monoclonal antibodies as therapeutic agents

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MONOCLONAL ANTIBODIES AS THERAPEUTIC AGENTS:

MONOCLONAL ANTIBODIES AS THERAPEUTIC AGENTS UNDER THE GUIDANCEOF R.RAGHUVEER Asst.professor Cmr college of pharmacy PRESENTED BY T.MOUNIKA M.PHARMACY 1 ST YEAR Phrmacology Cmr college of pharmacy 2

contents:

contents Introduction Types of monoclonal antibodies History Production of mAbs Therapeutic applications Conclusion References 3

introduction:

introduction What are antibodies..??? Antibody is a protein produced by plasma cells in response to a specific antigen. 4

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MONOCLONAL ANTIBODIES An antibody produced by a single clone of cells. monoclonal antibody is a single pure type of antibody. Monospecific antibodies are identical because they are produced by one type of immune cell that are all clones of a single parent cell. 5

Structure of antibody:

Structure of antibody 6

Functions of antibody:

Functions of antibody Antibodies have two major functions : Recognize and bind antigen Induce immune responses after binding The variable region mediates binding Affinity for a given antigen is determined by the variable region The variable region confers absolute specificity for an antigen The constant region mediates immune response after binding Different classes of constant regions generate different isotypes Different isotypes of antibody have differing properties 7

history:

history 1975 : Hybridoma Technology George Kohler and Cesar Milstein devised a method to obtain large amounts of a mAb. 1984 : The Nobel Prize for Medicine - In 1988, Greg Winter et al pioneered the techniques to humanize monoclonal antibodies 8

TYPES OF ANTIBODIES:

TYPES OF ANTIBODIES Human: - umab Humanized: - zumab Murine : - momab Chimeric : - ximab 9

evolution:

evolution 10

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METHODS OF PRODUCTION 11

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Therapeutic applications:

Therapeutic applications 13

Tissue transplantation:

Tissue transplantation Muromonoab-CD3: Muromonoab-CD3 is used for the treatment of acute organ transplant rejection. It is effective in preventing graft rejection after kidney, heart or livertransplantation . Muromonoab-CD3 is effective in patients who after acute cardiac or liver allograft rejection do not respond to steroid therapy. 14

In psoriasis:

In psoriasis Psoriasis is a disease of the immune system that involves T lymphocytes. The etiology and pathogenesis of psoriasis results from complex communications that cause activation of T lymphocytes and trafficking to the skin. Further reactivation causes inflammation and overproduction of skin, resulting in lesions and plaques 15

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Efalizumab is a humanized IgG1_ antibody produced by recombinant DNA technology. It exhibits immunosuppressive function. It binds to CD11a, which is the α-subunit of leukocyte function antigen (LFA)-1. Efalizumab decreases the cell surface expression of CD11a, which is expressed on all leukocytes. 16

Rheumatoid arthritis: :

Rheumatoid arthritis: Monoclonal antibodies have been shown to be clinically effective in suppressing inflammation in RA. They may be used to treat disease flares and in combination with conventional DMARDs to achieve better disease control. some mAbs, such as anti-CD4,improve disease for a prolonged period in animal models of RA. 17

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Infliximab ( Remicade ): It is a chimeric monoclonal antibody produced by recombinant DNA technology and is directed against TNF-α. It is composed of human constant and mouse variable regions. Infliximab binds to the soluble and the membrane bound form of TNFα , resulting in the neutralization of its biological activity. 18

Thrombosis :

Thrombosis Abciximab ( ReoPro ) Abciximab is a Fab fragment of a chimeric monoclonal antibody that is directed against GPIIb / IIIa receptors. These receptors are located on platelets where they are involved in platelet aggregation. Abciximab inhibits platelet aggregation by blocking GPIIb / IIIa receptors, thus preventing the binding of fibrinogen, vonWillebrand factor and other molecules promoting adhesion to the receptors on platelets. It increases bleeding and activated clotting times and reduces the response of platelets to adenosine diphosphate . 19

CANCER: :

CANCER: Radio immunotherapy Antibody-directed enzyme prodrug therapy (ADEPT) Immunoliposomes 20

mAbs as antitumor agents:

mAbs as antitumor agents Rituximab ( Rituxan ) Trastuzumab ( Herceptin ) Alemtuzumab ( Campath ) Bevacizumab ( Avastin ) 21

Monoclonal antibodies in allergy: :

Monoclonal antibodies in allergy: Allergic disorders, including asthma, allergic rhino conjunctivitis, atopic dermatitis, food allergies, urticaria and anaphylaxis have significant impacts on our daily lives. 22

