IMMUNOMODULATORS curretly available Seminar .pptx

immunomodulators

1. Immunomodulators By Dr Vishal Bonde (JR1) Department of Pharmacology TNMC & BYL Nair Hospital 16/03/2023 1

2. Overview Introduction – Physiology Immunosuppressants Drugs Calcineurin Inhibitors M-TOR inhibitors Anti-Proliferative drugs Glucocorticoids TNF - ɑ Inhibitors IL-1 inhibitors IL-2 Receptors Antibodies JAK Inhibitors Immunostimulants Drugs Vaccines Summary 2

3. Immunity It is defined as ‘a biological term that describes a state of having sufficient biological defenses to avoid infections, disease or other unwanted biological invasions.’ 3

4. Immunity Innate / Native Adaptive / Acquired Present intrinsically Start developing after birth & continues throughout life Non-Specific Specific Low memory Good memory Immediately available Progressively takes over 4

5. 5

6. Innate immunity 1. Anatomical Barrier – Skin, Mucous Membrane 2. PRR (pattern recognizing receptors) / Inflammasomes proteins 3. AMP (anti-microbial peptides) ~ 400 amino acids 4. NK cells - Largest WBC in body - Regulated by T cells (IL-2) 6

7. 5. Monocyte – Macrophage system 6. Dendritic cells – most potent APC 7. Granulocytes – Neutrophils, Eosinophils, Basophils 8. Complement cascades Innate immunity 7

8. Adaptive immunity Adapts with each new infection Highly specific & retains memory Types :- T cell mediated B cell mediated 8

9. B cells 10-20% Matures in bone marrow B cells ➜ Plasma cells ➜ Antibodies ➜ kill microbes Markers BCR – IgD / IgM CD 19 , CD20, CD21, CD22, CD23 CD 79a (Igα) CD 79b (Ig𝛽) t cells 60-70% Markers TCR CD 1, 2, 3 , 4, 5, 7, 8 & 28 CD 4 : CD 8 = 2:1 9

10. 10

11. PATHOPHYSIOLOGY OF GRAFT vs HOST DISEASE (GVHD) 11

12. 12

13. COMMON Mechanism of action 13

14. Calcineurin inhibitor 14

15. 15

16. A. Cyclosporine 16

17. MOA MOA 17

18. Dose & Pharmacokinetics IV - solution in ethanol-Polyoxyethylated Castor oil & diluted in 0.9% NaCl / 5% dextrose Oral Soft gelatin capsule (25mg/100mg) Oral solution (100mg/ml) Bioavailability decrease with food Oral Peak blood concentration in 1.5 - 2 hours Metabolized in Liver by CYP3A4 Excreted in bile t 1/2 = 5-18hrs 18

19. 19

20. ADVERSE EFFECTS 20

21. Macrolide antibiotic obtained from Streptomyces Tsukubaesis . More preferred over cyclosporine due to more potent and easier to monitor. MOA - Bind to FKBP-12 Inhibition of calcineurin inhibition of T-cell activation B. tacrolimus 21

22. Dose and Pharmacokinetics Available forms - oral, IV , topical Plasma protein binding = 75-99% (t 1/2 is 12 hours). Food decrease rate of absorption and extend t 1/2 . Metabolized by CYP3A4 and excretion by Bile. Target concentrations Pre-Operative = 10-15ng/ml Post-transplant = 6-8ng/ml 22

23. 23

24. 24

25. M-tor inhibitors 25

26. 26

27. 1. Sirolimus Macrolide antibiotics produced by Streptomyces hygroscopius . MOA :- Binds to FKBP-12 ➔ inhibits T-Lymphocytes activation & proliferation of IL-2 and other cytokines also blocks cell cycle progression at G 1 -S phase 27

28. Absorbs rapidly and reaches blood peak concentration within 1 hour. bioavailability is 15%. t 1/2 = 63 hours 40% plasma protein binding Metabolized by CYP3A4 and excreted by Biliary route. Loading dose = 1mg/m 2 Dose and Pharmacokinetics 28

