IFN-b: MOAs - Projects In Knowledge

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Transcript IFN-b: MOAs - Projects In Knowledge

Therapeutic Targets in MS
Slide 1 of 13
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
• Restores normal suppressor function1
• Shifts cytokines
– Downregulates proinflammatory cytokines (eg, IL-2,
IL-12, IL-13, IFN-gamma, TNF-alpha) and inhibits their
– Promotes Th2 cytokines (eg, IL-4, IL-10)1,2,5
Slide 2 of 13
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
Slide 3 of 13
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
Slide 4 of 13
MOAs for Glatiramer Acetate
• Modulates other functions of monocytes13
• Upregulates CD8+ cells (Tregs)12,22
• Restores Treg cell function, including CD4+CD25+FoxP3+
• 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
Slide 5 of 13
MOAs for Natalizumab
• Binds to a4b1 and a4b7 integrins expressed on
– 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
Slide 6 of 13
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
• Has cytocidal effects on proliferating and nonproliferating
– 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
Slide 7 of 13
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
Slide 8 of 13
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
• 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
Slide 9 of 13
MOAs of Investigational Monoclonal
• 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
Slide 10 of 13
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13. Ruggieri M, et al. CNS Drug Rev. 2007;13:178-191.
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19. Weber MS, et al. Neurotherapeutics. 2007;4:647-653.
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21. Chen M, et al. Mult Scler. 2001;7:209-219.
22. Tennakoon DK, et al. J Immunol. 2006;176:7119-7129.
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31. Lindberg RLP, et al. J Neuroimmunol. 2008;194:153-164.
32. Novantrone [PI]. Melville, NY: OSI Pharmaceuticals; 2008.
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36. Pelfrey CM, et al. J Neuroimmunol. 2006;175:192-199.
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