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TYPE TARGET MODE Omalizumab IgE Humanized Pascolizumab IL-4 Humanized Certolizumab TNF-α receptor Humanized Rituximab CD20 CD20 Chimeric 23

DRUGS IN PIPELINE:

DRUGS IN PIPELINE 24

IN DIABETES MELLITUS: :

IN DIABETES MELLITUS: In the treatment of diabetes, novel and improved therapeutic modalities for those individuals with impaired insulin secretory function would be helpful. Currently, long-acting basal insulins are given daily, or more often, and are associated with both hypoglycemia and weight gain. Therefore, a highly specific, ultra-long-acting activator of INSR, such as a monoclonal antibody, would represent a new paradigm in diabetes therapy. XMetA , an allosteric activator of INSR both in vitro and in vivo, has the potential to normalize glycemic control in a model of insulinopenic diabetes without causing hypoglycemia or promoting weight gain. 25

Monoclonal antibodies in infectious diseases:

Monoclonal antibodies in infectious diseases Of the more than 20 monoclonal antibodies generated to combat infectious diseases that are in clinical development in 2011, most are in phase 1 or 2 and are directed against either viruses or bacterial toxins. 26

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In the pipeline, there are a number of novel immunosuppressive drugs in preclinical development or in early clinical trials. The major target of new agents are cell-surface molecules important in immune cell interactions , signaling pathways that activate T cells, T-cell proliferation and trafficking and recruitment of immune cells responsible for rejection. IN CANCER 27

conclusion:

conclusion The success of monoclonal antibodies as new therapeutics agents in several disease areas such as oncology, inflammatory diseases, auto immune diseases and transplantation has trigged growing scientific, therapeutic and business interest in mAb technology. A particular challenge in drug development will be the combination therapy with different mAbs targeting different target antigens at the same time in order to use synergistic or additive effects of mAbs. Monoclonal antibodies have become very attractive therapeutics and will continue to be a focus area of drug discovery and development. 28

references:

references 1. Adams GP, Weiner LM(2005). Monoclonal antibody therapy of cancer. Nat Biotechnol 23(9):1147-57. 2 . Carter P(2002). Improving the efficacy of antibody-based cancer therapies. Nat Rev Cancer ,1,118-129 3. Cevdet Ozdemir (2009). Monoclonal Antibodies in Allergy; Current Applications and Promising Trials . J Recent Patents on Inflammation & Allergy Drug Discovery , 3, 201-210. 4. Daan.J.A.Crommelin,Robert D.Sindelar (2008).Pharmaceutical Biotechnology,Fundamentals&Applications.Informa health care, Newyork.Pg.No:312-315. 5. E. H. S. Choy, G. H. kingsley and G.S. Panayi (2001). monoclonal antibody therapy in rheumatoid arthritis. British journal of rheumatology, 37:484–490. 6. Flavio Vincenti (2012). New Immunosuppressive Drugs in Transplantation. American Journal of Transplantation Volume 2, Issue 10, 898–903. 7. Gerard Tortora,Bryan derrickson (2007). Anatomy and physiology. Wiley international publishers.Pg.no:829-831. 8. Janice M Reichert(2011). Antibody-based therapeutics to watch in 2011. J pub med,76-99. 29

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9.Joshi A, Bauer R,Kuebler (2007).An Overview of the pharmacokinetic & pharmacodynamics of efalizumab : A monoclonal antibody approved for use in Psoriasis. J Clin Pharmacol 46(1):10-20. 10.Kohler G,Milstein C.(1975). Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256(5517):495-7. 11.Neera gupta , A.Shrivastava (2012). Monocloanl antibodies as targeted therapy. Indian journal of pharmacology,183. 12. Nicole A.Weimert,Department of pharmacy services,Medical University of South Carolina U.S.A. Rita R.Alloway , Department of Nephrology,University of Cincinnati U.S.A. Pharmaceutical Biotechnology,Fundamentals&Applications.Informa health care, Newyork.Pg.No:3365-74. 13. Peter A. Ward , Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan. Jane Adams, Juvenile Diabetes Foundation, Washington, DC(2000). Committee on Methods of Producing Monoclonal Antibodies,5-8. 14. Poumian-Riz,Herlod kc (2011) .J pub med. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12037148. 15. Reichert JM.2012. J pub med . Available at :http://www.ncbi.nlm.nih.gov/pubmed/22327425. 16.Termeulin (2011). Vaccine Research, Merck Research Laboratories, West Point, PA 19486, USA. J pub med. 30

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