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- 1. Presented by Gajeshwar prasad M.S (Pharm.) Pharmacology & Toxicology s Under the guidance of Dr. (Prof.) Mangala Lahkar, Chief Academic Coordinator National Institute of Pharmaceutical Education and Research
- 2. INTRODUCTION Antibodies are group of glycoprotein molecules present in blood serum and tissue fluid. These are produced by a specialized group of cells called B-lymphocytes (plasma cells) in mammals. Antibodies are a part of defence system to protect the body against the invading foreign substance namely antigen (antibody generator or immunogen). Each antigen has specific antigenic determinants (epitopes) site located on it .Antibodies have complementary determining region(CDRs) which are mainly responsible for the antibody specificity. In response to an antigen (with several different epitopes), B-lymphocytes gear up and produce many different antibodies. Antibodies which can react with same antigen known as polyclonal antibodies.
- 5. HISTORY OF MONOCLONAL ANTIBODY 1964 Littlefield developed a way to isolate hybrid cells from 2 parent cell lines using the hypoxanthine-aminopterin-thymidine (HAT) selection media 1975 Kohler and Milstein provided the most outstanding proof of the clonal selection theory by fusion of normal and malignant cells. This resulted in the first monoclonal antibodies, for which they received the Nobel Prize in 1984.
- 6. DISCOVERY!!! The idea of a "magic bullet" was first proposed by Paul Ehrlich at beginning of 20th century. He 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 agent of selectivity.
- 7. DISCOVERY!!! George Kohler & Cesar Milstein in 1975 shared the Nobel Prize in Physiology or Medicine in 1984 for discovery of hybridoma technology.
- 8. MONOCLONAL ANTIBODY They are monospecific antibodies that are the same because they are made by identical immune cells that are all clones of a unique parent cell They have monovalent affinity, in that they bind to the same epitope. Given almost any substance, it is possible to produce monoclonal antibodies that specifically bind to that substance; they can then serve to detect that substance.
- 9. TYPES OF MONO-CLONAL ANTIBODIES 1- According To Evolution 2- According to design Throughout the progression of monoclonal drug development there have been four major antibody types developed: First generation murine Second generation Chimeric Humanised human. Naked Monoclonal Antibody Conjugated Monoclonal Antibody Immune-Toxin Monoclonal Antibody
- 10. THE MYELOMA THEORY In the 1970’s the B-cell cancer myeloma was discovered, and it was understood that these cancerous B-cells all produce a single type of antibody. This was used to study the structure of antibodies, but it was not possible to produce identical antibodies specific to a given antigen.
- 11. MYELOMA CELL Lost the ability to synthesize hypoxanthine-guanine-phosphoribosyl transferase (HGPRT). This enzyme enables cells to synthesize purines using an extracellular source of hypoxanthine as a precursor. Ordinarily, the absence of HGPRT is not a problem for the cell because cells have an alternate (de novo)pathway that they can use to synthesize purines. However, when cells are exposed to aminopterin (a folic acid analog), they are unable to use de novo pathway and are now fully dependent on HGPRT for survival.
