GUIADENCE : Mr.RANJITH (M.PHARMACY)

BY: THEERTHALA HARIKIRANROLL NO : 11Y41S0014

ANTICANCERTHERAPY USING MONOCLONAL

ANTIBODIES

Conventional Anti-Cancer Therapy

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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

History

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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

Rationale

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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

system.

Production of monoclonal antibodies

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Biotech Resources. 1989. Monoclonal antibody technology -- the basics.

Patho-physiology of Tumor Tissue

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Angiogenesis

Hyper vasculature

Impaired lymphatic drainage

***Due to these characteristics, tumors can be exploited for

tumor-selective drug delivery

IgG structure

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3 mechanisms resulting in apoptosis

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Antigen cross-linking

Activation of death receptors

Blockade of ligand-receptor growth or survival pathways

1. Antigen cross-linking

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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

2. Activation of death receptors

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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)

Apoptosis pathway

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3. Delivery of cytotoxic agents

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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

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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Toxin immunoconjugates

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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

the mAb

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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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Other examples of toxin-immunoconjugates

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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

Why are these toxin-immunoconjugates unsuccessful?

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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

ADEPT ENZYMES (Antibody-directed enzyme pro-drug therapy)

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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

Flow chart view

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Anti-growth factor mAb Therapy

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AngiogenesisFormation of nascent blood vessels

VEGFProtect endothelial cells from apoptosis Activity mediated by tyrosine kinase receptors, VEGFR

1 and VEGFR 2Functions indirectly as survival factor for tumor cells

Inhibit VEGF signalingBlock the receptorInhibits tumor growth and metastasisDeprives tumors of nutrient-providing blood vessels

RITUXIMAB (rituxan)

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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

MECHANISM OF ACTION

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Toxic effects of Rituximab

Short-lived mild reactions to infusion after first

treatment:

fever

chills

rashes and nausea

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FDA-approved monoclonal antibodies for cancer treatment

Name of drug Type of cancer it treats

Alemtuzumab (Campath) Chronic lymphocytic leukemia

Bevacizumab (Avastin)

Brain cancer Colon cancerKidney cancer Lung cancer

Cetuximab (Erbitux)Colon cancerHead and neck cancers

Source: Food and Drug Administration (FDA), Center for Drug Evaluation and Research

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Estimated New Cancer Cases and Deaths Worldwide for Leading Cancer Sites by Level of Economic Development, 2008. Source: GLOBOCAN

CONCLUSION

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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.