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Biological response modifiers
- 1. Biological Response ModifiersInBiological Response Modifiers In TherapeuticsTherapeutics Guided by Dr V M Motghare Professor & head Department of Pharmacology G.M.C.H. Nagpur Dr Ankita Jire JR
- 2. Overview Introduction History Types Mechanism ofaction Use of biological response modifiers Adverse effects Biosimilars Summary
- 3. Introduction Biological response modifiersare substances that modify immune responses. They can be both endogenous (produced naturally within body) & exogenous (as pharmaceutical drugs) & they can either enhance an immune response or suppress it
- 4. • A biologic medicalproduct is a vaccine, blood or blood component, allergenic,somatic cell, gene therapy, tissue recombinant therapeutic protein or living cell that is used as therapeutics to treat diseases • Often 200 to 1,000 times size of small molecule drug & are far more complex structurally • Highly sensitive, making them more difficult to characterize & produce
- 6. History • William BColey- Father of Biological Response Modifiers (BRM)
- 7. Some milestones……. 1982 Firstbiotech product (synthetic human insulin)discovered 1986 First monoclonal antibody (mAb) treatment approved 1997 Approval of first mAb-targeted chemotherapy 2002 New mAb therapy for rheumatoid arthritis 2003 • Human genome mapped • First mAb for allergic asthma 2004 • First mAb treatment for colorectal cancer • First mAb treatment for Multiple Sclerosis • First anti-angiogenic medicine for cancer • First mAb approved to treat EGFR-expressing metastatic colorectal carcinoma 2006 First vaccine for the prevention of cervical cancer
- 8. Types Monoclonal antibodies Costimulation inhibitors Angiogenicinhibitors IFN: IFNα IL: IL2, IL6, IL11 Tyrosine kinase inhibitors (TKIs)
- 9. TNFα Colony stimulating factors(CSFs) - Erythropoietin (EPO) Granulocytecolony stimulating factor (GCSF): filgrastim Granulocytemonocytecolony stimulating factor (GM CSF): sargramostim Thrombopoietin (TPO): recombinant human megakaryocyte growth & development factor (rhuMGDF),recombinant human thrombopoietin (rhuTPO)
- 10. Differentiating agentstretinoin, bexarotene Thalidomide Proteosomeinhibitors β-glucans
- 11. Classification Prefix Suffix - mab(Monoclonal antibody) - cept (Soluble receptor) - inib (kinase inhibitor)
- 12.
- 13. 1) Direct action Directcytotoxic action on tumor cells Ex- Monoclonal antibodies 2) Indirect action Restore, augment or modulate immune system to facilitate destruction of tumor cells Ex- IFNs & ILs
- 14. 3) Miscellaneous Promotion ofcell differentiation Ex- Colony Stimulating Factors Interference with neoplastic changes Ex- Retinoids Prevention of metastasis Ex- Angiogenic inhibitor
- 15. Monoclonal Antibodies The clonesof similar antibodies that are directed against specific target antigens Ex. Cancer cells express wide variety of antigens that are attractive targets for monoclonal antibodybased therapy Chimerization/humanization prolongs T1/2 reduce antigenicity
- 16. Nomenclature- suffix Human HumanizedMurine Chimeric umab zumab momab ximab
- 17. Humanized 17 Human Abwith complimentary determining region(CDR) or hypervariable region from non human source – Daclizumab – Trastuzumab
- 18. Chimeric 18 Antigen bindingparts (variable region) of mouse Ab with effector parts (constant region) of human – Infliximab – Abciximab – Rituximab
- 19. Murine 19 Derived frommice Patients treated with murine mAbs develop a human antimouse antibody (HAMA) response Rapid clearance of the mAb Poor tumour penetration Hypersensitivity reactions 90 Y-Ibritumomab 131 I -Tositumomab
- 21. Examples • ab- +-ci- + -xi- + -mab: chimeric monoclonal antibody used on the cardiovascular system • tras- + -tu- + -zu- + -mab: humanized monoclonal antibody used against a tumor • pali- + -vi- + -zu- + -mab: humanized mab used against a virus (RSV)
- 22. Classification On basisof mechanism 1)Interleukin receptors IL-1 – Anakinra 2)Action on CD cell CD3 – Muromonab 3)TNF α – Infliximab 4)VEGF – Bevacizumab 5)EGFR – Cetuximab 6)LFA1- Efalizumab 7)HER2/NEU – Transtuzumab 8)Platelet receptors – Abciximab 9)F-glycoprotein on surface of RSV – Palivizumab 10)IgE – Omalizumab 11)α1-integrin – Natalizumab