29. 29

30. 30

31. 2. everolimus Similar to Sirolimus in MOA, immunosuppressant property, drug interactions, adverse effects. Short acting than Sirolimus. t 1/2 is 40 hours, permits steady-state level to be reached earlier. Dosage :- Preventing transplant rejection 0.5-1 mg BD For cancer therapy 5-10mg BD 31

32. Uses 32

33. Antiproliferative drugs 33

34. 34

35. 1. azathioprine Purine antimetabolites which is more immunosuppressive than antitumor Active metabolite - 6-Mercaptopurine (6-MP) MOA :- Inhibits denovo synthesis and damages to DNA Selectively effects differentiation and function of T-cells Inhibits cytolytic lymphocytes 35

36. Pharmacokinetics Well absorbed orally and reaches maximum blood concentration within 1-2 hours. Rapidly removed from blood by oxidation / methylation in liver and erythrocytes. DRUGS t 1/2 Azathioprine 10 mins 6MP 1 hour other metabolites 5 hours 36

37. Uses and Dosage Prevention of renal and other graft rejection Rheumatoid arthritis (RA). Maintaining remission in Inflammatory bowl disease (IBD). For restoring near normal pigmentation in vitiligo patients with topical corticosteroids. Dose :- Starting dose 3-5 mg/kg/day for RA 1-2 mg/kg/day 37

38. 2. methotrexate MOA – Folic acid analogue that inhibits dihydrofolate reductase enzyme → blocks DNA synthesis. 50% plasma protein bound t 1/2 – 3-10 hours 38

39. 39

40. 3. cyclophosphamide Cytotoxic drug has marked effect on B cells and humoral immunity. Use Bone marrow transplantation. Low dose maintenance therapy in pemphigus, SLE, Idiopathic thrombocytopenic purpura. 40

41. 4. Mycophenolate mofetil (mmf) Active Metabolite = Mycophenolic acid. MMF + glucocorticoids + sirolimus = Non-nephrotoxic combination. MOA - Selectively inhibits Inosine monophosphate Dehydrogenase which is essential for de novo synthesis of guanosine nucleotide in T & B cells. 41

42. Pharmacokinetics & dosage 42

43. 43

44. Sphingosine-1-phosphate receptor ( S 1 PR) agonist. MOA – Reduces (reversibly) recirculation of lymphocytes from the lymphatic system to blood and periphery tissues i.e., away from inflammation. Does not impair T and B cell functions. USE – 1 st line drug in Multiple Sclerosis ADVERSE EFFECTS - Lymphopenia, negative chronotropic effect on heart 5. Fingolimod 44

45. Glucocorticoids 45

46. 46

47. Potent immunosuppressive and anti-inflammatory action. Marked effect on Cell Mediated Immunity (CMI) than Humoral immunity. MOA - Particularly inhibits MHC expression and activation / proliferation of T lymphocytes Production of adhesion molecules depressed Short lived rapid lymphogenic effect of steroids due to sequestration of lymphocytes in tissues glucocorticoids 47

48. 48

49. glucocorticoids DRUGS THERAPEUTIC USES Prednisone GVHD, autoimmune diseases, RA, Ulcerative colitis, Multiple sclerosis, SLE Prednisolone RA, Uveitis, Ulcerative colitis, Multiple sclerosis, Vasculitis, Sarcoidosis, SLE Dexamethasone RA, Idiopathic thrombocytopenic purpura 49

50. 50

51. TNF- ɑ Inhibitors 51

52. 52

53. TNF- ɑ Inhibitors TNF-α secreted by activated macrophages & other immune cells to act on TNF receptors. TNF- α amplifies immune inflammation by releasing other cytokines & enzymes like collagenases & metalloproteinase. 53

54. 54

55. TNF-α Inhibitors Severe Toxicities Monitoring Infliximab : 3 mg/kg IV to 10 mg/kg every 4 weeks ↑ Risk bacterial, fungal infections Reactivation of latent TB Drug-induced lupus Neurologic deficits LFTs periodically. Monitor for injection site Reactions. Etanercept : 50 mg SC weekly As above Adalimumab : 40 mg SC As above Golimumab : 50 mgSC As above Certolizumab : 400 mg SC As above 55

