
- IL-2: IL-2 has a central role in the clonal proliferation of T cells. (IL-2) helps
immune system cells grow and divide more quickly. A man-made version of IL-2 is
approved to treat advanced kidney cancer and metastatic melanoma. IL-2 can be
used as a single drug treatment for these cancers, or it can be combined with
chemotherapy or with other cytokines such as interferon-alfa. Using IL-2 with these
treatments might help make them more effective against some cancers, but the side
effects of the combined treatment are also increased. A related drug known as
denileukin diftitox (Ontak®) is an immune system protein known as interleukin-2
(IL-2) attached to a toxin from the germ that causes diphtheria, which makes it useful
for delivering the toxin to the cells that have Il-2 receptor.
Side effects of IL-2 can include flu-like symptoms such as chills, fever, fatigue, and
confusion. Most people gain weight. Some have nausea, vomiting, or diarrhea. Many
people develop low blood pressure, which can be treated with other medicines. Rare
but potentially serious side effects include an abnormal heartbeat, chest pain, and
other heart problems. Because of these possible side effects, if IL-2 is given in high
doses, it must be done in a hospital.
Interferons: Three main classes are identified: IFN- α, and IFN- β, both are of
leukocyte and fibroblast origin, and IFN- γ which is produced by activated T
lympocytes and NK cells. They help the body resist virus infections and cancers. Only
IFN-alfa is used to treat cancer. It boosts the ability of certain immune cells to attack
cancer cells. It may also slow the growth of cancer cells directly, as well as the blood
vessels that tumors need to grow.
Dr. Sawsan Harfouch Andalus University
Annual Scientific Harvest 14/4/2015
The FDA has approved IFN-alfa for use against these cancers: Hairy cell leukemia
Chronic myelogenous leukemia (CML), Follicular non-Hodgkin lymphoma,
Cutaneous (skin) T-cell lymphoma, Kidney cancer, Melanoma, Kaposi sarcoma
IFN- β is indicated in multiple Sclerosis at high doses. And IFN- γ is used in chronic
lymphogranuloma.
Side effects of interferons can include flu-like symptoms (chills, fever, headache,
fatigue, loss of appetite, nausea, vomiting), low white blood cell counts (which
increase the risk of infection), skin rashes, and thinning hair. These side effects can be
severe and can make treatment with interferon hard for many people to tolerate. Most
side effects don‘t last long after the treatment stops, but fatigue can last longer. Other
rare long-term effects include damage to nerves, including those in the brain and
spinal cord.
Immunosuppressants:
The modulation of immune responses has been considered as a treatment target,
especially in the situations where the immune system has been proved to be involved.
The immune-suppression is sought mainly in the case of organ transplantation and
auto-immune diseases to prevent the immune system from attacking the transplanted
organ, or self tissue
Immunosuppressants are classified in four principal groups:
Cyclosporine and tacrolimus: Cyclosporine is used in organ transplantation in
combination with corticosteroids. Cyclosporine and tacrolimus selectively inhibit
transcription of interleukin (IL)-2 and several other cytokines, mainly in T-helper
lymphocytes.
Glucocorticoids: They are very commonly used to prevent organ reject in the case
of transplantation. They have specific effects on macrophages and T lymphocytes.
On the other hand, they have non specific anti-inflammatory and
immunosuppressive effects.
Cytotoxic agents:
Dr. Sawsan Harfouch Andalus University
Annual Scientific Harvest 14/4/2015
Alkylants agents: They act by forming liaisons with nucleotides in the DNA chain,
inhibiting the replication. Cyclophosphamide is one of the most important agents in
this group, it inhibits B lymphocytes.
Anti-metabolite agents (antifolic): The methotrexate is a folate analogue which has
higher affinity for dihydrofolate reductasete. This competition leads to the
interruption of DNA synthesis. This group also includes: Azathioprine: a potent
mitotic inhibitor, which is often given just before and after transplantation to diminish
T-cell proliferation in response to the alloantigens of the graft, and mycophenolate
that inhibits DNA transcription in T and B cells, thus inhibiting the division of these
cells. It is indicated to prevent transplant reject.
Monclonal Antibodies:
Therapeutic antibodies have rapidly become a clinically important drug class: more
than 36 antibodies are approved for human therapy and more than 240 antibodies are
currently in clinical development worldwide for a wide range of diseases, including
autoimmunity and inflammation (Infliximab, Natalizumab, Tocilizumab), cancer
(Alemtuzumab, Rituximab, Bevacizumab), organ transplantation (Basiliximab,
muromonab, Daclizumab), cardiovascular disease (Abciximab), and infectious
diseases (Palivizumab). The clinical success of antibodies has led to a major
commercial impact, with rapidly growing annual sales that exceeded US$50 billion in
2012, and growing rate estimated more than 8% in 2016.
Antibodies are the antigen-binding proteins present on the B-cell membrane and
secreted by plasma cells. Membrane-bound antibody confers antigenic specificity on
B cells; antigen-specific proliferation of B-cell clones is elicted by the interaction of
membrane antibody with antigen. Secreted antibodies circulate in the blood, where
they serve as the effectors of humoral immunity by searching out and neutralizing
antigens or marking them for elimination. All antibodies share structural features,
bind to antigen, and participate in a limited number of effector functions.
Dr. Sawsan Harfouch Andalus University
Annual Scientific Harvest 14/4/2015
Structure of Antibodies:
Antibody molecules have a common structure of four peptide chains (Figure 1). This
structure consists of two identical light (L) chains, polypeptides of about 25,000
molecular weight, and two identical heavy (H) chains, larger polypeptides of
molecular weight 50,000 or more. Each light chain is bound to a
heavy chain by a disulfide bond, and by such noncovalent interactions as salt linkages,
hydrogen bonds, and hydrophobic bonds, to form a heterodimer (H-L).
Similar noncovalent interactions and disulfide bridges link the two identical heavy
and light (H-L) chain combinations to each other to form the basic four-chain (H-L)2
antibody structure, a dimer of dimers.
The exact number and precise positions of these interchain disulfide bonds differs
among antibody classes and subclasses. The first 110 or so amino acids of the amino-
terminal region of a light or heavy chain varies greatly among antibodies of different
specificity. These segments of highly variable sequence are called V regions:VL in
light chains and VH in heavy. All of the differences in specificity displayed by
different antibodies can be traced to differences in the amino acid sequences of V
regions. In fact, most of the differences among antibodies fall within areas of the V
regions called complementarity-determining regions (CDRs), and it is these CDRs, on
both light and heavy chains, that constitute the antigenbinding site of the antibody
molecule.
By contrast, within the same antibody class, far fewer differences are seen when one
compares sequences throughout the rest of the molecule. The regions of relatively
constant sequence beyond the variable regions
have been dubbed C regions, CL on the light chain and CH on the heavy chain.
Schematic diagram of structure of immunoglobulins derived from amino acid
sequencing studies.
Dr. Sawsan Harfouch Andalus University
Annual Scientific Harvest 14/4/2015
Mode of action:
Monoclonal antibodies can have various modes of actions in vitro, and the actual
mode of action once injected in patients is not always clear. The simplest mode of
action is mere binding of the antibody to its antigen, thereby interfering with its
activity and interaction with binding partners. The antigen can be a soluble ligand,
and examples of such antibodies include infliximab, adalimumab and certolizumab
(anti-TNFa) or bevacizumab (anti-vascular endothelial growth factor). On the other
hand, the antibody may target a receptor displayed at the cell surface, block its
interaction with a ligand, interfere with a multimerization process or trigger
internalization of receptors or apoptosis of targeted cells. Examples of such antibodies
include cetuximab and panitumumab [anti-EGFR (epidermal growth factor receptor)
or HER1 (human epidermal growth factor receptor)] and trastuzumab (anti-HER2).
Clinical applications:
Monoclonal antibodies have important clinical uses, they are proving to be very
useful as diagnostic, imaging, and therapeutic reagents in clinical medicine.
Initially,monoclonal antibodies were used primarily as in vitro diagnostic reagents.
Among the many monoclonal antibody diagnostic reagents now available are products
for detecting pregnancy, diagnosing numerous pathogenic microorganisms, measuring
the blood levels of various drugs, matching histocompatibility antigens, and detecting
antigens shed by certain tumors.
Radiolabeled monoclonal antibodies can also be used in vivo for detecting or locating
tumor antigens, permitting earlier diagnosis of some primary or metastatic tumors in
Dr. Sawsan Harfouch Andalus University
Annual Scientific Harvest 14/4/2015
patients. For example, monoclonal antibody to breast-cancer cells is labeled with
iodine-131 and introduced into the blood to detect the spread of a tumor to regional
lymph nodes. This monoclonal imaging technique can reveal breast-cancer metastases
that would be undetected by other, less sensitive
scanning techniques.
Production of monoclonal antibodies:
History
The production of MAbs by hybridoma technology was discovered in 1975 by
Georges Kohler of West Germany and Cesar Milstein of Argentina, who jointly with
Niels Kaj Jerne of Denmark were awarded the Nobel Prize for Physiology and Medi-
cine in 1984. In 1976, Kohler and Milstein developed a technique to fuse splenocyte
cells (separated from the spleen of an immunized mouse) with tumorous myeloma
cells. The hybrid cells were clones of antibody producing cells against a desired
antigen and propagate rapidly to produce very large amounts of antibody. The
hybridoma is capable of rapid propagation and high antibody secreting rates such as
in myeloma cells, which can maintain the antibody genes of mouse spleen cells. In
1988, Greg Winter used the first humanized MAbs to avoid reactions/responses
observed in patients injected with murine derived MAbs
Generation of fully human monoclonal antibodies
While the production of murine MAbs is routine, the production of human MAbs by
conventional hybridoma technology has been difficult because human hybridomas
and immortalized cell lines do not stably produce high levels of antibody and in vivo
immunization of humans is not feasible for many antigens. However, the development
of methods for the expression of antibody fragments such as Fab or ScFv in bacteria
and the display of antibody fragments on filamentous bacteriophage as well as
powerful techniques for the screening of antibody libraries made it possible to
generate human MAbs. This phagedisplay technology is the most used and well-
established technology for the development of new human antibodies. As an
alternative strategy for producing human MAbs, transgenic mice containing human
immunoglobulin germ line locus are used. Immunization of such transgenic mice
results in a human antibody response, from which hybridomas that produce human
Dr. Sawsan Harfouch Andalus University
Annual Scientific Harvest 14/4/2015
antibodies can be generated, as in traditional hybridoma technology. In 2002, the first
human MAb, Humira, developed by phage display, was approved by the FDA and
marketed.