- 23. On the basisof development
- 24. Types of monoclonalantibody • Naked/Unarmed/Unmodified • Conjugated/Armed 1) With toxin Ex.Denileukin diftitox 2) Cytotoxic conjugates Ex.Gemtuzumab 3) Radioimmune conjugates Ex.131 Iodine tositumomab 4) Bispecific Ab Ex.Catumaxomab
- 25. Mechanism of actionof Monoclonal Antibodies
- 26. Generation of monoclonalantibodies
- 27. Rituximab Chimeric monoclonalantibody against CD20 B cell antigen MOA : • Complement mediated lysis • Ab dependent cellular toxicity • Apoptisis of malignant cells & B cells • Given as two i.v. infusions of 1000 mg separated by 2 weeks
- 28. Uses of Rituximab Rhematoidarthritis Wegener’s granulomatosis Microscopic polyangitis Diffuse large B cell lymphoma Other B cell Non-Hodgkin’s lymphomas(NHLs) Chronic Lympocytic Leukemia (CLL) Malignant lymphoma
- 29. A/E of Rituximab Rash Anaphylactoidreaction Hypotension,GI disturbances,fever Serious fungal,bacterial & viral infections Reactivation of Hepatitis B virus Fatal mucocutaneous reaction Anemia & neutropenia
- 30. Infliximab • Chimeric(25% mouse, 75% human) Monoclonal antibody against TNF α • I.V. infusion with “induction” at 0, 2 & 6 weeks & maintenance every 8 weeks thereafter Uses Rheumatoid arthritis Ankylosing spondilysis Crohn’s disease Ulcerative colitis psoriasis
- 31. A/E of Infliximab Injectionsite reactions Alopecia areata,hypertrichosis,erosive lichen planus GI ulcers & large bowel perforation Activation of HBV Activation of latent TB
- 32. Monoclonal Antibody Target Indication Abciximab GpIIb/IIIa Antiplatelet Adalimumab TNF α RA(rheumatoid arthritis) Alefacept LFA-3 Plaque psoriasis Alemtuzumab CD 52 B cell CLL, Multiple sclerosis Basiliximab CD-25 Immunosuppressant Brentuximab CD 30 Hodgkin lymphoma, Anaplastic large cell lympoma Cetuximab EGFR Colorectal carcinoma Certolizumab TNFα Crohn’s disease Daclizumab CD-25 Immunosuppressant
- 33. Monoclonal Antibody Target Indication Denosumab RANKligand Osteoporosis Epratuzumab CD 22 SLE Etanercept TNF α RA (rheumatoid arthritis) Gemtuzumab CD 33 AML Golimumab TNFα RA, Psoriasis, Ankylosing Spondylosis Ibritumomab CD 20 B-cell NHL Natalizumab Integrin-α4 Multiple sclerosis Nimotuzumab EGFR Squamous cell carcinoma, Glioma Tocilizumab IL 6 SLE , RA
- 34. Monoclonal Antibody Target Indication Obinutuzumab CD-20CLL Ocrelizumab CD-20 Breast cancer Ofatumumab CD 20 SLE Omalizumab Ig E Bronchial asthma Palivizumab Fusion protein RSV Panitumumab EGFR Colorectal carcinoma Pertuzumab HER-2 Breast cancer Trastuzumab her-2/neu Breast cancer, GI carcinoma
- 35. Side effects • Headache,malaise, flu like syndrome • Nausea, vomiting, loss of appetite • Redness & irritation at injection site • Immune response producing HAMA ("human anti-mouse antibodies") • Immune complexes may cause damage to kidneys
- 36. Costimulation inhibitors Abatacept &belatacept • CTLA4-Ig fusion protein • Binds CD 80/86 • Resistant cases of rheumatoid arthritis & organ transplantation
- 37. Angiogenesis Inhibitors • Angiogenesisconsists of multiple coordinated, sequential & interdependent steps regulated by finely balanced equilibrium between proangiogenic & antiangiogenic factors • 5 strategies used as antiangiogenic therapy- Inhibition of-Activated endothelial cells (EC) -EC intracellular signaling -Extracellular matrix remodeling -Adhesion molecules -Angiogenic mediators or their receptors
- 38. Bevacizumab, cetuximab, panitumumab, trastuzumab Erlotinib,sorafenib, sunitinib Angiogenesis inhibitor Target Indication Toxicity Bevacizumab VEGF Metastatic colorectal Cancer metastatic RCC Non–small cell lung cancer Advanced breast cancer Hypertension , pulmonary hemorrhage, GI perforation Sunitinib VEGF -2 Metastatic Advanced RCC(Renal Cell Ca) GIST Bleeding, hypertension, fatigue Sorafenib VEGFR1 VEGFR2 VEGFR3 Hepatocellular carcinoma Metastatic Renal cell carcinoma Fatigue, nausea, anorexia, Bleeding, hypertension
