PHL 3 Introduction to Cell Based Immunotherapy PDF

BMD 6113 MOLECULAR MEDICINE PHARMACOLOGY LECTURE #3 INTRODUCTION TO CELL BASED & IMMUNOTHERAPY DR DAYANA MAHIZIR  Immunotherapy o Autoimmune disorders → rheumatoid arthritis, inflammatory bowel disease, psoriasis, etc Ø Are used primarily to prevent the immune system from...

BMD 6113 MOLECULAR MEDICINE PHARMACOLOGY LECTURE #3 INTRODUCTION TO CELL BASED & IMMUNOTHERAPY DR DAYANA MAHIZIR  Immunotherapy o Autoimmune disorders → rheumatoid arthritis, inflammatory bowel disease, psoriasis, etc Ø Are used primarily to prevent the immune system from recognizing self Ags as foreign and inducing inflammation v and tissue damage o Organ transplantation → immune system elicit a damaging immune response → rejection of the transplanted tissue Ø Suppress the immune system to prevent transplant rejection → maintain graft acceptance QUEST INTERNATIONAL UNIVERSITY (DU021(A)) | www.qiu.edu.my 2  Immunotherapy o Pharmacological approaches → selective eradication of immunocompetent cells or down regulation of the immune response without deleting the target cell Ø To optimize clinical efficacy while vpreventing adverse effects o Monotherapy → severe toxicities → synergistic combination of low dose immunosuppressive agents with different mechanism of action QUEST INTERNATIONAL UNIVERSITY (DU021(A)) | www.qiu.edu.my 3  Immune Ac0va0on Cascade o Signal 1 constitutes T-cell triggering at the CD3 receptor complex by an antigen on the surface of an antigen-presenting cell (APC) o Signal 2 (costimulation) occurs when CD80 and CD86 on the surface of APCs engage CD28 on T cells v o Both signals 1 and 2 activate several intracellular signal transduction pathways, one of which is the calcium–calcineurin pathway o These pathways trigger the production of cytokines such as interleukin (IL)-2 and T-cell dependent activation of B lymphocytes o IL-2 then binds to the IL-2 receptor (also known as CD25) on the surface of other T cells to activate mammalian target of rapamycin (mTOR), providing signal 3, the stimulus for T-cell proliferation QUEST INTERNATIONAL UNIVERSITY (DU021(A)) | www.qiu.edu.my 4  v QUEST INTERNATIONAL UNIVERSITY (DU021(A)) | www.qiu.edu.my 5  Cyclosporine o A calcineurin inhibitor o Mechanism of action Ø Binds to a cyclophilin in T cell → forms a complex that inhibit calcineurin action → inhibit synthesis of cytokines, v IL-2 § Calcineurin → dephosphorylating NFATc (cytosolic Nuclear Factor of Activated T cells) o Pharmacokinetics Ø Oral (variable absorption) & IV Ø Metabolised in liver Ø Biliary excretion QUEST INTERNATIONAL UNIVERSITY (DU021(A)) | www.qiu.edu.my 6  Cyclosporine o Therapeutic Uses Ø Used to prevent rejection of organ transplant (kidney, liver, cardiac, lung) § Combination therapy regimen (corticosteroids & antimetabolite) v Ø Recalcitrant psoriasis Ø Rheumatoid arthritis (resistant to other agents, eg: MTX) o Adverse Effects Ø Nephrotoxicity (common) Ø Hypertension, hyperlipidemia, hyperkalemia, tremor, hirsutism, & gum hyperplasia QUEST INTERNATIONAL UNIVERSITY (DU021(A)) | www.qiu.edu.my 7  Tacrolimus o A calcineurin inhibitor, macrolide o Mechanism of action Ø Similar MoA as cyclosporine but bind to FKBP-12 (FK-binding protein) v Ø ↑ potency, ↓ organ rejection than cyclosporine o Pharmacokinetics Ø Oral & IV Ø Oral absorption variable Ø Biliary excretion QUEST INTERNATIONAL UNIVERSITY (DU021(A)) | www.qiu.edu.my 8  Tacrolimus o TherapeuOc uses Ø Prevents liver and kidney rejec]ons § Combina]on therapy with glucocor]coids v Ø Ointment → atopic dermaOOs (eczema) o Adverse Effects Ø Nephrotoxicity Ø Development of post transplant type 1 diabetes Ø = cyclosporine QUEST INTERNATIONAL UNIVERSITY (DU021(A)) | www.qiu.edu.my 9  Sirolimus & Everolimus o Mechanism of action Ø Binds to FK-binding protein → binds to mTOR Ø Inhibits the progression of activated T cells from the G1 to the S phase of the cell cycle v Ø Inhibits T cell proliferation QUEST INTERNATIONAL UNIVERSITY (DU021(A)) | www.qiu.edu.my 10  Sirolimus & Everolimus o PharmacokineOcs Ø Oral Ø Sirolimus → long half-life (57 to 62 hours) v Ø Everolimus → shorter half life o TherapeuOc uses Ø Organ transplanta]on Ø Sirolimus-coated stents → inhibit restenosis of the blood vessels by reducing prolifera]on of the vascular cells QUEST INTERNATIONAL UNIVERSITY (DU021(A)) | www.qiu.edu.my 11  Sirolimus & Everolimus o Adverse effects Ø Hyperlipidaemia Ø Anemia, thrombocytopenia v QUEST INTERNATIONAL UNIVERSITY (DU021(A)) | www.qiu.edu.my 12  v QUEST INTERNATIONAL UNIVERSITY (DU021(A)) | www.qiu.edu.my 13  Belatacept (Costimulation Blocker) o Mechanism