Chimeric, humanized and human antibodies:
A major application of antibody engineering was the possibility to create chimeric
antibodies. The binding activity of IgG molecules is generated by the variable
domains of the heavy and light chains. As antibodies are well conserved through
evolution, it was possible to create chimeras by fusing murine variable domains,
responsible for the binding activity, with human constant domains leading to the
development of a new generation of therapeutic candidates.
These chimeric antibodies are 70% human and possess a fully human Fc portion,
which makes them considerably less immunogenic in humans and allows them to
interact with human effector cells and the complement cascade. With the development
of antibody engineering techniques, it became possible to decrease even further the
murine part of mAbs by replacing the hypervariable loops of a fully human antibody
with the hypervariable loops of the murine antibody of interest, using an approach
called complementarity-determining region grafting.
These antibodies, called ‗humanized‘, are 85–90% human and are even less
immunogenic than chimeric antibodies. However, complementarity-determining
region grafting is more technically demanding than a mere fusion, and directed
mutagenesis approaches are often needed to restore the affinity present in the murine
parental antibody (Figure 2). Most of the approved mAbs in current use are either
chimeric or humanized .
Another major improvement came with the development of in vitro selection
methods, the most successful one being phage display. With the ever increasing
power of antibody engineering, it became possible to clone entire repertoires of
antibody fragment genes, from immunized or nonimmunized animals, including
humans. A powerful selection method was therefore needed to select from this large
number of potential ligands, those able to bind the antigen of choice. Because of these
in vitro selection methods, it is now possible to rapidly
and efficiently select fully human antibody fragments against virtually any antigen by
using ‗universal‘, large, non-immunized libraries.
Dr. Sawsan Harfouch Andalus University
Annual Scientific Harvest 14/4/2015
Conjugated/loaded/labeled MAbs:
Conjugated MAbs are coupled with drugs and toxins and radioactive atoms are used
as delivery vehicles to Monoclonal antibodies take these substances through the body.
MAbs act as a homing device, circulating in the body until it finds a cancer cells with
a matching antigen. It delivers the toxic substance to site of body where it is needed
the most. This minimizes damage to other parts of the body. During chemotherapy,
the delivered drugs caused damage to tumor and normal tissues. During chemotherapy,
MAbs are conjugated with chemotherapeutic drugs and are known as chemo-labeled
antibodies. Currently, FDA approved chemolabeled antibodies for treating cancer are
brentuximab vedotin and ado-trastuzumab emtansine.
When conjugated with toxins (poisonous substance derived from plants or bacteria),
the antibodies are known as immune-toxins. Immune-toxins composed of tumor-
specific monoclonal antibodies coupled to lethal toxins are potentially valuable
therapeutic reagents. The toxins used in preparing immune-toxins include ricin,
Shigella toxin, and diphtheria toxin, all of which inhibit protein synthesis. These
toxins are so potent that a single molecule has been shown to kill a cell. Each of these
toxins consists of two types of functionally distinct polypeptide components, an
inhibitory (toxin) chain and one or more binding chains,which interact with receptors
on cell surfaces; without the binding polypeptide(s) the toxin cannot get into cells and
therefore is harmless.
An immune-toxin is prepared by replacing the binding polypeptide(s) with a
monoclonal antibody that is specific for a particular tumor cell. In theory, the attached
monoclonal antibody will deliver the toxin chain specifically to tumor cells, where it
Dr. Sawsan Harfouch Andalus University
Annual Scientific Harvest 14/4/2015
will cause death by inhibiting protein synthesis. The initial clinical responses to such
immunotoxins in patients with leukemia, lymphoma, and some other types of cancer
have shown promise, and research to develop and demonstrate their safety and
effectiveness is underway.
Naming convention for antibodies
The names are essentially split into four parts: (1) a unique prefix; (2) affix letters
identifying the type of target; (3) affix letters indicating the original source of the
variable chains, e.g. human, mouse, etc. as well as how those V-regions are
engineered, as noted above, e.g. chimeric, humanized, or fully human; and (iv) the
suffix ―mab‖. Hence, for golimumab, ―go‖ serves as the unique prefix, ―lim‖ refers to
an immune system target, ―u‖ refers to the fact that it contains fully human sequences,
and then ―mab.‖ An additional word may be included in the name to describe a small
molecule or toxin conjugate, e.g. gemtuzumab ozogamicin, whereby ―ozogamicin‖
refers to the calicheamicin (small molecule toxin) conjugate. The name for Ortho
Biotech‘s anti-CD3 monoclonal antibody, muromonab-CD3, was given prior to the
development of antibody naming convention, so its name does not follow the
convention. Muromonab-CD3 stands for ―murine monoclonal antibody targeting
CD3.‖
Dr. Sawsan Harfouch Andalus University
Annual Scientific Harvest 14/4/2015
Market for MAbs
In 2001, the MAbs that had hit the market in the 1997–1998 timeframe, were still just
getting off the ground in terms of sales. By 2010, however, all biologics combined for
sales of more than $107 bn, more than 300% growth in eight years, driven by the
rapid increase in the market for MAbs. Additionally, five therapeutic proteins
(Remicade®, Enbrel®, Avastin®, Humira®, Herceptin®) reached the top 10 in
worldwide drug sales by 2009. The market for therapeutic MAbs has been estimated
by various business groups to grow at an annual rate from 9% to 15% over the next
several years.
Dr. Sawsan Harfouch Andalus University
Annual Scientific Harvest 14/4/2015
The mAbs could be classified in several groups depending on the mechanism effect:
Cytokine antagonists:
1- TNF-α inhibitors:
TNF is a cytokine with both proinflammatory and immunoregulatory functions.
Biological activities attributed to TNFα include: induction of pro-inflammatory
cytokines such as interleukins (IL) 1 and 6, enhancement of leukocyte migration by
increasing endothelial layer permeability and expression of adhesion molecules by
endothelial cells. The role for TNF in both the pathologic inflammation and the joint
destruction in rheumatoid arthritis (RA) patients was identified in 1991. Soon after,
clinical trials using a chimeric murine–human mAb directed against TNF showed
significant clinical efficacy, validating TNF as a therapeutic target.
Golimumab (Simponi®):
Classification: Golimumab is a fully human monoclonal IgG1 antibody.
Mechanism: It is acting on both soluble and membrane-bound TNF-α.
Indications: Golimumab is approved by the FDA for RA, psoriatic arthritis (PsA),
and ankylosing spondylitis (AS).
Dosage and method of administration: The indicated dose for all three diseases is
50 mg monthly by SC injection. For RA, golimumab is administered in combination
with MTX; for PsA it may be administered alone or with MTX; and for AS, it may be
administered alone.
Adverse effects and safety: The main AEs are infections (mostly of the upper
respiratory tract URT) and nausea. Additional AEs include hypertension, abnormal
liver function paresthesia, dizziness, constipation, local skin reaction, and some cases
of malignancy (basal and squamous cell carcinomas, and prostate, lung, and breast
cancers) were reported.
Interactions: The concomitant use of SIMPONI with biologics approved to treat RA,
PsA, or AS is not recommended because of the possibility of an increased risk of
infection. Live vaccines should not be given concurrently with SIMPONI.
Dr. Sawsan Harfouch Andalus University
Annual Scientific Harvest 14/4/2015
Certolizumab (Cimzia®):
Classification: certolizumab is a humanized IgG4 Fab fragment produced by cell
culture in Escherichia coli and then chemically linked to polyethylene glycol.
Mechanism: It binds to and inhibits the inflammatory effects of TNF-alpha.
Indications: Certolizumab is approved by the FDA for the treatment of active
rheumatoid arthritis or psoriatic arthritis and reducing signs and symptoms of Crohn
disease in certain patients.
Dosage and method of administration: It is given as SC injection of 400 mg every 2
weeks for three consecutive cycles, followed by maintenance therapy of 200 mg SC
every 2 weeks. It may be used alone or in combination with other medicine.
Adverse effects and safety: In general, the modification of the Fab fragment
decreases metabolic clearance rates and extends the half-life of the molecule. In a
safety study of patients with RA, the AEs reported for certolizumab were headache,
nasopharyngitis, diarrhea, and sinusitis. A significantly higher incidence of serious
AEs were detected in patients receiving certolizumab, and these included bacterial
arthritis, salmonella arthritis, ischemic stroke, menorrhagia, mastitis, and increases in
blood creatinine and urea levels.
Adalimumab (Humira®):
Calssification: Adalimumab is a recombinant human IgG1 monoclonal antibody
specific for human tumor necrosis factor TNF.
Mechanism: Adalimumab binds specifically to TNF-alpha and blocks its interaction
with the TNF receptors. Adalimumab also lyses surface TNF expressing cells in vitro
in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin
(TNF-beta).
Indications: Adalimumab is indicated for reducing signs and symptoms and
inhibiting the progression of structural damage in adult patients with moderately to
severely active rheumatoid arthritis. Adalimumab can be used alone or in combination
with other anti rheumatoid agents. Juvenile Idiopathic Arthritis. Psoriatic Arthritis.
