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Therapeutic Targets in MS

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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

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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

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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

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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

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MOAs for Natalizumab

• Binds to 41and 47integrins 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

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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

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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

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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

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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-2RaCD25)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

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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.

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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.

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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.