1. ANTICANCER
THERAPY USING MONOCLONAL
ANTIBODIES
GUIADENCE : Mr.RANJITH (M.PHARMACY)
BY: THEERTHALA HARIKIRAN
ROLL NO : 11Y41S0014

2. Conventional Anti-Cancer Therapy
Chemotherapy: Imperfect
Systematic nature of cytoxicity
Agents lack intrinsic anti-tumor selectivity
Anti-proliferative mechanism on cells in cycle, rather
than specific toxicity directed towards particular cancer
cell
Host toxicity: treatment discontinued at dose levels well
below dose required to kill all viable tumor cells
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3. History
 Emil von Behring in 1890
Discovered antibodies
 Paul Ehrlich (16 years later)
Coined phrase, “magic bullets and poisoned arrows”
 Kohler and Milstein in 1975
Discovery of monoclonal antibodies (mAb) directed
against well-characterized antigens
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4. Rationale
 Mab as efficient carriers for delivery of anti-tumor agents
Enhanced vascular permeability of circulating
macromolecules for tumor tissue.
Normal tissue: blood vessels have intact endothelial
layer
Tumor tissue: blood vessels leaky and so small
Tumor tissue generally do not have a lymphatic drainage
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system.

5. Production of monoclonal antibodies
Biotech Resources. 1989. Monoclonal antibody technology -- the basics.
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6. Patho-physiology of Tumor Tissue
 Angiogenesis
 Hyper vasculature
 Impaired lymphatic drainage
***Due to these characteristics, tumors can be exploited for
tumor-selective drug delivery
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7. IgG structure
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8. 3 mechanisms resulting in apoptosis
 Antigen cross-linking
 Activation of death receptors
 Blockade of ligand-receptor growth or survival pathways
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9. 1. Antigen cross-linking
 Target growth factor receptor
Antagonize ligand-receptor signaling
Growth-factor signaling mediated by the receptor
tyrosine kinase is inhibited
EGFR (epidermal growth factor receptor)
FGFR (fibroblast growth factor receptor)
VEGFR (vascular endothelial growth factor)
Results in arrest of tumor cell growth
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10. 2. Activation of death receptors
 Death receptors : members of TNF receptors family.
 Cross-link targeted surface antigens on tumor cells and
antibody agonists that mimic ligand-mediated activation
of specific receptors
Response: intracellular Ca II ions increase
Activate caspase-3 and caspase-9 (involved in cell
apoptosis)
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11. Apoptosis pathway
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12. 3. Delivery of cytotoxic agents
 Physically link antibodies to toxic substances for delivery
Radio-immunoconjugates (aim of delivering radiation
directly to the tumor)
Toxin-immunoconjugates (deliver toxins intracellularly)
Antibody-directed enzyme pro-drug therapy (ADEPT):
localize enzymes to tumor cell surfaces
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13. General drug delivery system
 Drug molecules bound to
macromolecule through spacer
molecule
Drug released from
macromolecule after cellular
uptake of the conjugate
Targeting moiety =
monoclonal antibody
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14. Toxin immunoconjugates
3 methods to attach cytotoxic drug to variable regions of
mAb
a. Couple drug to lysine moieties in the mAb
b. Generation of aldehyde groups by oxidizing the
carbohydrate region and subsequent reaction with amino-
containing drugs or drug derivatives
c. Couple drugs to sulfhydryl groups by selectively
reducing the interchain disulfides near the Fc region of
14 the mAb

15. Immunoconjugate
 BR96-doxorubicin conjugate (BR96-DOX)
Promising toxin-immunoconjugate
mouse/human chimeric mAb
Targets antigen over-expressed on surface of human
carcinoma cells of breast, colon, lung, and ovary
Disulfide reduction attaches mAb to drug, BR96
Dose that can be safely administered every 3 weeks is
insufficient
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16. 16

17. Other examples of toxin-
immunoconjugates
KS1/4-MTX
Conjugate of methotrexate (MTX)
Coupling of MTX to the lysine moieties of the mAb
KS1/4-DAVLB
Conjugate of vinca alkaloid derivatives
Vinca alkaloid derivatives attached to amino groups of
lysine residues on KS1/4 mAb
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18. Why are these toxin-immunoconjugates
unsuccessful?
 Cause gastrointestinal toxicity
 Inner regions of solid tumors poorly vascularized and have
low blood flow (reduce amount of immunoconjugate
reaching these parts of the tumor)
 Antigen expression is heterogenous on tumor cells
Restricts the amount of cells that can be effectively
targeted by antibody conjugates
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19. ADEPT ENZYMES (Antibody-
directed enzyme pro-drug therapy)
 Chemically link the mAb to the enzyme of interest; can
also be a fusion protein produced recombinantly with the
antibody variable region genes and the gene coding the
enzyme
 Convert subsequently administered anti-cancer pro-drugs
into active anti-tumor agents
Upon binding to targeted enzymes, it is converted into
active drug
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20. Flow chart view
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21. Anti-growth factor mAb Therapy
 Angiogenesis
Formation of nascent blood vessels
 VEGF
Protect endothelial cells from apoptosis
Activity mediated by tyrosine kinase receptors, VEGFR
1 and VEGFR 2
Functions indirectly as survival factor for tumor cells
 Inhibit VEGF signaling
Block the receptor
Inhibits tumor growth and metastasis
Deprives tumors of nutrient-providing blood vessels
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22. RITUXIMAB (rituxan)
 1st therapeutic mAb approved by FDA in 1997
 CD20 antigen function: cell cycle progression
 Binding Rituximab to CD-20 causes: autophosphorylation,
activation of serine/tyrosine protein kinases -- induces
apoptosis
 Response rates of 50% to 70% in follicular lymphomas
 Response rates of 90% to 100% when used in combination
with various chemotherpay procedures
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23. MECHANISM OF ACTION
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24. Toxic effects of Rituximab
 Short-lived mild reactions to infusion after first
treatment:
 fever
 chills
 rashes and nausea
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25. FDA-approved monoclonal antibodies for cancer treatment
Name of drug Type of cancer it treats
Alemtuzumab (Campath) Chronic lymphocytic leukemia
Brain cancer
Colon cancer
Bevacizumab (Avastin)
Kidney cancer
Lung cancer
Colon cancer
Cetuximab (Erbitux)
Head and neck cancers
Source: Food and Drug Administration (FDA), Center for Drug Evaluation and Research
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26. Estimated New Cancer Cases and Deaths Worldwide for Leading Cancer Sites by Level of
Economic Development, 2008. Source: GLOBOCAN
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27. CONCLUSION
 Researchers hope to define the optimal combinations of the
use of mAb with conventional chemotherapeutic agents and
with radiation therapy
 Determine best therapy candidates and expand clinical
trials to other tumor types.
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