Monoclonal antibodies dr.elza

Monoclonal antibodies

1. MONOCLONAL ANTIBODIES By Dr. Elza Joy Munjely JR III Dpmt of Pharmacology Govt.Medical College,Kottayam

2. Those antibodies which are produced by a single clone of B lymphocytes and are directed against a single antigenic determinant

3. How are they made? Hybridoma technology Hybridoma = Specific B-lymphocyte + Mouse myeloma cell Retains the antibody forming ability of B-lymphocyte & the ability of myeloma cell to proliferate endlessly

4. Hybridoma Technology 1975, Georges K ö hler and Cesar Milstein - Nobel Prize in1984

5. Prof.Niels Kaj Jerne Prof.Georges J. F. Köhler Prof.César Milstein Hybridoma Technology 1975-Discovery,Nobel Prize in Medicine & Physiology 1984

6. Mouse immunized with antigen X Spleen cells Cell-culture Myeloma line Myeloma cells Fused in Polyethylene Glycol to produce Hybridomas Transfered to HAT medium Unfused plasma & myeloma Cells die Hybridomas that produce antibodies specifically against Antigen X are selected & Grown in bulk Monoclonal antibodies

7. Light chain Heavy chain Variable regions Of heavy & Light chains Constant regions Of heavy & Light chains ANTIBODY

8. Classification Murine Chimeric Humanised Human Highly immunogenic Least immunogenic 100% mouse 30% mouse 5-10% mouse 100% human

9. Nomenclature tu - tumour vi - virus ci - circulation If no prefix - immunomodulator Murine Chimeric Humanised Human omab ximab zumab umab

10. Examples Murine Chimeric Humanised Human omab ximab zumab umab Murom onab Ri tu ximab Ab ci ximab Infli ximab Alem tu zumab Beva ci zumab Tras tu zumab Omali zumab Pali vi zumab Adalim umab

11. Armed & unarmed monoclonal Abs ‘Unarmed / Naked’ Armed Not fused to a toxin Fused with a toxin or a radioisotope Acritumomab - labeled with Technetium 99  immunoscintigraphy Ibritumomab - labeled with Yttrium 90 relapsed/refractory low grade follicular/B-cell NHL

12. Mechanisms of anti- tumour effects of MAbs ADCC -Antibody dependent cellular cytotoxicity CDC - Complement dependent cytotoxicity Immunomodulation Altering signal transduction

13. Pharmacokinetics Routes of administration : Subcutaneously (Rituximab, Trastuzumab , Adalimumab ) Intramuscularly ( Palivizumab ) Intravenously IV route: preferred because of 100% bioavailability Route for elimination of antibodies Via uptake & catabolism by reticuloendothelial system & target tissue.

14. Patients treated with murine mAbs develop a Human Antimouse Antibody (HAMA) response which develops 7–10 days following exposure to murine antibody Rapid clearance of the mAb Poor tumour penetration Hypersensitivity reactions Half-life Chimeric : 4 –15 days Humanized: 3 - 24 days Recombinant human: 11– 24 days Pharmacokinetics

15. Allergic reactions, such as hives or itching Flu-like symptoms, including chills, fatigue, fever, muscle aches and pains Nausea Diarrhea Skin rashes Infection - infliximab Bone marrow suppression Cardiomyopathy – T rastuzumab Thromboembolism - Bevacizumab Side effects of monoclonal antibody

16. Uses of Mabs

17. THERAPEUTIC CLASSIFICATION Antitumor MABs MABs Used to Deliver Isotopes & Toxins to Tumors MABs Used as Immunosuppressants & Anti-Inflammatory Agents Other MABs

18. Antitumor MABs MABs Used to Deliver Isotopes & Toxins to Tumors MABs Used as Immunosuppressants & Anti-Inflammatory Agents Alemtuzumab Bevacizumab Cetuximab Panitumumab Rituximab Trastuzumab Toxin-linked MAbs : Gemtuzumab ozogamicin Radioisotope carrying MAbs : Ibritumomab (90Y) Tositumomab (131I) Muromonab - Anti CD-3 antibody Daclizumab, Basiliximab - IL-2 receptor antagonists Infliximab , Adalimumab - TNF α inhibitors: Omalizumab - Anti- IgE antibody

19. List of some important Mab Therapeutic agent Indication Alemtuzumab (CD52) B cell CLL Bevacizumab (VEGF) Met. Colorectal cancer Ranibizumab (VEGF-A) Neovas . Macular degeneration Cetuximab (EGFR) Met. Colorectal cancer Gemtuzumab (CD33) AML Panitumumab (EGFR) Met. Colorectal cancer Rituximab (CD20) Low grade NHL Trastuzumab (HER-2/ neu ) Met. Breast cancer Eculizumab (C5) PNH

20. List of some important Mab Therapeutic agent Indi cation Basiliximab (IL-2 Receptor) Renal, heart transplant Daclizumab (IL-2 Receptor) Renal transplant, M.Sclerosis Efalizumab (CD11a) Psoriasis Adalimumab (TNF α ) RA Infliximab (TNF α ) RA Abciximab ( GPIIb / IIIa receptor Acute coronary syndrome on activated platelets) Omalizumab ( IgE Ab ) Allergic asthma Palivizumab RSV infection Natalizumab ( integrins ) M.Sclerosis,Crohn’s disease