Ankylosing Spondylitis and Crohn‘s Disease.
Dosage and method of administration: The recommended dose of Adalimumab for
adult patients with rheumatoid arthritis is 40 mg administered every other week as a
subcutaneous injection. Some patients not taking concomitant MTX may derive
Dr. Sawsan Harfouch Andalus University
Annual Scientific Harvest 14/4/2015
additional benefit from increasing the dosing frequency of Adalimumab to 40 mg
every week.
Adverse effects and safety: Upper respiratory tract infections, bronchitis,
tuberculosis and urinary tract infections. Lymphomas have been observed in patients
treated with TNF blocking agents including Adalimumab. Cardiovascular disorder.
Confusion, multiple sclerosis. Lupus erythematosus syndrome.
Interactions: Adalimumab has been studied in rheumatoid arthritis patients taking
concomitant MTX. The data do not suggest the need for dose adjustment of either
Adalimumab or MTX. MTX, glucocorticoids, salicylates, nonsteroidal anti-
inflammatory drugs (NSAIDs), analgesics may be continued during treatment with
Adalimumab.
Contraindications: Adalimumab should not be administered to patients with known
hypersensitivity to Adalimumab or any of its components.
Etanercept (Enbrel®):
Calssification: Enbrel (etanercept) is a dimeric fusion protein consisting of the
extracellular ligand-binding portion of the human tumor necrosis factor receptor
(TNFR) linked to the Fc portion of human IgG1.
Mechanisme: Etanercept binds specifically to tumour necrosis factor (TNF) and
blocks its interaction with cell surface TNF receptors. Etanercept did not induce
complement-mediated cytolysis of murine T cells that expressed TNF on the cell
surface.
Indications: Rheumatoid Arthritis. Psoriatic Arthritis. Ankylosing Spondylitis.
Plaque Psoriasis. Juvenile Idiopathic Arthritis.
Dosage and method of administration: The recommended dose of etanercept is 50
mg per week, given as a subcutaneous injection, etanercept is given once weekly as a
single 50 mg injection OR twice weekly as two separate 25 mg injections given 3-4
days apart.
Adverse effects and safety: Significantly higher incidence of injection site reactions
(erythema and/or itching, pain, bleeding, bruising or swelling). An increased rate of
lymphoma up to several fold has been reported in the rheumatoid arthritis patient
population. Psoriasis. Very Common Infections (URT infections, bronchitis).
Common Serious infections (pneumonia, cellulitis, septic arthritis, parasitic infection).
Dr. Sawsan Harfouch Andalus University
Annual Scientific Harvest 14/4/2015
Contraindications: Known hypersensitivity to etanercept or to any of its excipients.
Patients with, or at risk of, sepsis. Treatment with etanercept should not be initiated in
patients with serious, active infection including chronic or localized infections.
Concurrent treatment with Interleukin-1 antagonists.
Interactions: In clinical studies, concurrent administration of abatacept and
etanercept resulted in increased incidences of serious adverse events, including
infections, and did not demonstrate increased clinical benefit. Use of etanercept with
abatacept is not recommended. Patients treated with etanercept and anakinra were
observed to have a higher rate of serious infection. The use of etanercept in patients
receiving concurrent cyclophosphamide therapy is not recommended. Combination
use with sulfasalazine leads to significant decrease in mean white blood cell counts.
Infliximab (Remicade®):
Calssification: Infliximab, the active ingredient in Remicade, is a chimeric IgG1κ
monoclonal antibody (composed of human constant and murine variable regions)
specific for human tumor necrosis factor-alpha (TNFα).
Mechanisme: Infliximab neutralizes the biological activity of TNFα by binding with
high affinity to the soluble and transmembrane forms of TNFα and inhibits binding of
TNFα with its receptors.
Indications: Crohn‘s Disease. Ulcerative Colitis. Rheumatoid Arthritis. Ankylosing
Spondylitis. Psoriatic Arthritis. Plaque Psoriasis.
Dosage and method of administration: The recommended dose of Infliximab is 5
mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a
maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of adults
with moderately to severely active Crohn‘s disease or fistulizing Crohn‘s disease.
Adverse effects and safety: Infusion-related reactions such as fever or chills,
cardiopulmonary reactions (primarily chest pain, hypotension, hypertension or
dyspnea), pruritus, urticaria. Respiratory tract infections (including sinusitis,
pharyngitis, and bronchitis) and urinary tract infections. More Infliximab -treated
patients developed malignancies. The majority of the malignancies developed in the
lung or head and neck. Higher incidences of mortality and hospitalization due to
worsening heart failure. Severe liver injuries.
Contraindications: Infliximab at doses >5 mg/kg should not be administered to
patients with moderate to severe heart failure. Infliximab treatment at 10 mg/kg was
Dr. Sawsan Harfouch Andalus University
Annual Scientific Harvest 14/4/2015
associated with an increased incidence of death and hospitalization due to worsening
heart failure. Infliximab should not be re-administered to patients who have
experienced a severe hypersensitivity reaction to Infliximab.
Interactions: An increased risk of serious infections was seen in clinical studies of
other TNFα-blocking agents used in combination with anakinra or abatacept, with no
added clinical benefit. The use of tocilizumab in combination with biological TNF
antagonists, including Infliximab, should be avoided because of the possibility of
increased immunosuppression and increased risk of infection. Concomitant MTX use
may decrease the incidence of anti-infliximab antibody production and increase
infliximab concentrations.
2- IL-1β inhibitors:
IL-1β is a pro-inflammatory cytokine that acts as mediator of the peripheral immune
response during infection and inflammation, but is also implicated in acute and
chronic autoimmune diseases, diabetes, pain and neurological disorders. IL-1β exerts
its action on target cells through the receptor IL-1RI.
Dysregulated IL-1β activity is characteristic of autoimmune diseases and may occur
due to either abnormally increased levels of the cytokine, or qualitative or quantitative
deficiency of IL-1RI endogenous antagonist. Anti-IL-1β treatment has been proved to
be effective in several autoinflammatory diseases.
Canakinumab (Ilaris ®):
Classification: Canakinumab is an anti-IL-1 IgG1 mAb.
Mechanism: It binds to and inhibits the inflammatory effects of Il-1 .
Dr. Sawsan Harfouch Andalus University
Annual Scientific Harvest 14/4/2015
Indications: It is specifically indicated in adults and in children aged 4 years and
older for the treatment of cryopyrin-associated periodic syndromes CAPS, including
familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome
(MWS). The pathogenesis of these syndromes is mostly related to the presence of
mutations in genes encoding proteins involved in the innate immune system
regulation or in inflammatory response adjustment, resulting in an immense
production of proinflammatory cytokines, in particular interleukin- (IL-) 1.
Dosage and method of administration: For adults, it is administered via SC
injection at a dose of 150 mg every 8 weeks.
Adverse effects and safety: Canakinumab is well tolerated. The most AEs reported
were cold symptoms; diarrhea; dizziness; headache, swelling, warmth; mild sore
throat; nausea; runny nose; stomach pain; vomiting; weight gain. The SEVERE but
rare side effects were: Severe allergic reactions (rash; hives; itching; difficulty
breathing or swallowing; tightness in the chest; swelling of the mouth, face, lips, or
tongue); coughing up blood; fainting; persistent cough; persistent pain, swelling, or
redness at the injection site; signs of infection (eg, fever, sweats or chills, cough, flu
symptoms, or painful skin; increased or painful urination).
3- IL-6 inhibitors:
Interleukin (IL)-6 plays essential roles not only in the immune response, but also in
haematopoiesis and the central nervous system. IL-6 binds to either membrane-bound
or soluble IL-6R, and this complex in turn binds to the 130 gp signal transducer. This
process enhances the inflammatory cascade, amplifying the activity of adhesion
molecules. It is also responsible for activating both B and T helper cells, and is
involved in B-cell differentiation. Deregulated production of IL-6 has been found in
chronic inflammatory autoimmune diseases, such as rheumatoid arthritis (RA),
systemic onset juvenile idiopathic arthritis (soJIA), Crohn's disease (CD) and
systemic lupus erythematosus (SLE). Furthermore, IL-6 activities can explain many
symptoms of these diseases.
In this category, the FDA had approved:
Dr. Sawsan Harfouch Andalus University
Annual Scientific Harvest 14/4/2015
Tocilizumab (Actemra ®):
Classification: Tocilizumab is a recombinant monoclonal IgG1, anti-human IL-6
receptor.
Mechanism: More importantly, serum levels of IL-6 are correlated with disease
activity. Tocilizumab binds specifically to both soluble and membrane-bound IL-6
receptors (sIL-6R and mIL-6R), and has been shown to inhibit IL-6-mediated
signaling through these receptors.
Indications: Actemra is Indicated for the treatment of adult patients with moderately
to severely active rheumatoid arthritis (RA) who have had an inadequate response to
one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs). It is also
indicated for the treatment of active polyarticular juvenile idiopathic arthritis (PJIA)
and active systemic juvenile idiopathic arthritis (SJIA) in patients 2 years of age and
older.
Dosage and method of administration: Intravenous infusion, subcutaneous
injection of 8 mg/kg every four week
Adverse effects and safety: TCZ was well tolerated for more than 2.4 years of
treatment, and the AEs were less severe compared with other biologic therapies. The
most common AEs were infections, mostly of the upper respiratory tract (URTI) and
gastrointestinal (GI) tract. More severe AEs included cardiac events, serious
infections, solidorgan malignancies, non-melanoma skin tumors, and hematological
disturbances.
Contraindications: The application of tocilizumab is contraindicated during acute
infections, as well as under latent tuberculosis.