56. Il-1 inhibitors 56

57. 57

58. Anakinra Non-glycosylated form of human IL-1 receptor antagonist. Use in treatment of Rheumatoid Arthritis. Canakinumab IL-1β monoclonal antibody. Use in treatment of active systemic juvenile idiopathic arthritis and chronic obstructive pulmonary disease (COPD). Rilonacept Fusion protein that binds with IL-1. Use in treatment of Gout. 58

59. Il-2 Receptor antibodies 59

60. 60

61. IL-2 receptor inhibitors Daclizumab Basiliximab (Daclizumab has lower affinity & longer t 1/2 .) MOA – IL-2 receptor antagonist Inhibits T cell activation & proliferation USE – Prophylaxis of GVHD 61

62. JAK Inhibitors 62

63. 63

64. JAK Inhibitors (JAKis or JAKinibs) JAK - initiate intracellular signaling cascades mediating biological functions such as STAT, which initiate the expression of growth-promoting & inflammatory gene programs MOA - JAKinibs target the ATP binding site of the JAK tyrosine kinase. JAK 1 & 2 inhibitors JAK 1 inhibitors JAK 3 inhibitors Ruxolitinib Upadacitinib Tofacitinib Baricitinib Filgotinib Abrocitinib 64

65. TOFACITINIB MOA – Specific inhibitor of JAK 3 → blocking the activity of IL-2, IL-4, IL-15, IL-21 → helper T cell differentiation is blocked USE – Psoriasis & RA ADVERSE REACTION – Upper respiratory tract infections (URTI), headache, diarrhea 65

66. baricitinib MOA – acts as inhibitor of JAK 1 & JAK 2 USES – It was 1 st approved for Rheumatoid arthritis. In May 2022, it approved for COVID -19 ADVERSE REACTION – Upper respiratory tract infections Hypercholesterolemia Other opportunistic infections like herpes zoster, herpes simplex. 66

67. IL-6 receptor inhibitors 67 Tocilizumab Siltuximab Uses Tocilizumab – Large cell lung carcinoma, Ovarian cancer, Rheumatoid arthritis, severe pneumonia in critically ill COVID -19. Siltuximab – Prostate cancer, Ovarian cancer

68. immunostimulants 68

69. Immunostimulants - Introduction Drugs that enhances immunological & non – specific defenses. Such agents may act by: Increasing the humoral antibody responses Enhancing the phagocytic activity of macrophages Modifying the cell – medicated immune responses. 69

70. Thalidomide MOA : Anti inflammatory – inhibits the production of TNF𝛼 & interferon and has stimulatory effect on IGF1, IL-6, IL-2. Immunomodulatory – It reduces phagocytosis by neutrophils & enhances CMI by interacting with T cells Antiangiogenic – It inhibits the induction of COX -2 & biosynthesis of PGE 2 Due to birth defects , it was banned in 1961. It was approved in the United States in 1998 for use as a treatment of cancer. 70

71. Pharmacokinetics 71

72. 72

73. Levamisole Synthesized originally as an anti-helminthics. It enhances T cell - mediated immunity. USE – adjuvant therapy with 5 – Fluorouracil (5FU) after surgical resection in patients with Duke’s stage C colon cancer. DOSE 50 mg orally every 8 hours for 3 days. Given as maintenance therapy for 3 days at 2 weeks intervals for 1 year. Due to risk for fatal agranulocytosis, Levamisole was withdrawn. 73

74. Glatiramer acetate Synthetic copolymer with some immunological similarity to myelin basic protein. Given subcutaneously Reduce the relapse rate in relapsing-remitting multiple sclerosis 74

75. aldesleukin MOA – - Enhancement of lymphocytes proliferation & growth of IL-2 dependent cell lines. - Enhancement of lymphocyte mediated cytotoxicity & killer cell activity & induction of interferon activity. Uses - Metastatic renal cell carcinoma & melanoma - 0.037mg/kg 8 hourly iv infusion for 14 days Adverse reaction – capillary leak syndrome 75