- 12. B cell B cell has the enzyme HGPRT But B cells die soon They do not have the capacity to grow indefinitely because of their limited life span Scanning Electron Microscopic view of a B cell
- 13. HYBRIDOMA TECHNOLOGY 1. Immunisation of a mouse 2. Isolation of B cells from the spleen. 3. Cultivation of myeloma cells. 4. Fusion of myeloma and B cells. 5. Separation of cell lines. 6. Screening of suitable cell lines. 7. in vitro (a) or in vivo (b) multiplication. 8. Harvesting
- 16. ADVANTAGES 1)Homogeneity: Monoclonal antibody represents a single antibody molecule that binds to antigens with the same affinity and promote the same effectors functions. 2) Specificity: • The product of a single hybridoma reacts with the same epitope on antigens. 3) Immunizing Antigen: • Need not be characterized and is ultimately not needed in large quantities to produce large quantities of antibody. 4) Selection: • It is possible to select for specific epitope specificities and generate antibodies against a wider range of antigenic determinants. 5) Antibody Production: • Unlimited quantities of a single well-defined monospecific reagent
- 17. DISADVANTAGES Average affinity of monoclonal antibodies are generally lower than polyclonal antibodies Monoclonals against conformational epitopes on native proteins may lose reactivity with antigens. Antibodies sometimes display unexpected crossreactions with unrelated antigens. Time and effort commitment: VERY LARGE. Immune rejections
- 18. ADVERSE EFFECTS Fever Chills Weakness Headache Nausea Vomiting Diarrhea Rashes Hypo/Hypertension
- 19. APPLICATION Diagnostic applications : Biochemical test – Pregnancy Cancers Hormonal disorder Infectious diseases Diagnostic imaging – Myocardial infraction Deep vein thrombosis Cancers Bacterial infection
- 20. Cont..... THERAPEUTIC APPLICATION MAbs as Direct therapeutic agents – Pathogenic organisms Cancer treatment Immunosuppression AIDS treatment Autoimmune diseases MAbs as targeting agents – Immunotoxin (cancer) Drug delivery Dissolving blood clot Radioimmunotherapy (of tumors)
- 21. Cont..... Protein purification & drugs Counteract transplant rejection
- 22. NEW METHODS Nowadays ,two new alternative methods are also available for production of monoclonal antibody – Phase Display Transgenic mice
- 23. List of FDA’s Approved Monoclonal antibody Antibody Brand name Target Indication year Muromonab- CD3 Orthoclone- Okt3 CD3; Murine IgG2a Reversal of kidney transplant rejection 1986 Rituximab Rituxan CD20; Chimeric IgG1 Non-Hodgkin's lymphoma 1997 Infliximab Remicade TNFa; Chimeric IgG1 Crohn disease 1998 Trastuzumab Herceptin HER2; Humanized IgG1 Breast cancer 1998 Adalimumab Humira TNF; Human IgG1 Rheumatoid arthritis 2002 Omalizumab Xolair IgE; Humanized IgG1 Asthma 2003 Bevacizumab Avastin VEGF; Humanized IgG1 Colorectal cancer 2004
- 24. List of FDA’s Approved Monoclonal antibody Antibody Brand name Target Indication year Ustekinumab Stelara IL12/23; Human IgG1 Psoriasis 2009 Tocilizumab Actemra IL6R; Humanized IgG1 Rheumatoid arthritis 2010 Brentuximab vedotin Adcetris CD30; Chimeric IgG1; immunoconjugate Hodgkin lymphoma, systemic anaplastic large cell lymphoma 2011 Pertuzumab Perjeta HER2; humanized IgG1 Breast Cancer 2012 Adotrastuzumab emtansine Kadcyla HER2; humanized IgG1; immunoconjugate Breast cancer 2013 Obinutuzumab Gazyva CD20; Humanized IgG1; Glycoengineered Chronic lymphocytic leukemia 2013
- 25. List of FDA’s Approved Monoclonal antibody Antibody Brand name Target Indication year Siltuximab Sylvant IL-6; Chimeric IgG1 Castleman disease 2014 Vedolizumab Entyvio α4β7 integrin; humanized IgG1 Ulcerative colitis, Crohn disease 2014 Ramucirumab Cyramza VEGFR2; Human IgG1 Gastric cancer 2014 Pembrolizumab Keytruda PD1; Humanized IgG4 Melanoma 2014 Evolocumab PCSK9; Human IgG2 High cholesterol Review Secukinumab IL-17a; Human IgG1 Psoriasis Review Nivolumab PD1; Human IgG4 Melanoma, non-small cell lung cancer Review
- 26. List of FDA’s Approved Monoclonal antibody Antibody Brand name Target Indication year Blinatumomab CD19, CD3; Murine bispecific tandem scFv Acute lymphoblastic leukemia Review Necitumumab EGFR; Human IgG1 Non-small cell lung cancer Review Mepolizumab IL-5; Humanized IgG1 Severe eosinophilic asthma Review
- 28. CONCLUSION Monoclonal antibodies are Antigen specific, can be produced against any type of antigen, hence vast diagnostic applications. Target specificity, a novel therapeutic approach particularly in cancer.
- 29. REFERENCE Justin K.H. Liu* “The history of monoclonal antibody development - Progress, remaining challenges and future innovations” T.Mohammad, Funelas C.,and Suria H.“Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies” Golay j., Introna M.“Mechanism of action of therapeutic monoclonal antibodies: Promises and pitfalls of in vitro and in vivo assays” www. wikipedia.com/monoclonal antibodies U.satyanararayana, “Biotechnology”