Interactions: There are no certain interactions with other drugs. The blood plasma
levels of simvastatin were reduced by 57% after a single dose of tocilizumab, but it is
not known whether this is clinically relevant. A possible mechanism is that the
elevated IL-6 levels of patients with RA suppress the biosynthesis of various
cytochrome P450 enzymes, notably CYP1A2, CYP2C9, CYP2C19 and CYP3A4.
Tocilizumab lowers IL-6 and thus normalises cytochrome levels, increasing the
metabolization of simvastatin (and possibly other cytochrome metabolised drugs).
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4- IL-12 and IL-23 inhibitors:
Ustekinumab (STELARA ®):
Classification: Human monoclonal IgG1 antibody.
Mechanism: Ustekinumab is designed to interfere with the triggering of the body's
inflammatory response through the suppression of certain cytokines. Specifically,
CNTO 1275 blocks interleukin IL-12 and IL-23 which help activate certain T-cells. It
binds to the p-40 subunit of both IL-12 and IL-23 so that they subsequently cannot
bind to their receptors.
Indication: Stelara is indicated in patients with severe plaque psoriasis.
Dosage and method of administration: Patients enrolled in clinical trials of
Ustekinumab are scheduled to receive the drug by subcutaneous injections at doses of
either 45 or 90 mg. The dosage and frequency varies by study and application (type of
disease targeted). Generally the initial dosing interval once every three months, after
the first two doses are administered four weeks apart.
Adverse effects and safety: According to information provided by several clinical
trials. The side effects include an increased risk of infection, such as by tuberculosis
and an increased risk of certain types of cancer. As with some other
immunosuppressant drugs like cyclosporine, the brain swelling of posterior reversible
encephalopathy syndrome is a risk. The pharmaceutical company also reports serious
allergic reaction as a possible side effect. More common side effects are upper
respiratory infection, headache, and tiredness.
5- IL-2 inhibitors:
BASILIXIMAB (Simulect®):
Classification: A chimeric monoclonal antibody, anti-interleukin-2 receptor (IL-2R_,
also known as CD25 antigen).
Mechanisme: Simulect specifically binds to and blocks the interleukin-2 receptor
alpha chain (IL-2R), thereby inhibiting IL-2 driven proliferation of activated T-cells,
which play a key role in organ rejection. Two 20-mg doses block the receptor for 4 to
6 weeks post-transplantation, the critical risk period for acute organ rejection.
Indications: Prophylaxis of acute organ rejection in patients receiving renal
transplants. Used as part of an immunosuppressive regimen that includes cyclosporine
and corticosteroids. Dosing regimen may also include either azathioprine or
mycophenolate.
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Dosage and method of administration: The recommended dose is 20 mg IV given
on day 0, two hours prior to transplant surgery, followed by 20 mg IV given on day 4
after transplantation.
Adverse effects and safety: Abdominal pain, anemia, constipation, diarrhea, edema,
fever, headache, hyperkalemia, hypersensitivity reactions (including anaphylaxis,
bronchospasm, cardiac failure, pruritus, pulmonary edema, rash, respiratory failure,
sneezing, tachycardia, urticaria), hypertension, insomnia, nausea, pain, peripheral
edema, upper respiratory infections, urinary tract infections.
Contraindications: Known hypersensitivity to basiliximab or any of its components
(composite of human and murine antibodies).
Drug interactions: It has been administered concurrently with antilymphocyte
globulin, antithymocyte globulin, azathioprine, corticosteroids, cyclosporine,
muromonab CD3, and mycophenolate, no additional adverse reactions noted. May
increase or decrease numerous lab values, including serum calcium and potassium and
fasting blood glucose.
Daclizumab (Zenapax®):
Calssification: Humanized IgG1 Mab that binds to the human interleukin-2 receptor.
Mechanisme: Daclizumab functions as an IL-2 receptor antagonist that binds with
high-affinity to the Tac subunit of the high-affinity IL-2 receptor complex and inhibits
IL-2 binding. Daclizumab binding is highly specific for Tac, which is expressed on
activated but not resting lymphocytes. Daclizumab inhibits IL-2-mediated activation
of lymphocytes, a critical pathway in the cellular immune response involved in
allograft rejection.
Indications: Daclizumab is indicated for the prophylaxis of acute organ rejection in
patients receiving renal transplants. It is used as part of an immunosuppressive
regimen that includes cyclosporine and corticosteroids. The efficacy of daclizumab
for the prophylaxis of acute rejection in recipients of other solid organ allografts has
not been demonstrated. Pregnancy Category C. However, the clinical experience of
daclizumab exposed pregnancies is still limited. Daclizumab should not be used in
pregnant women unless the potential benefit justifies the potential risk to the fetus.
Women of childbearing potential should use effective contraception before beginning
Daclizumab therapy, during therapy, and for 4 months after completion of daclizumab
therapy.
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Dosage and method of administration: The recommended dose for daclizumab in
adult and pediatric patients is 1.0 mg/kg. The calculated volume of daclizumab should
be mixed with 50 mL of sterile 0.9% sodium chloride solution and administered via a
peripheral or central vein over a 15-minute period.
Adverse effects and safety: constipation, nausea, diarrhea, vomiting, abdominal pain.
Tremor, headache, dizziness. Oliguria, dysuria, renal tubular necrosis. Hypertension.
Pulmonary edema, coughing. Impaired wound healing without infection, acne.
Musculoskeletal pain, back pain. Tachycardia, thrombosis.
Contraindications: contraindicated in patients with known hypersensitivity to
daclizumab or to any components of this product. Increased risk for developing
lymphoproliferative disorders and opportunistic infections.
Interactions: Concumentant use with cyclosporine, mycophenolate, and
corticosteroids was associated with an increase in mortality, particularly in patients
receiving concomitant anti-lymphocyte antibody therapy and in patients who
developed severe infections.
B cells Inhibitors:
Tositumomab (Bexxar ®):
Classification: Tositumomab is a chimeric monoclonal antibody that is linked with a
radioactive atom Iodine 13. This approach, termed radioimmunotherapy. (RIT),
allows for the delivery of radionuclides directly to the surface of target tumor cells.
Mechanism: This monoclonal antibody is specifically targeted to the CD20 molecule
on the surface of mature B cells and B-cell lymphomas.
Indications: It is approved for the treatment of certain types of non-Hodgkin's
lymphomas that have recurred after, or have not responded to prior treatment.
Dosage and method of administration: Tositumomab injection comes as a liquid to
be injected into a vein. The patient will receive an infusion of tositumomab injection
without radioactive material, followed by an infusion of tositumomab injection with
radioactive material. The first infusion will last about 60 minutes, and the second
infusion about 30 minutes. On the same day, the patient will undergo an imaging scan
to see how tositumomab injection has spread through the body. On the second and
third visits, the patient will undergo additional imaging scans to see how tositumomab
injection has spread through the body. If tositumomab has spread as expected, the
patient will receive another infusion of tositumomab injection lasting 60 minutes,
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followed by an infusion of tositumomab injection with radioactive material lasting 30
minutes.
Adverse effects and safety: Low blood counts. This can put you at increased risk for
infection, anemia and/or bleeding. In addition, there are less common side effects
(occurring in 10-29%) for patients receiving tositumomab like: Infusion related
reactions including bronchospasm, shortness of breath, fever, low blood pressure,
Infection, Hypothyroidism, Poor appetite, Diarrhea. The doctor have to Protect the
thyroid gland of the patient, as it can absorbs the radioactive form of iodine blood
stream. The patient will be given a prescription for medication to protect his thyroid
gland.
Ofatumumab (Arzerra ®):
Classification: Ofatumumab is a humanised anti-CD20 monoclonal antibody.
Mechanism: The CD20 antigen is expressed on solely B cell lymphocytes. Compared
with rituximab, ofatumumab binds more tightly to CD20 with a slower off-rate. It
causes cytotoxicity in the cells that express CD20 by means of complement-
dependent cytotoxicity (CDC) and antibody-dependent cytotoxicity (ADCC).
Indications: It is FDA approved for treating chronic lymphocytic leukemia that is
refractory to fludarabine and alemtuzumab (Campath) and has also shown potential in
treating Follicular non-Hodgkin‘s lymphoma, Diffuse large B cell lymphoma,
rheumatoid arthritis and relapsing remitting multiple sclerosis.
Dosage and method of administration: Ofatumumab injection comes as a solution
(liquid) to be added to fluid and injected intravenously (into a vein) by a doctor or
nurse in a medical office or hospital. It is usually injected once a week for 8 weeks
then once a month for 4 months.
Adverse effects and safety: Very common (>10% frequency): Lower respiratory
tract infection, including pneumonia - Upper respiratory tract infection - Rash-
Anaemia –Neutropenia.
Contraindications: It is contraindicated in individuals that have hypersensitivity to
ofatumumab or any of its excipients.
Interactions: No formal drug interaction studies have been conducted with
ofatumumab. Although it is advised that patients are not administered live virus
vaccines (e.g. the oral polio vaccine) while undergoing treatment with ofatumumab
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due to the compromised ability to fight the attenuated viruses seen in patients being
treated with ofatumumab.
Ibritumomab (Zevalin®):
Calssification: A murine IgG1 kappa monoclonal antibody directed against the CD20
antigen. The chelate tiuxetan, which tightly binds In-111 or Y-90, is covalently linked
to the amino groups of exposed lysines and arginines contained within the antibody.
Mechanisme: The complementarity-determining regions of Ibritumomab bind to the
CD20 antigen on B lymphocytes. Ibritumomab, like Rituximab, induces apoptosis in
CD20+ B-cell lines in vitro. The beta emission from Y-90 induces cellular damage by
the formation of free radicals in the target and neighboring cells.
