1 / 13

Therapeutic Targets in MS

Therapeutic Targets in MS. MOAs for Interferon Beta. Inhibits antigen presentation and downregulates major histocompatibility complex (MHC) and costimulatory molecules 1-4 Inhibits T-cell (and other cell) stimulation and proliferation 1 Restores normal suppressor function 1 Shifts cytokines

lschumacher
Download Presentation

Therapeutic Targets in MS

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Therapeutic Targets in MS

  2. MOAs for Interferon Beta • Inhibits antigen presentation and downregulates major histocompatibility complex (MHC) and costimulatory molecules1-4 • Inhibits T-cell (and other cell) stimulation and proliferation1 • Restores normal suppressor function1 • Shifts cytokines • Downregulates proinflammatory cytokines (eg, IL-2,IL-12, IL-13, IFN-gamma, TNF-alpha) and inhibits their production1-3,5,6 • Promotes Th2 cytokines (eg, IL-4, IL-10)1,2,5

  3. MOAs for Interferon Beta • Stabilizes blood-brain barrier • May alter adhesion molecule expression and T-cell adhesion to blood-brain barrier3,4,7 • Inhibits matrix metalloproteinase (MMP) production and MMP’s effects on blood-brain barrier permeability1,2,4,8 • Upregulates CD73 on endothelial cells, which inhibits CD4+ cell transmigration into parenchyma9

  4. MOAs for Glatiramer Acetate • Binds to class I and II MHC10-12 • Competes with and displaces antigen, eg, myelin basic protein (MBP), from MHC11,13 • May be T-cell receptor antagonist of MBP (controversial)14 • Inhibits MBP reactivity at level of cytokine secretion15 but not proliferation16,17 (frequency of this is not certain) • Shifts cytokines • Modulates antigen-presenting cells, which influences T-cells toward Th218,19 • Promotes Th1 to Th2 shift in periphery19-21 • Promotes Th2 cells that secrete anti-inflammatory cytokines and neurotrophic factors in CNS13

  5. MOAs for Glatiramer Acetate • Modulates other functions of monocytes13 • Upregulates CD8+ cells (Tregs)12,22 • Restores Treg cell function, including CD4+CD25+FoxP3+ Tregs19 • Promotes secretion of brain-derived neurotrophic factor and other growth factors and cytokines13,23 • Downregulates chemokine receptors that help draw Th1 cells to sites of inflammation24 • Induces clonal anergy and/or clonal deletion via apoptosis of CD4+ T-cells25-27 • Induces antiglatiramer antibodies that may promote remyelination and do not diminish glatiramer efficacy28

  6. MOAs for Natalizumab • Binds to a4b1and a4b7integrins expressed on leukocytes29 • Inhibits binding to ligands (VCAM-1 and MAdCAM-1) on vascular endothelial cells, reducing migration of these cells into CNS29 • Preferentially inhibits effector T-cells, not Tregs30 • Inhibits leukocyte inflammatory activity and recruitment of activated immune cells, as a result of inhibiting integrin/CAM binding29 • Affects B-cell production or migration30 • Has downstream effects on gene regulation31

  7. MOAs for Mitoxantrone • Intercalates into DNA through hydrogen binding causing crosslinks and strand breaks32 • Interferes with RNA32 • Inhibits topoisomerase II (which uncoils and repairs damaged DNA)32 • Has cytocidal effects on proliferating and nonproliferating cells32 • Decreases proliferation and functions of T-cells, B-cells, and macrophages, including proinflammatory cytokine secretion32,33 • Induces apoptosis of antigen-presenting cells33 • Inhibits macrophage-mediated myelin degradation34 • Decreases CXCR235 • Increases number of naive CD8+ cells36

  8. MOAs for Rituximab • Targets anti-CD20 surface molecule onB-cells and some immature B-cells (not on plasma cells)37 • Reduces B-cell numbers in periphery and CSF37 • May eventually reduce plasma cells38 and Ig39 • Inhibition of B-cell functions unrelated to function of plasmablasts and plasma cells40 • Antigen presentation • Cytokine secretion • Apparent effect on blood-brain barrier

  9. MOAs of Investigational Therapies in MS • Cladribine: antimetabolite; reduces number ofT-cells; some preferential effect on CD4+ cells41 • Laquinimod: uncertain, but some effect on Th1to Th2 shift42 • Teriflunomide: antimetabolite; inhibits pyrimidine synthesis43 • Fingolimod: agonist and perhaps indirect antagonist of S1P1 and related receptors on inflammatory cells44 • Prevents emigration from secondary lymphoid organs44 • Receptors are also on neurons, glia, and vascular cells44