76. Oprelvekin Recombinant human IL-11 Stimulates hematopoiesis, intestinal epithelial cell growth & osteoclast genesis USE – Severe thrombocytopenia associated with chemotherapy for non myeloid malignancies ADVERSE EFFECT – Fluid retention, tachycardia, palpitations, oedema & shortness of breath 76

77. vaccines 77

78. Vaccines Vaccines are biological products which act by reinforcing the immunological defense of the body against foreign bodies. Vaccine impart active immunity : they act as antigens which induce production of specific antibodies and/or cell mediated immunity by the recipient himself. 78

79. 79

80. Killed (inactivated) vaccines Consists of microorganism killed by heat or chemicals. Generally, require to be given by a series of injection for primary immunization. Immunity relatively shorter-lasting; booster dose mostly needed. 80

81. Live attenuated vaccine Consists of live organisms which have been rendered avirulant. Usually produce long lasting immunity. 81

82. toxoids Modified bacterial exotoxins Toxicity is lost but antigenicity is retained. 82

83. Herbal immunomodulators Ginseng Astragalus Ashwagandha Liquorice Guduchi Haldi 83

84. Drug Name MOA USES Voclosporin new oral semisynthetic structural analogue of cyclosporine organ transplantation & autoimmune diseases such as psoriasis Cemiplimab Blocks PD-1 pathway Advanced / metastatic basal cell carcinoma Ublituximab Anti CD20 monoclonal antibody Relapsing forms of Multiple Sclerosis Recent advances Recent advances 84

85. SUMMaRY Immunology is probably one of the most rapidly developing areas of medical biotechnology research & has great promises regarding the prevention & treatment of a wide range of disorders. Immunomodulation is a normalizing process, which correct weak immune systems & temper immune systems that are overactive. They are becoming a viable adjunct to established modalities offering a novel approach for the treatment of autoimmune disease & organ transplantation in the coming decades of 21 st century. 85

86. 86

87. References Sharma KH, Sharma K.K. Principles of Pharmacology, 1 st ed. Paras Medical Publishers, New Delhi; 2007:428-453 Tripathi KD. Essentials of pharmacology for dentistry. 4th ed. New Delhi, India: Jaypee Brothers Medical; 2020. Knollmann B, Brunton L, Hilal-Dandan R. Goodman and gilman’s the pharmacological basis of therapeutics. 13th ed. Columbus, OH: McGraw-Hill Education; 2017. Hartono C, Muthukumar T, Suthanthiran M. Immunosuppressive drug therapy. Cold Spring Harb Perspect Med. 2013;3(9):a015487. Mehta HM, Malandra M, Corey SJ. G-CSF and GM-CSF in neutropenia. J Immunol. 2015;195(4):1341–9. 87

88. Catanzaro M, Corsini E, Rosini M, Racchi M, Lanni C. Immunomodulators inspired by nature: A review on curcumin and Echinacea. Molecules. 2018;23(11):2778. Bascones -Martinez A, Mattila R, Gomez-Font R, Meurman JH. Immunomodulatory drugs: Oral and Systemic Adverse Effects. Medicina Oral Patología Oral y Cirugia Bucal . 2014;19(1):24–31. Amaria RN, Reuben A, Cooper ZA, Wargo JA. Update on use of aldesleukin for treatment of high-risk metastatic melanoma. ImmunoTargets Ther . 2015;4:79–89 Yuan J, Ni G, Wang T, Mounsey K, Cavezza S, Pan X, et al. Genital warts treatment: Beyond imiquimod. Hum Vaccin Immunother [Internet]. 2018;14(7):1815–9. Titanji BK, Farley MM, Mehta A, Connor-Schuler R, Moanna A, Cribbs SK, et al. Use of baricitinib in patients with moderate to severe Coronavirus disease 2019. Clin Infect Dis [Internet]. 2021;72(7):1247–50. Available from: http:// dx.doi.org /10.1093/ cid /ciaa879 References 88