Indications: Ibritumomab, as part of the ibritumomab therapeutic regimen, is
indicated for the treatment of patients with relapsed or refractory low-grade, follicular,
or transformed B-cell non-Hodgkin‘s lymphoma, including patients with Rituximab
refractory follicular non-Hodgkin‘s lymphoma. Determination of the effectiveness of
the ibritumomab therapeutic regimen in a relapsed or refractory patient population is
based on overall response rates. The effects of the ibritumomab therapeutic regimen
on survival are not known. Pregnancy Category D: Y-90 Ibritumomab can cause fetal
harm when administered to a pregnant woman.
Dosage and method of administration: The Ibritumomab therapeutic regimen is
administered in two steps: Step 1 includes a single infusion of 250 mg/m2 Rituximab
preceding a fixed dose of 5.0 mCi (1.6 mg total antibody dose) of In-111 Ibritumomab
administered as a 10 minute IV push. Step 2 follows step 1 by seven to nine days and
consists of a second infusion of 250 mg/m2 of Rituximab prior to 0.4 mCi/kg of Y-90
Ibritumomab administered as a 10 minute IV push.
Adverse effects and safety: The most serious adverse reactions caused by the
ibritumomab therapeutic regimen include infections (predominantly bacterial in
origin), allergic reactions (bronchospasm and angioedema), and hemorrhage while
thrombocytopenic (resulting in deaths). In addition, patients who have received the
ibritumomab therapeutic regimen have developed myeloid malignancies and
dysplasias. Fatal infusion reactions have occurred following the infusion of Rituximab.
The most common toxicities reported were neutropenia, thrombocytopenia, anemia,
gastrointestinal symptoms (nausea, vomiting, abdominal pain, and diarrhea),
increased cough, dyspnea, dizziness, arthralgia, anorexia, anxiety, and ecchymosis.
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Contraindications: The ibritumomab therapeutic regimen is contraindicated in
patients with known Type I hypersensitivity or anaphylactic reactions to murine
proteins or to any component of this product, including Rituximab, yttrium chloride,
and indium chloride.
Interactions: No formal drug interaction studies have been performed with
Ibritumomab. Due to the frequent occurrence of severe and prolonged
thrombocytopenia, the potential benefits of medications which interfere with platelet
function and/or anticoagulation should be weighed against the potential increased
risks of bleeding and hemorrhage. Patients receiving medications that interfere with
platelet function or coagulation should have more frequent laboratory monitoring for
thrombocytopenia.
Rituximab (Mabthera®):
Calssification: Rituximab is a chimeric monoclonal antibody against the protein
CD20.
Mechanisme: Rituximab binds specifically to the CD20 antigen on B-lymphocytes
and initiates immunologic reactions that mediate B-cell lysis. Possible mechanisms of
cell lysis include complement-dependent cytotoxicity (CDC), antibody-dependent
cellular cytotoxicity (ADCC), and induction of apoptosis.
Indications: Non-Hodgkin‘s lymphoma. Chronic lymphocytic leukaemia.
Rheumatoid arthritis. Granulomatosis with polyangiitis and Microscopic polyangiitis.
Dosage and method of administration: The recommended dose for non-Hodgkin‘s
lymphoma is 375 mg/m2 of Mabthera as an IV infusion weekly for four doses, and for
rheumatoid arthritis Mabthera is administered as two IV infusions separated by an
interval of 15 days.
Adverse effects and safety: Bacterial and viral infections, neutropenia, leucopenia,
angiooedema, myocardial infarction and arrhythmias, hyperglycaemia, weight
decrease, agitation, insomnia, vasodilatation, dizziness, anxiety.
Contraindications: Mabthera is contraindicated in patients with known
hypersensitivity to rituximab, to any component of the product or to murine proteins.
Interactions: At present, there are limited data on possible interactions with
Mabthera. In CLL patients, co-administration with Mabthera did not appear to have
an effect on the pharmacokinetics of fludarabine or cyclophosphamide, in addition;
there were no apparent effects of fludarabine and cyclophosphamide on the
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pharmacokinetics of Mabthera. Co-administration with methotrexate had no effect on
the pharmacokinetics of Mabthera in rheumatoid arthritis patients.
Belimumab (Benlysta, LymphoStat-B®):
Classification: Belimumab is a fully human recombinant IgG1λ monoclonal antibody
produced from a recombinant NS0 cell line stably transfected with the belimumab
heavy chain and light chain genes.
Mechanism: Belimumab selectively binds to soluble human B lymphocyte stimulator
protein (BLyS) so that BLyS is unable to bind to receptors on B lymphocytes. The
binding of BLyS to its receptor is essential for the survival of B lymphocytes.
Consequently, belimumab reduces B-cell mediated immunity and the autoimmune
response.
Indications: Belimumab is an intravenous immunosupressant for the adjunctive
treatment of systemic lupus erythematosus (SLE). It is the first biological treatment
approved for the indication of SLE.
Dosage and method of administration: 10 mg/kg IV at 2-week intervals for the first
3 doses and at 4-week intervals thereafter.
Adverse effects and safety (AEs): Common adverse effects reported with
belimumab include nausea, diarrhea, fever, as well as hypersensitivity and infusion-
site reactions (severe in 0.9% of patients). It is suggested that patients be treated with
an antihistamine prior to a belimumab infusion. A greater number of serious infections
and deaths were reported in patients treated with belimumab than in those treated with
placebo. Infections are due to the immunosuppressant properties of the drug.
Contraindications and interaction: Concomitant use with live or inactivated
vaccines must be avoided. Combination of belimumab with other
immunosuppressants, especially those targeting B lymphocytes such as anti-CD20
therapies, could increase the risk of severe infections. Likewise, the combination with
cyclophosphamide is not recommended.
Omalizumab (Xolair®):
Classification: Omalizumab is a biological engineered, humanized recombinant
monoclonal anti-IgE antibody.
Mechanism: The anti-IgE antibody inhibits IgE functions blocking free serum IgE
and inhibiting their binding to cellular receptors. This antibody acts by reducing
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serum IgE levels and IgE receptor expression on inflammatory cells in the context of
allergic cascade. IgE effector functions are inhibited, because the IgE binding to high-
affinity receptors on IgE effector cells is blocked, as well as the following activation
of mast cells and basophils.
Indications: Xolair is developed for the treatment of allergic diseases and with clear
efficacy in adolescent and adult patients with severe allergic asthma.
Dosage and method of administration: Omalizumab is used for almost 24 weeks at
the dose of 150-300 mg every four weeks.
Adverse effects and safety: This antibody is well tolerated, and expresses a high
degree of isotype specificity and can neutralize serum free IgE without affecting other
antibody classes. The most frequent AE observed in patients were nasopharyngitis;
the assessment of laboratory parameters did not show any significant effect of
omalizumab on blood cells counts, renal and liver function.
Obinutuzumab (Afutuzumab - Gazyva®):
Classification: Obinutuzumab is a glycoengineered, humanized, IgG1 monoclonal
antibody.
Mechanism: Obinutuzumab binds selectively to the extracellular domain of the
human CD20 antigen present on the B cell surface in various B cell malignancies. The
Fc region carbohydrates of the antibody, enriched in bisected non-fucosylated
glycosylation variants, contribute to its higher binding affinity for human FcγRIII
receptors compared to non-glycoengineered antibodies, which is believed to result in
enhanced antibody-dependent cellular cytotoxicity (ADCC) and caspase-independent
apoptosis.
Indications: Obinutuzumab is used as a combination treatment with chlorambucil to
treat patients with untreated chronic lymphocytic leukemia.
Dosage and method of administration: Chlorambucil 0.5 mg/kg PO on days 1 and
15 and Obinutuzumab IV every 28 days for 6 cycles. Obinutuzumab premedications
vary depending on cycle / treatment day.
Premeds to be administered at least 30 min pre-obinutuzumab infusion:
• PO analgesic/antipyretic (acetaminophen 1000mg)
• PO or IV antihistamine (diphenhydramine 50mg or equivalent)
Premeds to be administered at least 1 hour pre-obinutuzumab infusion:
• IV corticosteroid (prednisolone 100mg, dexamethasone 20 mg or equivalent).
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Adverse effects and safety: The most common side effects for obinutuzumab (in
combination with chlorambucil) include infusion related reaction, myelosuppression ±
infection, bleeding, ↑ lfts, creatinine increased, nausea, vomiting, cough, dyspnea,
diarrhea, fever, abnormal electrolyte(s) and fatigue. Dividing the dose over two days
and use of premedication may reduce the frequency and severity of these. Patients
with preexisting cardiac or pulmonary conditions are at increased risk and should be
monitored closely. Serious cardiovascular events have been reported as part of
infusion reactions or worsening of preexisting cardiovascular disease.
Contraindications: Patients who have a hypersensitivity to this drug or any of its
component. Patients with active hepatitis or active infection.
Alemtuzumab (Campath®):
Calssification: Alemtuzumab is a recombinant human IgG-derived monoclonal
antibody that binds to antigen CD52.
Mechanisme: Campath binds to CD52, an antigen present on the surface of B and T
lymphocytes, a majority of monocytes, macrophages, NK cells. The proposed
mechanism of action is antibody-dependent cellular-mediated lysis following cell
surface binding of Campath to the leukemic cells.
Indications: Campath is indicated as a single agent for the treatment of B-cell chronic
lymphocytic leukemia (B-CLL).
Dosage and method of administration: Administer as an IV infusion over 2 hours.
Escalate to recommended dose of 30 mg/day three times per week for 12 weeks.
Premedicate with oral antihistamine and acetaminophen prior to dosing.
Adverse effects and safety: The most common adverse reactions with Campath are:
infusion reactions (pyrexia, chills, hypotension, urticaria, nausea, rash, tachycardia),
cytopenias (neutropenia, lymphopenia, thrombocytopenia, anemia), infections (CMV
viremia, CMV infection, other infections), gastrointestinal symptoms (nausea, emesis,
abdominal pain), and neurological symptoms (insomnia, anxiety).
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T cell inhibitor:
Ipilimumab (Yervoy®
):
Classification: Ipilimumab is a fully human IgG1κ antibody.