- 39. Interferons • Act viaspecific cellular receptors linked with JAK STAT pathway to stimulate formation of specific proteins which mediate their actions • 3 major classes of human IFNs: alpha, beta & gamma • 3 forms- • Subcutaneous or intravenous • Recently oral use- recommended Recombinant Natural Pegylated forms Recombinant Natural Pegylated forms
- 40. Clinical Uses ofInterferons INF-α -chronic myelogenous leukemia -hairy cell leukemia -AIDS related Kaposis Sarcoma -Malignant melanoma -Hepatitis B & C -Renal Cell Ca INF-β -Relapsing multiple sclerosis INF-ɣ -Chronic granulomatous disease
- 41. Side effects •Fever, chills,myalgia, headache, depression, nausea, anorexia, weight loss (flu-like syndrome) •Myelosuppression –Rare, reversible within 1–3 days of discontinuation
- 42. Interleukins • Cytokines producedin body by lymphocytes are known as Interleukins • IL2 Increases cytolytic activity of antigen-specific cytotoxic T lymphocytes & natural killer (NK) cells Increases gene expression responsible for encoding lytic component of cytotoxic granules - perforin & granzymes Lymphokine-activated killer (LAK) cells (Lymphocytes stimulated by IL-2) - effective in destroying tumors
- 43. Uses of IL-2(Aldesleukin) 1) Metastatic RCC (Renal cell Cancer ) 2) Malignant melanoma Other Interleukins • IL-6 , IL-11 • Oprelvekin (Recombinant form of IL-11) Approved for treatment of malignancy- induced thrombocytopenia
- 44. Early side effects •Infusion reaction • flu-like symptoms • gastrointestinal effects Toxicity • Hypotension • Ascites • Anasarca • Pulmonary edema
- 45. IL 1 inhibitors •Anakinra • Recombinant form of IL-1 receptor antagonist • Dose – 100 mg s/c daily • Uses Rheumatoid arthritis Behcets disease • A/E – Injection site reaction – Headache – ↑ risk of bacterial, viral infections
- 46. Tyrosine kinase inhibitors(TKIs) Block phosphorylation & activation of downstream signaling of EGFR & other kinases Imatinib Gefitinib Erlotinib Dasatinib Nilotinib Lapatinib
- 47. Sr.No Tyrosine Kinase Inhibitor(TKI) Therapeutic Uses 1. Imatinib First-line therapy in accelerated phase, chronic phase & blast crisis of chronic myeloid leukemia 2. Geftinib -Advanced NSCLC -Esophageal squamous cell Carcinomas -An initial treatment for pulmonary Adenocarcinoma 3. Erlotinib Locally advanced or metastatic NSCLC 4. Dasatinib Imatinib-resistant CML 5. Nilotinib Imatinib-resistant CML 6. Lapatinib -Front-line therapy in breast cancer -An adjuvant therapy when patients have progressed on Herceptin
- 48. Tumor Necrosis Factorα Secreted by macrophages activated by endotoxins Binds to receptor on cell membranes,initiates cellular activity & is cytotoxic Cause direct destruction of tumor cell & its vasculature or stimulate NK cells
- 49. Dose neededfor clinical efficacy is extremely toxic Phase I/II studies - IV infusion produces severe hypotension & hepatotoxicity Isolated limb perfusion was tried in treatment of malignant melanoma & soft tissue sarcome sarcoma
- 50. Colony stimulating factors(CSFs) • Growth factors that mediate proliferation, maturation, regulation & activation of hematopoietic cells. G-CSF: Granulocyte GM-CSF : Granulocyte & Macrophage lineage EPO : Erythrocytes TPO : Platelets
- 51. Recombinant humanG-CSF (filgrastim) & GM-CSF (sargramostim) IV bolus/continuous i.v. infusion or SC Administered 24 –72 h after chemotherapy until high neutrophil count (1000/µL) has persisted for 3 consecutive days Uses -Neutropenic fever secondary to cytotoxic chemotherapy -To reverse leukopenia as adjunctive therapy for HIV-associated infections
- 52. Erythropoietin Patients with chronicrenal failure HIV patients treated with zidovudin Cancer patients treated with chemotherapy
- 53. Adverse effects ofCSF G-CSF - Mild to moderate bone pain GM-CSF – An acute reaction at first dose- fever, chills, hypotension & dyspnea EPO - Increased thromboembolic & cardiovascular events (Hb >12 g/dL)
- 54. Differentiating agents Tretinoin MOA-Retinoids bind with retinoic acid receptor α which dimerizes with retinoid X receptor, which in turn displaces repressor of differentiation Use-Acute promyelocytic leukemia Clinical trials A/E-Dry skin, cheilitis, bone tenderness, hyperlipidemia & retinoic acid syndrome Reversal of oral, skin, cervical malignancies Prevention of head and neck, lung, skin tumor
