major seminar1
TRANSCRIPT
GUIADENCE : Mr.RANJITH (M.PHARMACY)
BY: THEERTHALA HARIKIRANROLL NO : 11Y41S0014
ANTICANCERTHERAPY USING MONOCLONAL
ANTIBODIES
Conventional Anti-Cancer Therapy
2
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
3
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
4
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
5
Biotech Resources. 1989. Monoclonal antibody technology -- the basics.
Patho-physiology of Tumor Tissue
6
Angiogenesis
Hyper vasculature
Impaired lymphatic drainage
***Due to these characteristics, tumors can be exploited for
tumor-selective drug delivery
IgG structure
7
3 mechanisms resulting in apoptosis
8
Antigen cross-linking
Activation of death receptors
Blockade of ligand-receptor growth or survival pathways
1. Antigen cross-linking
9
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
10
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
11
3. Delivery of cytotoxic agents
12
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
13
Toxin immunoconjugates
14
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
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
16
Other examples of toxin-immunoconjugates
17
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?
18
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)
19
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
20
Anti-growth factor mAb Therapy
21
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)
22
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
23
24
Toxic effects of Rituximab
Short-lived mild reactions to infusion after first
treatment:
fever
chills
rashes and nausea
25
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
26
Estimated New Cancer Cases and Deaths Worldwide for Leading Cancer Sites by Level of Economic Development, 2008. Source: GLOBOCAN
CONCLUSION
27
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.