Mechanism: Ipilimumab binds to CTLA-4 (cytotoxic T lymphocyte-associated
antigen 4), a molecule on T-cells that is indicated for unresectable or metastatic
melanoma. The absence or presence of CTLA-4 can augment or suppress the immune
system's T-cell response in fighting disease. Ipilimumab is designed to block the
activity of CTLA-4, thereby sustaining an active immune response in its attack on
cancer cells. The proposed mechanism of action is indirect, and may be through T-cell
- mediated anti-tumor immune responses.
Indications: Ipilimumab was approved by the FDA in March 2011 to treat patients
with late-stage melanoma that has spread or cannot be removed by surgery. On
February 1, 2012, Health Canada approved ipilimumab for "treatment of unresectable
or metastatic melanoma in patients who have failed or do not tolerate other systemic
therapy for advanced disease. Additionally Ipilimumab was approved in the European
Union (EU), for second line treatment of metastatic melanoma, November 2012.
Dosage and method of administration: Ipilimumab is given as an infusion into a
vein (IV), usually over about 90 minutes. It is given once every 3 weeks for a total of
4 doses. The dose given is based on the body weight.
Adverse effects and safety: Ipilimumab treatment has been associated with severe
and potentially fatal immunological adverse effects due to T cell activation and
proliferation. Most of the serious adverse effects are associated with the gastro-
intestinal tract; they include stomach pain, bloating, constipation or diarrhea, but also
fever, breathing or urinating problems. A "risk evaluation and mitigation strategy" has
been set up to inform prescribers of the potential risks.
Contraindications and interaction: The combination of ipilimumab with either
leflunomide or vemurafenib may lead to increased hepatotoxicity. Systemic
corticosteroids should be avoided before starting ipilimumab; however, systemic
corticosteroids may be used to treat an immune-related adverse reaction that arises
from ipilimumab treatment. Patients taking anticoagulants with ipilimumab should be
monitored due to an increased risk of gastrointestinal bleeding.
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Alefacept (Amevive®):
Calssification: Recombinant LFA-3/IgG1 Fusion Protein.
Mechanisme: Alefacept interferes with lymphocyte activation by specifically binding
to the lymphocyte antigen, CD2, and inhibiting leukocyte function antigen-3 (LFA-3)
LFA-3/CD2 interaction. Activation of T lymphocytes involving the interaction
between LFA-3 on antigen-presenting cells and CD2 on T lymphocytes plays a role in
the pathophysiology of chronic plaque psoriasis.
Indications: Alefacept is indicated for the treatment of adult patients with moderate
to severe chronic plaque psoriasis who are candidates for phototherapy or systemic
therapy. Pregnancy Category B there are no adequate and well-controlled studies in
pregnant women.
Dosage and method of administration: The recommended dose of Alefacept is 15
mg given once weekly as an intramuscular IM injection. The recommended regimen
is a course of 12 weekly injections.
Adverse effects and safety: Lymphopenia. Alefacept may increase the risk of
malignancies. Has the potential to increase the risk of infection and reactivate latent,
chronic infections. Hypersensitivity reactions (urticaria, angioedema). Hepatic injuries.
Contraindications: Alefacept should not be administered to patients infected with
HIV. Alefacept reduces CD4+ T lymphocyte counts, which might accelerate disease
progression or increase complications of disease in these patients. Alefacept should
not be administered to patients with known hypersensitivity to Alefacept or any of its
components. Alefacept should not be administered to patients with a history of
systemic malignancy.
muromonab-CD3 (Orthoclone OKT3®):
Classification: Muromonab-CD3 is a murine monoclonal IgG2a anti-CD3 antibody.
Mechanisme: Muromonab-CD3 acts as an immunosuppressant by interfering with
normal T-cell function, which play a major role in acute allograft rejection.
muromonab-CD3 reacts with and blocks the function of CD3 in the membrane of
human T cells. Binding of muromonab-CD3 to T lymphocytes results in blocking T
cell production and functions. Therapeutic effects: Reversal of graft rejection in
transplant patients.
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Indications: Acute renal allograft rejection reactions in transplant patients that have
occurred despite conventional anti-rejection therapy. Acute corticosteroid-resistant
hepatic or cardiac allograft rejection reactions. Pregnancy Category C.
Dosage and method of administration: IV (Adults): 5 mg/day for 10–14 days
(pretreatment with corticosteroids, acetaminophen, and/or antihistamines
recommended). IV (Children): 0.1 mg (100 mcg)/kg/day for 10–14 days.
Adverse effects and safety: tremor, aseptic meningitis, dizziness. Pulmumary edema,
dyspnea, shortness of breath, wheezing. chest pain. diarrhea, nausea, vomiting.
infections, chills, fever, hypersensitivity reactions, risk of lymphoma.
Interactions: Additive immunosuppression with other immunosuppressives.
Concurrent prednisone and azathioprine dosages should be modified during
muromonab therapy (risk of infection and lymphoproliferative disorders).
Cyclosporine should be discontinued during muromonab-CD3 therapy (risk of
infection and lymphoproliferative disorders). Risk of adverse CNS reactions with
indomethacin. Risk of adverse reactions from live-virus vaccines.
Contraindications: Hypersensitivity to muromonab-CD3, fever. chickenpox or
recent exposure to chickenpox; herpes zoster. Use cautiously in: active infections;
depressed bone marrow reserve; chronic debilitating illnesses; pregnancy, lactation, or
children.
Comlement inhibitors:
Eculizumab (Soliris®):
Classification: This antibody is a humanized IgG.
Mechanism: It was developed to specifically target cleavage of C5 thus preventing
release of C5a and activation of the terminal pathway of the complement system
Indications: It was approved by the United States Food and Drug Administration and
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the European Medicines Agency in 2007 for the treatment of paroxysmal nocturnal
hemoglobinuria (PNH) and in 2011 for the treatment of atypical hemolytic uremic
syndrome (aHUS). PNH and aHUS are 2 diseases with distinctly different underlying
molecular mechanisms. In PNH, progeny of hematopoietic stem cells that harbor
somatic mutations lead to a population of peripheral blood cells that are deficient in
complement regulators resulting in hemolysis and thrombosis. In aHUS, germline
mutations in complement proteins or their regulators fail to protect the glomerular
endothelium from complement activation resulting in thrombotic microangiopathy
and renal failure. Understanding this step has led to the study of eculizumab as a
treatment for these diseases.
Dosage and method of administration: Eculizumab is usually given 600 mg weekly
for the first 4 weeks, followed by 900 mg for the fifth dose 1 week later, then 900 mg
every 2 weeks thereafter.
Adverse effects and safety: Human IgG activates complement and has a
proinflammatory effect on binding to its target - to minimize this, the hybrid region
uses the desirable properties both IgG2, which fails to bind Fc receptors, and IgG4,
which does not activate complement to reduce the proinflammatory potential of the
antibody. Eculizumab was well tolerated during the study. The most frequent adverse
events (AEs) were headache, nasopharyngitis, and upper respiratory tract infection.
The AEs was significantly lower in the last 26 weeks suggesting that there was no
cumulative toxicity.
Contraindications: Soliris is contraindicated in patients with unresolved serious
Neisseria meningitidis infection and those who are not currently vaccinated against
Neisseria meningitidis, unless the risks of delaying Soliris treatment outweigh the
risks of developing a meningococcal infection.
Receptor activator of nuclear factor kappa B ligand (RANKL)
inhibitor:
Denosumab (Prolia, Xgeva®):
Classification: Denosumab is a fully human monoclonal IgG2 antibody.
Mechanism: Denosumab is designed to target RANKL (RANK ligand), a protein that
acts as the primary signal to promote bone removal/resorption. In many bone loss
conditions, RANKL overwhelms the body's natural defense against bone destruction.
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Denosumab prevents RANKL from activating its receptor, RANK, on the surface of
osteoclasts and their precursors. Prevention of the RANKL/RANK interaction inhibits
osteoclast formation, function, and survival, thereby decreasing bone resorption and
increasing bone mass and strength in both cortical and trabecular bone.
Indications: Prolia is indicated for the treatment of postmenopausal women with
osteoporosis at high risk for fracture. It reduces the incidence of vertebral,
nonvertebral, and hip fractures. Prolia is also indicated as a treatment to increase bone
mass in women at high risk for fracture receiving adjuvant aromatase inhibitor
therapy for breast cancer. It can also be used in men with osteoporosis at high risk for
fracture or in men receiving androgen deprivation therapy for nonmetastatic prostate
cancer to increase bone mass. Xgeva is indicated for the prevention of skeletal-related
events in patients with bone metastases from solid tumors.
Dosage and method of administration: The recommended dose of Xgeva for
preventing cancer-related bone problems is 120 mg (1.7 mL) injected subcutaneously
once every four weeks, just under the skin in the abdomen (lower stomach area).
Adverse effects and safety: The most common side effects include infections of the
urinary and respiratory tracts, cataracts, constipation, rashes, and joint pain. Another
trial showed significantly increased rates of eczema and hospitalization due to
infections of the skin. It has been proposed that the increase in infections under
denosumab treatment might be connected to the role of RANKL in the immune
system. RANKL is expressed by T helper cells, and is thought to be involved in
dendritic cell maturation.
Contraindications and interaction: Denosumab is contraindicated in patients with
hypocalcemia, and sufficient calcium and vitamin D levels must be reached before
starting on denosumab therapy. Similarly to bisphosphonates, denosumab appears to
be implicated in increasing the risk of osteonecrosis of the jaw (ONJ) following
extraction of teeth or oral surgical procedures.
Anti-toxin antibody:
Raxibacumab (ABthrax ®):
Classification: Raxibacumab is a human IgG1 monoclonal antibody against Bacillus
anthracis protective antigen.