  10. MOAs of Investigational Monoclonal Antibodies • Alemtuzumab • Binds to CD52 surface molecule on T-cells, B-cells, monocytes, and eosinophils37 • Induces cell death37 • Daclizumab • Binds to IL-2RaCD25)which is upregulated on activated and autoreactive T-cells37 but also highly expressed on Tregs (eg, CD4+CD25+FoxP3+Tregs) • Increases CD56 NK cells (which have immunoregulatory functions)37

  11. References 1. Markowitz CE. Neurology. 2007;68(suppl 4):S8-S11. 2. Dhib-Jalbut S. Neurology. 2002;58:S3-S9. 3. Yong VW, et al. Neurology. 1998;51:682-689. 4. Yong VW. Neurology. 2002;59:802-808. 5. Chabot S, et al. Neurology. 2000;55:1497-1505. 6. Wang X, et al. J Immunol. 2000;165:548-557. 7. Graber J, et al. J Neuroimmunol. 2005;161:169-176. 8. Stüve O, et al. Ann Neurol. 1996;40:853-863. 9. Niemela J, et al. Eur J Immunol. 2008;38:2718-2726. 10. Arnon R, et al. PNAS. 2004;101:14593-14598. 11. Fridkis-Hareli M, et al. PNAS. 1994;91:4872-4876. 12. Karandikar NJ, et al. J Clin Invest. 2002;109:641-649. 13. Ruggieri M, et al. CNS Drug Rev. 2007;13:178-191. 14. Aharoni R, et al. PNAS. 1999;96:634-639.

  12. References 15. Chen M, et al. J Neurol Sci. 2002;201:71-77. 16. Burns J, et al. Neurology. 1991;41:1317-1319. 17. Lisak RP, et al. J Neurol Sci. 1983;62:281-293. 18. Vieira PL, et al. J Immunol. 2003;170:4483-4488. 19. Weber MS, et al. Neurotherapeutics. 2007;4:647-653. 20. Arnon R, et al. PNAS. 2004;101(suppl 2):14593-14598. 21. Chen M, et al. Mult Scler. 2001;7:209-219. 22. Tennakoon DK, et al. J Immunol. 2006;176:7119-7129. 23. Ziemssen T, et al. Brain. 2002;125(Pt 11):2381-2391. 24. Allie R, et al. Arch Neurol. 2005;62:889-894. 25. Ziemssen T, et al. Int Rev Neurobiol. 2007;79:537-570. 26. Gran B, et al. Neurology. 2000;55:1704-1714. 27. Ragheb S, et al. Mult Scler. 2001;7:43-47. 28. Ure DR, et al. FASB J. 2002;16:1260-1262. 29. Tysabri [PI]. Cambridge, MA: Biogen Idec; 2008.

  13. References 30. Krimbholz M, et al. Neurology. 2008;71:1350-1354. 31. Lindberg RLP, et al. J Neuroimmunol. 2008;194:153-164. 32. Novantrone [PI]. Melville, NY: OSI Pharmaceuticals; 2008. 33. Fox EJ. Neurology. 2004;63(suppl 6):S15-S18. 34. Watson CM, etal. Int J Immunopharmacol. 1991;13:923-930. 35. Bielecki B, et al. J Clin Immunol. 2008;28:122-130. 36. Pelfrey CM, et al. J Neuroimmunol. 2006;175:192-199. 37. Lutterotti A, et al. Lancet Neurol. 2008;7:538-547. 38. Petereit HF, et al. Acta Neurol Scand. 2008;117:399-403. 39. Teng YKO, et al. Arthritis Rheum. 2007;56:3909-3918. 40. McFarland HF. N Engl J Med. 2008;358:664-665. 41. Stelmasiak Z. ComtecMED Web site. http://www.comtecmed.com/CONY/2008/Uploads/assets/speakers%20abstracts/stelmasiak.pdf 42. Zou LP, et al. Neuropharmacology. 2002;42:731-739. 43. Cherwinski HM, et al. J Pharmacol Exp Ther. 1995;275:1043-1049. 44. Horga A, et al. Expert Rev Neurother. 2008;8:699-714.

More Related