This document discusses monoclonal antibodies (mAbs) and their applications in cancer therapy. It describes how mAbs are produced, the different types (murine, chimeric, humanized, human), and their mechanisms of antitumor effects such as antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Examples of mAbs used in cancer treatment are discussed, including cetuximab, panitumumab, bevacizumab, and alemtuzumab. The document also covers mAb-conjugates such as those linked to toxins, radioisotopes (e.g. ibritumomab), and immunoliposomes for targeted drug delivery.

1. Monoclonal Antibodies in Cancer therapy
By
Mr. Ankit Tribhuvane

2. INDEX
1. Introduction
2. Discovery
3. Production of monoclonal Antibodies
4. Types
5. Apllications
6. Antitumor MABs
7. Mechanism of antitumor effect
8. ADEPT (Antibody directed enzyms prodrug therapy)
9. MABs conjugate with radioisotopes
10. Conclusion
11. REFERENCES

3. Introduction
• Monoclonal Antibodies that are identical because they were produced by
one type of immune cell (B cell), all clones of a single parent cell.
• specifically bind to target cells. This may then stimulate the patient's
immune system to attack those cells.
• It is possible to create a mab specific to almost any extracellular/ cell
surface target, and thus there is a large amount of research and
development currently being undergone to create monoclonals for
numerous serious diseases (such as rheumatoid arthritis, multiple
sclerosis and different types of cancers).

4. Discovery
Production of monoclonal antibodies involving human–mouse hybrid
cells was described by Jerrold Schwaber in 1973
In 1988, Greg Winter and his team pioneered the techniques to
humanize monoclonal antibodies

5. Production of monoclonal antibodies
• By HYBRIDOMA TECHNIQUE

6. Types of Monoclonal Antibodies

7. Murine antibody
• Whole of the antibody is of murine origin
 Major problems associated with murine antibodies include
• reduced stimulation of cytotoxicity
• Formation of complexes after repeated administration
• allergic reactions
• anaphylactic shock

8. Chimeric antibodies
 Chimeric antibodies are composed of
murine variable regions fused onto
human constant regions.
 Antibodies are approximately 65% human.
 This reduces immunogenicity and thus
increases serum half-life.

9. Humanised mab
• Humanised antibodies are
produced by grafting murine
hypervariable amino acid domains
into human antibodies.
• This results in a molecule of
approximately 95% human origin

10. Human Monoclonal antibody
Human monoclonal antibodies are produced by transferring human
immunoglobulin genes into the murine genome, after which the
transgenic mouse is vaccinated against the desired antigen, leading to the
production of monoclonal antibodies

11. Applications of Monoclonal Antibodies
 Diagnostic Applications
- Detects protein of interest either by blotting
or immunofloroscence
 Therapeutic Applications
• Transplant rejection
• Cancer
• Autoimmune disorders
• Inflammatory disease

12. Antitumor MABs

13. A.Murin source mAbs:
rodent mAbs with excellent affinities and specificities, generated using
conventional hydrioma technology. Clinical efficacy compromised by
HAMA(human anti murine antibody) response, which lead to allergic or
immune complex herpersensitivities.
B.Chimeric mAbs:
chimers combine the human constant regions with the intact rodent
variable regions. Affinity and specificity unchanged. Also cause human
antichimeric antibody response (30% murine resource)
C.Humanized mAbs:
contained only the CDRs of the rodent variable region grafted onto
human variable region framework

14. Mechanism of antitumor effect
• Antibody dependent cellular cytotoxicity (ADCC)
• Complement dependent cytotoxicity (CDC)
• Direct induction of apoptosis
• mab may be conjugated with a toxin e.g. gemtuzumab-ozogamicin
• mab can also be conjugated with radioisotope

15. A. mAbs act directely when binding to a cancer specific antigens and
induce immunological response to cancer cells. Such as inducing cancer
cell apoptosis, inhibiting growth, or interfering with a key function.
B. mAbs was modified for delivery of a toxin, radioisotope, cytokine or
other active conjugates.
C. it is also possible to design bispecific antibodies that can bind with their
Fab regions both to target antigen and to a conjugate or effector cell

16. ADEPT (Antibody Directed Enzyme Prodrug Therapy)
 Involves the application of
cancer associated monoclonal
antibodies which are linked to
a drug-activating enzyme.
 Subsequent systemic
administration of a non-toxic
agent results in its conversion
to a toxic drug, and resulting
in a cytotoxic effect which can
be targeted at malignant cells.