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Annual Scientific Harvest 14/4/2015
Mechanism: Raxibacumab inhibits the binding of PA to its cellular receptors,
preventing the intracellular entry of the anthrax lethal factor and edema factor, the
enzymatic toxin components responsible for the pathogenic effects of anthrax toxin. It
does not have direct antibacterial activity.
Indications: Raxibacumab is indicated for the treatment of adult and pediatric
patients with inhalational anthrax due to Bacillus anthracis in combination with
appropriate antibacterial drugs, and for prophylaxis of inhalational anthrax when
alternative therapies are not available or are not appropriate.
Dosage and method of administration: Intravenous infusion of a single dose of 40
mg/kg over 2 hours and 15 minutes after dilution in 0.9% Sodium Chloride Injection,
with 25 to 50 mg diphenhydramine within 1 hour prior to raxibacumab infusion to
reduce the risk of infusion reactions.
Adverse effects and safety: Adverse effects associated with the use of raxibacumab
may include, but are not limited to, the following: rash - extremity pain – itching.
Platelets inhibitors:
Abciximab (ReoPro®):
Classification: Abciximab is the Fab fragment of the chimeric human-murine
monoclonal antibody 7E3, which inhibits glycoprotein IIb/IIIa.
Mechanism: Binds to glycoprotein (GP) receptors on platelet surfaces (GP IIb/IIIa),
resulting in decreased platelet aggregation. This decreased incidence of restenosis of
coronary arteries and improved myocardial perfusion.
Indications: Used with heparin and aspirin to decrease cardiac ischemic
complications before or after percutaneous coronary intervention (PCI). In
combination with heparin and and/or low-dose alteplase or reteplase to enhance
coronary perfusion in patients with acute coronary syndromes (ACS).
Dosage and method of administration: IV (Adults): 250 mcg (0.25 mg)/kg bolus
10–60 min prior to PCI, followed by 0.125 mcg/kg/min (up to 10 mcg/min)
continuous infusion for 12 hr; patients with unstable angina not responding to
conventional therapy and who are planned to undergo PCI within 24 hours—250 mcg
(0.25 mg)/kg bolus followed by 10 mcg/ min continuous infusion for 18–24 hr,
ending 1 hr after PCI.
Adverse effects and safety: Abnormal thinking, dizziness, headache. Hypotension,
atrial fibrillation/ flutter, bradycardia, complete AV block, supraventricular
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tachycardia, vascular disorder, chest pain, peripheral edema. Bleeding,
thrombocytopenia, allergic reactions including anaphylaxis.
Contraindications: Hypersensitivity to abciximab. Active internal bleeding; Recent
significant GI or GU bleeding. History of bleeding disorder. Recent oral anticoagulant
therapy. Platelet count_100,000 cells/mm3; Recent trauma or major surgery.
Intracranial neoplasm; Aneurysm or AV malformation; Severe uncontrolled
hypertension; History of vasculitis; Concurrent use of another parenteral GP IIb/IIIa
inhibitor; Recent or concurrent dextran therapy.
Interactions: Risk of bleeding may be increased by concurrent thrombolytics,
warfarin, NSAIDs, cefoperazone, cefotetan, dipyridamole, dextran, clopidogrel,
heparin, heparin-like drugs, valproates, or ticlopidine, although concurrent use with
heparin and aspirin is recommended.
Monoclonal antibodies directed against tumor antigens in the
treatment of cancer:
Clinical trials of newer mAbs are now being done on many types of cancer.
Compared with chemotherapy drugs, naked mAbs tend to have fewer serious side
effects. But they can still cause problems in some people.
Cell killing by antibodies can be summarized as being due to several mechanisms:
direct action of the antibody (through receptor blockade or agonist activity, induction
of apoptosis or delivery of a drug or cytotoxic agent); immune-mediated cell killing
mechanisms (including, complement-dependent cytotoxicity (CDC), antibody-
dependent cellular cytotoxicity (ADCC) and regulation of T cell function); and
specific effects of an antibody on tumour vasculature and stroma. All of these
approaches have been successfully applied in the clinic.
Catumaxomab (removab®):
Classification: A hybrid IgG consists of mouse IgG2a and rat IgG2b.
Mechanism: Catumaxomab is able to destroy EpCAM positive tumor cells in the
peritoneal cavity known as the main cause of malignant ascites. In addition,
catumaxomab is a potential therapeutic option for several primary tumors since the
EpCAM molecule is expressed on the majority of epithelial carcinomas. One specific
antigen binding site binds T cells via CD3, the other site binds tumor cells via the
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EpCAM antigen. The Fc region provides a third functional binding site that is able to
selectively bind and activate Fc on some effector cells such as
macrophages. In preclinical studies several killing mechanisms including T cell
mediated lysis, cytotoxicity by released cytokines (e.g., IL1β, IL-2, IL-6, IL-12 or),
phagocytosis or ADCC were identified.
Indications: Removab is indicated in malignant ascites (the accumulation of
peritoneal fluid due to the spread of malignant cells in the peritoneal cavity),
peritoneal carcinomatosis, ovarian cancer, and gastric cancer.
Dosage and method of administration: Removab must be given as an
intraperitoneal (into the peritoneal cavity) infusion using a pump system. It is usually
given as four infusions in increasing doses from 10 to 150 micrograms over 11 days.
There must be an interval of at least two days between infusions, but the interval can
be increased if the patient has side effects. The overall treatment period should not be
longer than 20 days. it is recommended that patients are given medicines to reduce
pain, fever and inflammation.
Contraindications: Removab is not recommended for use in patients below the age
of 18 years because of a lack of information on safety and effectiveness in this age
group.
Adverse effects and safety: The side effects with fever, nausea, vomiting and
abdominal pain are due to cytokine release. Thus, prednisolone was chosen as
additional premedication with the objective of reducing the cytokine release related
symptoms without affecting the efficacy of catumaxomab.
Drug interactions: Chemotherapies are known for their influence on the quantity and
function of peripheral T cells that are important for the mode of action of
catumaxomab. Nevertheless, several recent studies have produced unexpected results
indicating that there is a strong and developing case for combining chemotherapy and
immunotherapy in cancer treatment. One proposed explanation is that tumor cell
death due to chemotherapy yields tumor-antigen cross-presentation and enforces the
enhancement of immunotherapy response.
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Ranibizumab (Lucentis®):
Classification: Lucentis an IgG1 humanized monoclonal antibody Fab engineered to
bind with high affinity and to inhibit all biologically active isoforms of VEGF-A
(vascular endothelial growth factor).
Mechanism: VEGF is a signal protein produced by cells that stimulates
vasculogenesis and angiogenesis. It is implicated in the inflammatory disorders in the
eye causing vessel permeability and angiogenesis. Lucentis is developed to block the
interaction between VEGF and its receptor. It is developed to prevent pathologic
angiogenesis, tumor growth and tissue destruction, especially in the eye.
Indications: Lucentis®
(ranibizumab injection) is indicated for the treatment of
patients with neovascular (wet) age-related macular degeneration (wAMD), Macular
edema following retinal vein occlusion (RVO), Diabetic macular edema (DME).
Dosage and method of administration: This antibody has a small molecule size (48
kDa) and seems to be able to penetrate all layers of the retina. The recommended dose
of Lucentis is 0.5 mg given once a month in one intravitréeenne injection. The
treatment will be administered once a month and continued until maximum visual
acuity is achieved, that‘s means until the patient's visual acuity is stable for three
consecutive monthly assessments performed during treatment with ranibizumab. If no
improvement in visual acuity is ascertained at the end of a first series of three
injections, the further processing is not recommended.
Adverse effects and safety: Ranibizumab was specifically designed not to promote
inflammation because it lacks the Fc region. Several studies showed that ranibizumab
is safe and well-tolerated. Ocular AEs included endophthalmitis, uveitis, vitreous
hemorrhage, retinal detachment, retinal tear, or lens damage. Non-ocular (systemic)
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AEs included thromboembolic events (stroke, myocardial infarction), hypertension,
and non-ocular hemorrhage.
Panitumumab (Vectibix®):
Classification: Panitumumab is a recombinant IgG2 fully humanized monoclonal
antibody that targets EGFR by binding with high affinity to its extracellular domain.
Mechanism: Upon ligand binding homo or heterodimerization of EGFR occurs,
following autophosphorylation and the initiation of a signaling cascade that ultimately
leads to cell proliferation, invasion, metastasis development, and apoptosis evasion.
Vectibix can inhibit proliferation in EGFR-expressing cell lines as demonstrated in
vitro, Moreover, panitumumab has been proposed to induce autophagy in cell lines
and also to inhibit angiogenesis by reducing in vitro the tumor production of
inflammatory and proangiogenic factors, such as IL-8 or VEGF. Antibody-dependent
cell-mediated cytotoxicity (ADCC), may also contribute to panitumumab activity.
Indications: It is approved in the treatment of Colorectal cancer.
Dosage and method of administration: The approved dose of Vectibix is 6 mg/kg
administered intravenously every 2 weeks and the infusion must be given slowly can
take up to 90 minutes to complete. The administration of higher drug doses has been
shown to decrease the serum clearance.
Adverse effects and safety: Panitumumab has a good overall tolerability profile, as
most of the toxicity is usually grade 2 or less. The most characteristic side effects
include skin rash, diarrhea, and hypomagnesemia.
Cetuximab (Erbitux®):
Classification: a murine-human chimeric antibody composed of the variable region
of a murine anti-EGFR antibody joined with human IgG1 heavy and light chain
regions, which binds to the extracellular domain of the EGF receptor with a twofold
greater affinity than its natural ligands EGF.
