Transcript IFN-b: MOAs - Projects In Knowledge

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 a4b1 and a4b7 integrins 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 on
B-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 of
T-cells; some preferential effect on CD4+ cells41
• Laquinimod: uncertain, but some effect on Th1
to 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-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
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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.
Slide 11 of 13
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.
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