- 55. Thalidomide MOA : SuppressesTNF-α production Reduce expression of proangiogenic factors such as VEGF & IL-6 Reduces phagocytosis by neutrophils Induce NK cells Use First-line therapy in Multiple myeloma in combination with dexamethasone Myelodysplastic syndrome (MDS)
- 56. • Adverse effects Lenalidomide& Pomalidomide approved for use in patients with primary & refractory Myeloma Sedation & constipation- Most common Peripheral sensory neuropathy- most serious
- 57. Proteosome inhibitors Bortezomib Proteasomeinhibitor Prevent break up & degradation of Protein IkB so NFkB is not released Use- Multiple Myeloma & refractory mantle cell lymphoma A/E-Peripheral neuropathy, diarrhoea, fatigue, Bone Marrow supression, thrombocytopenia
- 58. β – Glucans:Naturally occurring BRMs β-Glucan occur naturally in some fungi & plants as components of cell wall. Common sources -Medicinal mushrooms, bakers yeast & grains such as oats & barley Ganoderma lucidium Trametes versicolor
- 59. •Natural polysaccharide (complexsugar molecule) made up of chains of many glucose sugar units •Promote cancer cell elimination by enhancing activity of macrophages, neutrophils, T cells, NK cells & B cells with appropriate antibodies •β-Glucan is only found in nature & can not be synthesized in laboratory
- 60. Biosimilars World Health Organization “Abiotherapeutic product which is similar in terms of quality, safety & efficacy to an already licensed reference biotherapeutic product.”
- 62.
- 63. References • The pharmacologicalbasis of therapeutics(Goodman and Gillman)12th edition • Basic And Clinical Pharmacology (Katzung) 13th edition • Bisht M, Bist SS, Dhasmana DC. Biological response modifiers: current use and future prospects in cancer therapy.Indian Journal of Cancer 2010; 47( 4):443-9 • Medicine update 2016(KK Pareek ;Gurpreet Wander)
- 64. • K.Sri Janakiet al /Int.J. ChemTech Res.2010,2(4) • Alain Beck (2011) Biosimilar, biobetter and next generation therapeutic antibodies, mAbs, 3:2, 107- 110, DOI: 10.4161/mabs.3.2.14785 • General pharmacology-Basic concepts(HL Sharma & KK Sharma)2nd edition • Pharmacology For MBBS (S K Shrivastava)
Editor's Notes
- #7 Observed that many cancer patients recovered after developing postoperative infections. He, thereby, concluded that fever upregulates the immunesystem in cancer patients, which then recognizes and destroys the invading tumor cells
- #31 Tnf alpha is oncostatic,causes macrophage activation,proinflammatory
- #51 CSFs are growth factors that mediate the proliferation, maturation, regulation, and activation of hematopoieticcells. [19] Generally, CSFs are named after the major cell lineages, which are affected by them; myeloid growthfactors include GMCSF, which affects both granulocyte and macrophage lineage and GCSF, which targets onlygranulocytes; EPO targets erythrocyte production; and TPO is associated with platelet generation
- #53 Endogenous erythropoietin is primarily produced in the kidney. In response to tissue hypoxia, more erythropoietin is produced through an increased rate of transcription of the erythropoietin gene. This results in correction of the anemia, provided that the bone marrow response is not impaired by red cell nutritional deficiency (especially iron deficiency), primary bone marrow disorders (see below), or bone marrow suppression from drugs or chronic diseases.
- #55 The loss of differentiation is one of the hallmarks of malignancy RAS-Characterized by fever, peripheral edema, pulmonary opacities, hypoxemia, respiratory distress, hypotension, renal and hepatic dysfunction, rash, and serositis resulting in pleural and pericardial effusions. It is a cytokine release syndrome, sometimes called "cytokine storm," and all of the pathophysiologic consequences result from the release of inflammatory cytokines from malignant promyelocytes, probably independent of their differentiation to segmented neutrophils and hyperleukocytosis.