17. Immunoliposomes
• Immunoliposomes are antibody-conjugated liposomes.
• Liposomes can carry drugs or therapeutic nucleotides and when
conjugated with monoclonal antibodies.

18. Cetuximab, Panitumumab
• MAB that targets epidermal growth factor receptor (EGFR)
• Binding of cetuximab to EGFR inhibits tumor growth by variety of
mechanisms, including decrease in kinase activity, MMP activity, growth
factor production and increased apoptosis
• Approved for metastatic colorectal carcinoma whose tumor
overexpresses EGFR.
• Cetuximab 400 mg/kg loading followed by 200 mg/kg weekly IV alone or
in combination with irinotecan

19. Bevacizumab, Ranibizumab
• Humanized antibody against Vascular endothelial growth facto, thus
preventing angiogenesis
• Approved 5 mg/kg IV every 2 weekly ,For non–small-cell lung cancer.
• S/E – Since it is antiangiogenic, pt should be watched for hemorrhage, GI
perforations and wound healing problems

20. Alemtuzumab
• Humanised anti CD52 antiboby that binds to normal and malignant B and
T cells, NK cells
• Approved 30 mg IV once weekly for treatment of B-cell CLL failed to
respond to alkylating agents
• S/E – neutropenia, thrombocytopenia, pt should be closely monitored for
opportunistic infections
Some others-
• Gemtuzumab
• Rituximab
• Ofatumumab
• Trastuzumab
• Denileukin diftitox

21. MABs conjugated with radioisotopes
• Provide targeted delivery of radionucleotides to tumor cells
• generally preferred because it is readily available, inexpensive and easily
conjugated
• Can be used for diagnosis as well as therapeutic purpose
Ibritumomab
• Anti CD20 murine antibody coupled with isotopic yttrium (90
Y)
• Approved for refractory B cell non hodgkins lymphoma, not even responding
to rituximab therapy
• S/E – common to both ibritumomab and
tositumomab are severe cytopenias

22. Tositumumab
• Used for refractory non hodgkins lymphoma not responding to rituximab and
chemotherapy agents.
Drugs in pipeline-
• Ibalizumab: an anti-CD4 monoclonal antibody for the treatment of HIV-1
infection
• HN125: A Novel Immunoadhesin Targeting MUC16 with Potential for
ovarian cancer Therapy.
• AMU32901 - Anti-phospholipid human monoclonal antibodies inhibit
CCR5-tropic HIV-1

23. Conclusion
• Antigen specific, can be produced against any type of antigen, hence vast
diagnostic applications
• Target specificity, a novel therapeutic approach particularly in cancer

24. References
• Douglas Lake, Immunopharmacology; Bertram G. Katzung, Basic and
clinical pharmacology:11:963-85;2009
• Bruce A. Chamber, Jeol Neal et.al, Targeted therapies, Tyrosine kinase
inhibitors, monoclonal antibodies; Goodman and Gilmans,
Pharmacological basis of therapeutics; 12;1731-50; 2010.
• Ronald V.M.,Immunomodulation; Harrisons Principle of internal medicine;
17; 1600-20;2009.
• HL Sharma and KK Sharma, Immunomodulation and immunotherapy,
Principles of Pharmacology;2;871-91;2010
• Tripathi K.D.,Immunotherapy; Essentials to medical pharmacology; 6;710-
18;2009

25. • Raben D, Helfrich B,The effects of cetuximab alone and in combination
with radiation and/or chemotherapy in lung cancer, PubMed; 2010
• Uehara K, Ishiguro S, Bevacizumab for Locally Advanced Rectal Cancer,
Pub Med; 2009
• Bruno CJ, Jacobson JM, Ibalizumab: an anti-CD4 monoclonal antibody for
the treatment of HIV-1 infection; J Antimicrob Chemother;1839-41; 2010