1. Monoclonal Antibodies And Their Use in The Treatment Of Cancer 1

2. Contents: Monoclonal Antibodies History Production of Monoclonal Antibodies Types of Monoclonal Antibodies Nomenclature How Monoclonal Antibodies work? Antibodies approved for use in Cancer treatment 2 3. Monoclonal Antibodies are cells derived by cell division from a single ancestral cell. It is a class of antibodies with identical offspring of a hybridoma and are very specific for a particular location in the body derived from a single clone and can be grown indefinitely. Monoclonal Antibodies recognize and bind to antigens in order to discriminate between specific epitopes which provides protection against disease organisms. Monoclonal Antibodies 3 4. Discovery The idea of a "magic bullet" was first proposed by Paul Ehrlich who at the beginning of the 20th century postulated that if a compound could be made that selectively targeted a disease-causing organism, then a toxin for that organism could be delivered along with the agent of selectivity. 4 5. 5 6. In 1988 Greg Winter and his team pioneered the techniques to humanize monoclonal antibodies, removing the reactions that many monoclonal antibodies caused in some patients. 6 7. Production of monoclonal antibodies: Somelymphocytes (called B lymphocytes) make antibodies but cannot divide. Scientists combine mouse B lymphocytes which have been stimulated to make a particular antibody with a type of tumour cell to make a cell called ahybridoma. Hybridoma cells can both make a specific antibody and divide. The hybridoma cells are cloned to make a large number of identical cells which all make the same antibodies. The antibodies are collected and purified. These are monoclonal antibodies - antibodies from a single clone of cells 7 8. Production of monoclonal antibodies 8 9. Types of Monoclonal Antibodies 9 10. 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 Murine source Mab 10 11. 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) Chimeric Monoclonal Antibody 11 12. Contained only the CDRs of the rodent variable region grafted onto human variable region framework Humanized Mab 12 13. Nomenclature Every monoclonal antibody has the following components in its name Variable-Target Substem-Source Substem-Stem-Additional words(in special cases) 13 14. Bevacizumab So Bevacizumab is a Humanised Monoclonal Antibody targetting a protein in Circulatory System Beva- Variable ci- Circulatory System zu- Humanised mab- Monoclonal Antibody Example 14 15. Rituximab So Rituximab is a Chimeric Monoclonal Antibody targetting a Tumour Ri- Variable tu- Tumour xi- Chimeric mab- Monoclonal Antibody 15 16. How monoclonal antibodies work??? 16 17. By Triggering the immune system Video 18. By Blocking signals telling cancer cells to divide Video 19. By Carrying cancer drugs or radiation to cancer cells Video 20. . Antibodies approved for use in cancer treatment 20 21. RITUXIMAB Rituximab is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. The antibody is an IgG1 kappa immunoglobulin containing murine light- and heavy-chain variable region sequences and human constant region sequences. Rituximab is composed of two heavy chains of 451 amino acids and two light chains of 213 amino acids 21 22. Therapeutic indications: For treatment of CD20-positive non-Hodgkins lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis. 22 23. Rituximab binds to the CD20 antigen, which is predominantly expressed on mature B cells and on >90% of B-cell non-Hodgkin's lympohomas. The antibody leads to selective killing of B-cells The Fab regions of rituximab binds to the CD20 antigen on B lymphocytes, while the Fc domain recruits antibodies and complements to mediate cell lysis. Mechanism of action: 23 24. Adverse Effects Hypotension Bronchospasm Angioedema Chills Fever Cardiac Arrythmias Tumour Lysis Syndrome (This Syndrome consists of acute renal failure that may require dailysis, hyperkalemia, hypercalcemia, hyperuricemia, hyperphosphatasemia, leukopenia 24 25. Therapeutic indication: For treatment of EGFR-expressing metastatic colorectal cancer in patients who are refractory to other irinotecan-based chemotherapy regimens. Cetuximab is also indicated for treatment of squamous cell carcinoma of the head and neck in conjucntion with radiation therapy. Cetuximab 25 26. Mechanism of action: Cetuximab binds to the epidermal growth factor receptor (EGFr) on both normal and tumor cells. EGFr is over-expressed in many colorectal cancers. Cetuximab competitively inhibits the binding of epidermal growth factor (EGF) and TGF alpha, thereby reducing their effects on cell growth and metastatic spread. 26 27. Used in the treatment of colorectal cancer, cetuximab binds specifically to the epidermal growth factor receptor (EGFr, HER1, c-ErbB-1) on both normal and tumor cells. EGFr is over-expressed in many colorectal cancers. Cetuximab competitively inhibits the binding of epidermal growth factor (EGF) and other ligands, such as transforming growth factoralpha. Binding of cetuximab to the EGFr blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, decreased matrix metalloproteinase secretion and reduced vascular endothelial growth factor production. 27 28. Adverse Reactions: Rash Fever Constipation Abdominal pain 28 29. Bevazicumab Therapeutic indications: As part of combination therapy for metastatic colorectal cancer and HER2-negative metastatic breast cancer. 29 30. Mechanism of Action: Bevacizumab binds VEGF and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. This prevents blood vessel proliferation and tumour metastasis. 30 31. Bevacizumab prevents or reduces the formation of blood vessels (angiogenesis) thereby preventing or reducing metatstatic disease progressing. Bevacizumab binds VEGF and prevents vascular endothelial growth and endothelial cell proliferation. 31 32. Adverse Effects: Poor wound healing, Impaired collateral formation around Atherosclerotic vessels, Hypertension and Bleeding. 32 33. Trastuzumab Therapeutic indications: For treatment of early stage HER2-positive breast cancer, or metastatic breast cancer that substantially overexpress HER2. 33 34. Mechanism of Action: Trastuzumab binds to the HER2 (or c- erbB2) proto-oncogene, an EGF receptor- like protein found on 20-30% of breast cancer cells. The binding leads to antibody mediated (complement mediated) killing of the HER2 positive cells. 34 35. Used in the treatment of HER2- positive breast cancer. HER2 protein overexpression is observed in 25%-30% of primary breast cancers.Trastuzumab has been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumor cells that overexpress HER2. It is a mediator of antibody dependent cellular cytotoxicity, in that the binding of the antibody to HER2 overexpressing cells leads to preferential cell death. 35 36. Congestive heart failure Fever Chills Headache Dizziness Nausea Adverse Reactions 36 37. 37