Innovation in Immunology General Principles and Immunotherapeutic - PDF document

6/2/18 Innovation in Immunology General Principles and Immunotherapeutic Reference: Chapter 18 (Medical Micro. Murray PR./ 6 th Ed) Chapter 19 (Kuby Immunology 7 th ED) Narendra Kumar PhD. 1

6/2/18 Learning Objectives: • Describe immune system and its role of in combating cancer • Describe strategies for cancer immunotherapy • Describe mAb and pAb and their production • Describe a few FDA approved mAb drugs and their MOA •Describe biosimilar and a few FDA approved biosimilar drugs • Describe recent trends in immunomodulators Key concepts: • All the application of antibodies (Abs) are based on the only one property, and that is its specificity. Immune system through alphabet soup C C M G T B N Mφ/D NEB NK&K Ph Kill AP O/M TLRs and cyto 2 nd Line 1 st Line S S Ab C 2

6/2/18 Site for T-cell Development 1. Receptors ? 2. +ve Selection? 3. -ve selection? Thymus (TS) Overall Effects of the Immune System • Beneficial: • Protection from Invaders • Elimination of Altered Self Detrimental: • • Discomfort and collateral damage (inflammation) • Damage to self (hypersensitivity or autoimmunity) 3

6/2/18 How does the immune system combat cancer? Principles of immunotherapy 1. Immune system in combating cancer 2. Clinical aspects Specific Learning Objectives: • Describe role of immune system in combating cancer • Describe immunotherapy for cancer • Describe mAb and pAb and their production • Describe a few applications of Ab in serological diagnostics (ELISA, Western Blot, Immunofluorescence, FACS) • Describe a few FDA approved mAb drugs and their MOA • Describe the concepts of biosimilar Key concepts: • All the application of antibodies (Abs) are based on the only one property, and that is its specificity. TSA and TAA Alpha-fetoprotein (AFP): mg in fetal serum to 50 ng after birth. Increased level sign of ovarian, testicular or liver cancer/lesion. Carcinoembryonic antigen (CEA): GI and liver of 2-6 m old. 90% with advance and 50% with early CRC have elevated level. Used for post-surgical monitoring of cancer. HER2 for breast cancer. 4

6/2/18 Tumor antigen 1. Encoded by genes exclusively expressed by tumors (viral genes). 2. Encoded by variant forms of normal genes. 3. Expressed only at certain stage of development. 4. Over-expressed in particular tumor. Immunotherapy: anti-idiotypic vaccine Immunotherapy: Prostrate cancer vaccine 5

6/2/18 Immunotherapy: DC-directed therapy Immunotherapy: CTL-directed therapy Antibodies Monoclonal antibodies ( mAb or moAb ) are produced by B-cells that are all clones of a single parent B-cell. Given (almost) any substance, it is possible to create monoclonal antibodies that specifically bind to that substance; they can then serve to detect or purify that substance. When used as medications, the generic name ends in –mab . Polyclonal antibodies ( pAb) are produced by B-cells that are all clones of multiple parent B-cell. Monoclonal antibody therapy is the use of monoclonal antibodies to specifically target cells. The main objective is stimulating the patient's immune system to attack the malignant tumor cells and the prevention of tumor growth by blocking specific cell receptors or killing of tumor where a radioactive dose is localized on target cell, through antibody linked radiochemical (e.g. radioimmunotherapy) 6

6/2/18 Production of Antibodies Myeloma cells are cancerous Plasma cells and the fusion product of myeloma and normal plasma cells are called hybridoma cells Types and nomenclature of mAbs 1. Stem (mab) 2. Sub-stem for origin a. Murine (0%) (suffix -omab) b. Chimeric (65%) (suffix -ximab) c. Humanized (95%) (suffix -zumab) d. Human (100%) (suffix -humab) 3. Sub-stem for target The sub-stem preceding the source of the antibody refers to the medicine's target. Examples are tumors, organ systems (circulatory, lymphoid etc.), or infectious agents (bacteria/viruses). “CVC-rule”. Examples ; -ci(r)- circulatory system, -li(m)- lymphocyte, and -ne(r)- nervous system etc. Drug examples: Tositumomab, Ibritumomab; Cetuximab, Rituximab; Trastuzumab; Panitumumab; Bevacizumab. 7

6/2/18 1. Source: wiki Biosimilar or copycat drugs Original Product Proper Name Biosimilar Product Use Avastin bevacizumab Mvasi Certain colorectal, lung, brain, kidney, and cervical cancers Enbrel etanercept Erelzi Rheumatoid arthritis, psoriatic arthritis, plaque psoriasis Neupogen filgastrim Zarxio Neutropenia, bone marrow transplantation Remicade infliximab Renflexis Crohn’s disease, ulcerative colitis, rheumatoid arthritis, psoriatic arthritis, plaque psoriasis Remicade Inflectra Crohn’s disease, ulcerative colitis, rheumatoid arthritis, psoriatic arthritis, plaque psoriasis Herceptin trastuzumab Ogivri Certain breast and stomach cancers Humira adalimumab Cyltezo Rheumatoid arthritis, Crohn’s disease, ulcerative colitis, plaque psoriasis, psoriatic arthritis Humira Amjevita Rheumatoid arthritis, Crohn’s disease, ulcerative colitis, plaque psoriasis, psoriatic arthritis Engineered monoclonal antibodies Mechanism of targeting mAbs to cancer cells: 1. Radioimmunotherapy (RIT) 2. Antibody-directed enzyme prodrug therapy (ADEPT) 3. Immunoliposomes (antibody-conjugated liposomes). 8

6/2/18 Immunotherapy and vaccines for Cancer Antibody directed enzyme prodrug therapy (ADEPT) Charting a Era of Medicines Formulation/patent Indications MOA VE303(Carb-X/Vedanta) C. difficle restore colonization resistance against gut pathogens VE202 (Janssen/Vedanta) IBD T reg VE416 Food allergy VE800 Melanoma, H&NC, CD8 T-cell (CTL) (+CHK-point inhibitors) bladder, lung Diagnostic Applications of Antibodies -ELISA: Enzyme-Linked Immuno-Sorbent Assay is a technique to detect the presence of an antibody or an antigen in a sample. The ELISA has been used as a diagnostic tool in medicine and quality control check in various industries. -In ELISA an unknown amount of antigen is affixed to a surface, and then a specific antibody is washed over the surface so that it can bind to the antigen. This antibody is linked to an enzyme, and in the final step a substance is added that the enzyme can convert to some detectable signal. -In the case of fluorescence ELISA , when light of the appropriate wavelength is beamed upon the sample the antigen/antibody complexes will fluoresce so that the amount of antigen in the sample can be inferred through the magnitude of the fluorescence. -In sandwich ELISA the antigen is sandwiched between two antibodies, the capture Ab and the detection Ab. The detection Ab binds to a third enzyme liked-Ab. e.g. Pregnancy Test 9

6/2/18 At this time you should know: • Role of immune system in cancer suppression • Role of immune system in cancer activation • Immunotherapy and cancer vaccines • Monoclonal antibodies in treatment of cancer and other diseases • Future of medicine 10

6/2/18 CPE Codes • RPH: Uz9r • CPHT: 8fUK 11