of action Ø Binds to CD80 and CD86 on APCs → inhibits CD28-mediated costimulation of T lymphocytes Ø Prevents the downstream stimulatoryv signals promoting T-cell survival, proliferation, and IL-2 production o Pharmacokinetics Ø The first IV maintenance immunosuppressant Ø Long half-life (8-10 days) § First phase: high-dose § Second/maintenance phase: reduce dose, once a month administration QUEST INTERNATIONAL UNIVERSITY (DU021(A)) | www.qiu.edu.my 14  Belatacept o Therapeutic uses Ø Kidney transplantation (combined with basiliximab, mycophenolate mofetil, and corticosteroids) Ø Replaces calcineurin inhibitors for long-term v maintenance immunosuppressive therapy o Adverse Effects Ø Post-transplant lymphoproliferative disorder Ø Anemia, diarrhea, urinary tract infection, and edema QUEST INTERNATIONAL UNIVERSITY (DU021(A)) | www.qiu.edu.my 15  An0metabolites: Azathioprine o A prodrug o Mechanism of action o Azathioprine → 6-mercaptopurine (6-MP) → 6-thioinosine monophosphate (TIMP), a purine analogue v o Incorporates into DNA & disrupts the function of endogenous purines o Affects lymphocytes which depend on de novo purine synthesis o Well absorbed after oral administration QUEST INTERNATIONAL UNIVERSITY (DU021(A)) | www.qiu.edu.my 16  Antimetabolites: Azathioprine o Combined with corticosteroids & cyclosporine/ tacrolimus to prevent rejection of kidney and other organ allografts o Adverse effects: bone marrow suppression v QUEST INTERNATIONAL UNIVERSITY (DU021(A)) | www.qiu.edu.my 17  An#metabolites: Mycophenolate Mofe#l o Replaced azathioprine because of its safety and efficacy in prolonging graft survival o Mechanism of action Ø Inhibits inosine monophosphate dehydrogenase v → inhibits formation of guanosine monophosphate → deprives the rapidly proliferating T and B cells of nucleic acids QUEST INTERNATIONAL UNIVERSITY (DU021(A)) | www.qiu.edu.my 18  Antimetabolites: Mycophenolate Mofetil o PharmacokineOcs Ø IV Ø Well absorbed orally v Ø Excreted renally o TherapeuOc uses Ø Prevents acute rejec]on of organ transplants (combine with sirolimus, tacrolimus & prednisone) o Adverse effects Ø Diarrhea, nausea, vomi]ng, and abdominal pain QUEST INTERNATIONAL UNIVERSITY (DU021(A)) | www.qiu.edu.my 19  Antibody: Antithymocyte Globulins o Polyclonal antibodies + other immunosuppressive agents → used at the time of transplantation to prevent early allograft rejection o Treat severe rejection episodes or corticosteroid-resistant acute rejection o Mechanism of action v Ø Antibodies bind to the surface of circulating T lymphocytes → undergo various reactions § Complement-mediated destruction § Antibody-dependent cytotoxicity § Apoptosis § Opsonization QUEST INTERNATIONAL UNIVERSITY (DU021(A)) | www.qiu.edu.my 20  Antibody: Antithymocyte Globulins o PharmacokineOcs Ø IV (slowly infused) Ø Half-life → 2 to 3 days v o Adverse effects Ø Infusion reacOons → chills and fever Ø Leukopenia and thrombocytopenia Ø Infec]ons Ø Skin rashes QUEST INTERNATIONAL UNIVERSITY (DU021(A)) | www.qiu.edu.my 21  Antibody: Basiliximab o Monoclonal antibody o Mechanism of action Ø Anti-CD25 antibody → binds to the α chain of the IL-2 receptor on activated T cells → interferes with the proliferation v of T cells o IV infusion, half-life → 7 days o Two doses: the first at 2 hours before transplantation, second at 4 days after the surgery o Prophylaxis of acute rejection in renal transplantation in combination with cyclosporine and corticosteroids o Adverse effects: Arrhythmias & hypersensitivity reactions QUEST INTERNATIONAL UNIVERSITY (DU021(A)) | www.qiu.edu.my 22  Corticosteroids o Prednisone & methylprednisolone o Binds to glucocorticoid-responsive elements on DNA to decrease the expression of proinflammatory and activate the expression of antiinflammatory genes o Used to suppress acute rejection of solid v organ allografts and in chronic graft- versus-host disease (bone marrow transplant) o Adverse effects Ø Diabetogenic Ø Cataracts Ø Osteoporosis Ø Hypertension QUEST INTERNATIONAL UNIVERSITY (DU021(A)) | www.qiu.edu.my 23  References o Karen Whalen, Richard S Finkel & Thomas A Panaveli. Lippincott Illustrated Reviews: Pharmacology. 8th Edition Wolters Kluwer, 2022. o Katzung, Bertram G.: Basic & Clinical Pharmacology, 15th ed., Mc Graw Hill, 2020. v o Laurence L. Brunton, John S. Lazo, Keith L. Parker: Goodman & Gilman's, The pharmacological basis of therapeutics, 14th ed., Mc Graw Hill, 2022. o Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale’s Pharmacology, 10th ed., Elsevier Churchill Livingstone, 2023. QUEST INTERNATIONAL UNIVERSITY (DU021(A)) | www.qiu.edu.my 24