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Monoclonal antibodies

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  • 1. Dr. Suhail Qureshi Monoclonal Antibodies
  • 2. Journey so far…  1st generation of MAbs : limited effectiveness in trials  Concerns : Imunogenicity & inefficient effector functions  Murine origin  Development of human antimouse antibody responses  Engineered chimeric, humanized and fully human MAbs redefining cancer therapeutics
  • 3. Monoclonal Antibodies  Monoclonal antibodies (MAbs) are antibodies that are identical because they are produced by one type of immune cell, all clones of a single parent cell.  Hybridoma technology (Kohler & Milstein ; Nobel prize winners 1984) made it possible to produce large quantities of antibodies with high purity and monospecificity for single binding region (epitope) on an antigen  Antibody based conjugates employ targeting specificity of antibodies to deliver toxic compounds like chemotherapy drugs specifically to the tumour site
  • 4. Immunoglobulin structure
  • 5. Immunoglobulin structure  Fab domains mediate the binding of IgG to their cognate Antigens  Each chain in the Fab domain has variable & constant regions  Variable region contains the hypervariable or complementarity determining regions (CDRs)  Ag contact residues reside in the CDRs  The heavy & light chain variable regions each contain three CDRs (CDR 1, 2 &3)  All 6 CDRs combine to form the antigen-binding pocket  CDR3 plays a dominant role
  • 6. Immunoglobulin structure  Fab = Fragment, antigen binding  Fc = Fragment, crystalline  Fc domain : defines the different isotypes of immunoglobulins  The Fc fragment specifies other biological activities of the molecule & determines how an antibody mediates its effector functions. For example, the Fc fragment may determine whether the antibody simply prevents signaling through a receptor, or causes the cell’s destruction through complement fixation or targeting immune effector cells.
  • 7. Unfulfilled Promise?  Early antibodies displayed insufficient activation of human effector functions (i.e. the antibodies did not kill the infecting organism or cell)  Production of human anti-mouse antibodies (HAMA)  Antigen distribution of malignant cells is highly heterogeneous, so some cells may express tumor antigens, while others do not.  Tumor blood flow is not always optimal  High interstitial pressure within the tumor can prevent the passive monoclonal antibody from binding.  Insufficient tumour specificity of target antigens
  • 8. Types of MAb designed  Murine source: Rodent MAbs with excellent affinities & specificities, generated using conventional hybridoma technology. Clinical efficacy compromised by HAMA response, which lead to allergic or immune complex herpersensitivities.  Chimeric : Chimers combine the human constant regions with the intact rodent variable regions. Affinity and specificity unchanged. Also cause human anti- chimeric antibody response (HACA) (30% murine resource)  Humanized : Contain only the CDRs of the rodent variable region grafted onto human variable region
  • 9. Evolution of Therapeutic Antibodies
  • 10. Nomenclature of MAbs PRODUCT SOURCE IDENTIFIERS  -e-  -a-  -i-  -o-  -xi-  -zu-  -u-  Hamster  Rat  Primate  Mouse  Chimeric  Humanized  Human
  • 11. Mechanisms of anti-tumour effects of MAbs  Cell mediated cytotoxicity (ADCC-Antibody dependent cellular cytotoxicity)  Complement dependent cytotoxicity  Immunomodulation E.g. CTLA-4 Inhibitory receptor of T-cell activation Abs directed against CTLA-4Increase CD8+ & CD4+ immune response & induce tumour regression • Altering signal transduction (Bevacizumab-Anti VEGF)
  • 12. Immunoconjugates  Immunotoxins(Eg. BL22) Highly potent, Catalytic action, well defined biology & chemistry  Drug Immunoconjugates (Eg. Gemtuzumab) Proven efficacy of antineoplastic component, well defined efficacy & toxicity, Bystander effect, Internalization not reqd  Radioimmunoconjugates(Eg. Ibritumomab) Multiple available isotopes permit customized approaches, Internalization not reqd, Predictable toxicity based on dosimetry
  • 13. Anti-tumour effects of MAbs
  • 14. Unconjugated Antibodies approved for use in Solid tumours
  • 15. Trastuzumab (Herceptin)  Herceptin is an anti-cancer antibody that acts on HER2/neu (c-erbB-2) receptor, a member of the EGFR family which is overexpressed in 25% breast cancer.  Only cells overexpressing this receptor are susceptible.  Such cells, when treated with Herceptin, undergo arrest in the G1 phase of the cell cycle and experience a reduction in proliferation.  This can reduce the rate of relapse of breast cancer by 50% during the first year in the adjuvant setting  Combination with chemotherapy shows improved responses than chemotherapy alone  Myocardial dysfunction seen with increased frequency
  • 16. Cetuximab (Erbitux)  Targets the EGFR & inhibits ligand induced activation of this tyrosine kinase receptor  Approved for Colorectal Ca & Sq. Cell Ca of Head & Neck  CRC : Combination of Erbitux with Irinotecan increased overall response & median duration of response as compared to Erbitux alone  Patients with KRAS mutations in codon 12 or 13 should not receive anti-EGFR therapy
  • 17. Panitumumab (Vectibix)  Binds to EGFR with a higher affinity than Cetuximab  Interferes with EGFR-Ligand (EGF, TGF α) interactions  Setting : Metastatic CRC  Patients with Metastatic CRC who have KRAS mutations in codon 12 or 13 should not receive this therapy
  • 18. Bevacizumab (Avastin)  Recombinant humanized monoclonal antibody against VEGF-A  Approved in 2004 for use in combination therapy with 5- FU based regimens in the Rx of mCRC  Other approvals: GBM (Prog.disease), Metastatic RCC (with IFN-α) and in combination with Pacli/Carbo for 1st line Rx of unresectable, locally advanced, recurrent or metastatic non-squamous, NSCLC  Binds VEGF & prevents its interaction with its EC receptors (Flt-1)  Side effects : Grade 3 HT, Grade 1 or 2 proteinuria, a slight increase in grade 3 or 4 bleeding & impaired surgical wound healing.
  • 19. Rituximab  Rituximab is a chimeric monoclonal antibody that targets the CD20 B-cell antigen.  This antigen is expressed on 90% of B-cell neoplasms  The precise biological functions of CD20 are uncertain, but the antibody is believed to function by flagging the B-cells for destruction by the body’s own immune system, including ADCC, CDC, and apoptosis.  This antibody thus leads to the elimination of all B-cells from the body (including cancerous ones), allowing new, healthy B-cells to be produced from lymphoid stem cells.
  • 20. Gemtuzumab ozogamicin (Mylotarg)  This monoclonal antibody is conjugated to the cytotoxic agent calicheamycin  It is used to treat relapsed CD33+ acute myeloid leukemia (AML),  This monoclonal antibody attacks the CD33 receptor, which is found in most leukemic blast cells, but not in normal hematopoietic stem cells  Represents the only FDA-approved immunodrug conjugate
  • 21. THANK YOU