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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

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Therapeutic Targets in MS

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moas for interferon beta
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
moas for interferon beta1
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
moas for glatiramer acetate
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
moas for glatiramer acetate1
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
moas for natalizumab
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
moas for mitoxantrone
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
moas for rituximab
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
moas of investigational therapies in ms
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
moas of investigational monoclonal antibodies
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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