Mechanism: Binding of Cetuximab to the EGFR results in competitive inhibition of
ligand binding and receptor phosphorylation, in addition to inhibition of these
pathways, the effects of cetuximab therapy may also be mediated by antibody-
dependent, cellmediated cytotoxicity (ADCC), complement-mediated cytotoxicity and
adaptive immunity-mediated by CD8+ cytotoxic T lymphocytes. EFGR is frequently
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overexpressed in epithelial malignancies, which providing a target for tumor antigen
(TA)-targeted monoclonal antibody (mAb)-based immunotherapy.
Indications: In addition to its role in colorectal carcinoma (CRC), cetuximab is
approved by both the FDA and the European Medicines Agency (EMA) for treatment
of locally advanced untreated squamous cell carcinoma of the head and neck
(SCCHN) in combination with chemoradiotherapy and as a single agent.
Dosage and method of administration: Erbitux is injected into a vein through an IV.
The injection must be given slowly, and the IV infusion can take up to 2 hours to
complete. Erbitux is usually given once every week for 6 to 7 weeks or until your
body no longer responds to the medication. Erbitux is often used in combination with
other cancer medications and/or radiation treatments. You may receive another cancer
medicine 1 hour after your Erbitux injection. The initial dose is 400 mg/m2
administered as a 2 hour intravenous infusion, and the maintenance dose is 250 mg/m2
infused over 1 hour once a week.
Adverse effects and safety: The most common of which is the development of a
characteristic skin rash. Interestingly, the skin rash may correlate with improved
response to therapy and better clinical outcome for cetuximab-treated patients.
Bevacizumab (Avastin®):
Classification: Bevacizumab is a recombinant humanized IgG1 monoclonal antibody.
Mechanism: Bevacizumab is an anti-VEGF antibody (Vascular Endothelial Growth
Factor). It binds to VEGF, a key factor of vasculogenesis and angiogenesis, thereby
inhibiting the binding of VEGF to its receptors, Flt-1 (VEGFR-1) and KDR (VEGFR-
2), to the cell surface endothelial. Neutralizing the biological activity of VEGF
regresses tumor vessels, normalizes the remaining tumor vessels and inhibits the
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formation of new tumor vessels, thereby inhibiting tumor growth.
Indications: Bevacizumab was approved by the U.S. Food and Drug Administration
(FDA) for certain metastatic cancers. It received its first approval in 2004, for
combination use with standard chemotherapy for metastatic colon cancer. It has since
been approved for use in certain lung cancers, renal cancers, ovarian cancers.
Dosage and method of administration: The recommended dose of Avastin,
administered as an intravenous infusion, is either 5 mg/kg or 10 mg/kg of body weight
given once every 2 weeks or 7.5 mg/kg or 15 mg/kg of body weight given once every
3 weeks. It is recommended that treatment be continued until progression of the
underlying disease or until unacceptable toxicity.
Adverse effects and safety (AEs): High blood pressure, bleeding, poor wound
healing, blood clots, and kidney damage. The overall safety profile of Avastin is
based on data from over 4,500 patients with various malignancies, predominantly
treated with Avastin in combination with chemotherapy in clinical trials. Analyses of
the clinical safety data suggest that the occurrence of hypertension and proteinuria
with Avastin therapy are likely to be dose-dependent.
Brentuximab (Adcetris ®):
Classification: Chimeric (mouse/human) IgG1.
Mechanism: Brentuximab vedotin is composed of 3 parts: a chimeric human-murine
IgG1 that targets CD30, monomethyl auristatin E (MMAE),which is a microtubule
disrupting agent, and a protease-susceptible linker that covalently links the antibody
and MMAE. The IgG1 antibody enables brentuximab vedotin to target tumor cells
expressing CD30 on their cell surface then brentuximab vedotin gets internalized into
the cell. Once inside, the linker is cleaved releasing MMAE which binds disrupts the
microtubule network.
Indications: On August 19, 2011, the FDA granted accelerated approval to
brentuximab vedotin for two indications: The treatment of patients with Hodgkin
lymphoma after failure of autologous stem cell transplant (ASCT) or after failure of at
least two prior multi-agent chemotherapy regimens in patients who are not candidates
for ASCT. And for the treatment of patients with systemic anaplastic large cell
lymphoma (ALCL) after failure of at least one prior multi-agent chemotherapy
regimen.
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Adverse effects and safety: Brentuximab vedotin was studied as monotherapy in 160
patients in two phase II trials. Across both trials, the most common adverse reactions
(≥20%), regardless of causality, were chemotherapy-induced peripheral neuropathy (a
progressive, enduring and often irreversible tingling numbness, intense pain, and
hypersensitivity to cold, beginning in the hands and feet and sometimes involving the
arms and legs), neutropenia (an immune system impairment), fatigue, nausea, anemia,
upper respiratory tract infection, diarrhea, fever, rash, thrombocytopenia, cough and
vomiting.
Dosage and method of administration: Intravenous, 1.8 mg/kg (maximum dose:
180 mg) every 3 weeks.
Pentuzumab (Perjeta; Omnitarg
®):
Classification: Pertuzumab is a humanized monoclonal antibody.
Mechanism: Pertuzumab is designed to bind to the human epidermal growth factor
receptor 2 HER2 and inhibit the ability of HER2 to interact with other HER family
members (HER1, HER2, HER3, and HER4) on the surface of cancer cells. The HER
signaling pathway plays a role in the formation and growth of numerous cancers, and
previous clinical trials of pertuzumab in a single agent setting had suggested clinical
activity - including stable disease - in heavily pretreated patients with advanced
ovarian and breast cancers.
Indications: The FDA approved pertuzumab in June 2012 for the patients with
HER2-positive late-stage (metastatic) breast cancer.
Dosage and method of administration: Pertuzumab injection comes as a solution
(liquid) to be injected into a vein over a 30 to 60 minutes by a doctor or nurse in a
hospital or medical facility. It is usually given every 3 weeks.
Adverse effects and safety: Pertuzumab injection may cause many side effects:
Nausea- diarrhea - decrease in appetite - difficulty falling asleep or staying asleep-
pain, burning, numbness, or tingling in the hands or feet - teary eyes - pale or dry skin
- hair loss and mouth sores.
Trastuzumab emtansine (Kadcyla®):
Classification: Humanized anti-HER2 IgG1, and produced in the mammalian
Chinese Hamster Ovary cells.
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Annual Scientific Harvest 14/4/2015
Mechanism: The antibody portion is trastuzumab, which is humanized anti-HER2
IgG1. The drug portion is DM1, which is a maytansine derivative that inhibits
microtubules. These two portions are covalently connected by 4-[N-
maleimidomethyl] cyclohexane-1-carboxylate (MCC), which is a stable thioether
linker. Together MCC and DM1 are called emtansine and are produced by chemical
synthesis. Ado-trastuzumab emtansine binds to the HER2 receptor‘s sub-domain IV
and goes into the cell by receptor-mediated endocytosis. Lysosomes degrade ado-
trastuzumab emtansine and release DM1. DM1 binds to tubulin in microtubules and
inhibits microtubule function producing cell arrest and apoptosis. As well, similar to
trastuzumab, in vitro studies have shown that both HER2 receptor signalling
inhibition and antibody-dependent cytotoxicity are mediated by ado-trastuzumab
emtansine.
Indications: Ado-trastuzumab is used in HER2-positive, metastatic breast cancer
patients who have already used taxane and/or trastuzumab for metastatic disease or
had their cancer recur within 6 months of adjuvant treatment.
Dosage and method of administration: Usual dose for breast cancer is: 3.6 mg/kg
IV every 3 weeks. The maximum dose: 3.6 mg/kg IV every 3 weeks. Until disease
progression or unacceptable toxicity.
Adverse effects and safety: During clinical trials, the most common adverse effects
of trastuzumab emtansine were fatigue, nausea, musculoskeletal pain,
thrombocytopenia (low platelet counts), headache, increased liver enzyme levels, and
constipation.
Trastuzumab (Herceptin®):
Calssification: The antibody is an IgG1 kappa that contains human framework
regions with the complementarity-determining regions of a murine anti-p185 HER2
antibody that binds to HER2.
Mechanisme: Trastuzumab selectively targets the human epidermal growth factor
receptor 2 protein (HER2). Overexpression of HER2 is observed in 25% - 30% of
primary breast cancers and 7% - 43% of advanced gastric cancers. Trastuzumab
inhibits the proliferation of human tumour cells that overexpress HER2.
Indications: Metastatic breast cancer. Early breast cancer. Advanced gastric cancer.
Herceptin should be avoided during pregnancy and since trastuzumab may persist in
the circulation for up to 27 weeks, pregnancy should be avoided for 7 months after the
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last dose of Herceptin, unless the anticipated benefit for the mother outweighs the
unknown risk to the foetus.
Dosage and method of administration: Adjuvant Treatment of Breast Cancer:
Administer at either: Initial dose of 8 mg/kg over 90 minutes IV infusion, then 6
mg/kg over 30−90 minutes IV infusion every three weeks for 52 weeks. Metastatic
Breast Cancer: Initial dose of 4 mg/kg as a 90 minute IV infusion followed by
subsequent weekly doses of 2 mg/kg as 30 minute IV infusions. Metastatic Gastric
Cancer Initial dose of 8 mg/kg over 90 minutes IV infusion, followed by 6 mg/kg
over 30 to 90 minutes IV infusion every 3 weeks.
Adverse effects and safety: Flu-like symptoms, nausea, diarrhea, headache, dizziness,
joint pain, rash, vomiting or breathlessness. Heart problems such as low blood
pressure or palpitations and these are usually not serious.
Contraindications: Herceptin is contraindicated in patients with known
hypersensitivity to trastuzumab or to any of its excipients.Herceptin.
Interactions: No formal interaction studies have been performed with Herceptin in
humans. Administration of paclitaxel in combination with Herceptin resulted in a
slightly less than two-fold decrease in trastuzumab clearance in a non-human primate
study and in a 1.5-fold increase in Herceptin serum levels in clinical studies.