Table II.
Pre-clinical studies of BTK-inhibitors for autoimmunity.
| Autoimmune disease studies | Models | Drug | Immune outcomes | Disease outcomes |
|---|---|---|---|---|
| Murine autoimmune arthritis Ref: (100) 2007 |
Collagen induced arthritis (CIA) | “Compound 4” by Celera | ND | Improved arthritis scores |
| Murine Lupus Ref: (125) 2010 |
MRL/Fas | Ibrutinib | Decreased autoantibodies | Improved renal impairment |
| Murine autoimmune arthritis Ref:(88) 2011 |
CIA, serum transfer models: collagen autoantibody induced arthritis (CAIA) and K/BxN | CGI1746 | Decreased FcγR mediated inflammation induced by immune complexes; prevented autoantibody production | Prevented autoimmune (CIA) and inflammatory arthritis (CAIA and K/BxN) |
| Rat autoimmune inflammatory arthritis Ref: (126) 2011 |
Rat Collagen induced arthritis | GDC-0834 | ND | Reduced ankle swelling |
| Murine autoimmune and inflammatory arthritis Ref: (89) 2011 |
CIA and CAIA | Ibrutinib | Reduced inflammatory cytokine release by macrophages and monocytes | Prevented arthritis in both CIA and CAIA. |
| Rodent arthritis Refs: (90, 104) 2012, 2015 |
mouse CIA, CAIA, and rat adjuvant-induced arthritis (AIA) | RN486 | Reduced tumor necrosis factor α (TNFα) production by monocytes stimulated with IgG-coated beads, reduced B cell activation, reduced autoantibodies and inflammatory markers in serum | Prevented arthritis in CIA and CAIA models and reduced arthritis when used therapeutically in CIA; reduced splenomegaly and AIA in rats |
| Glomerular nephritis (Lupus) Ref: (127) 2012 |
B6.sle1 and B6.Sle1.Sle3 | PCI-32675 (Ibrutinib), given for 56 days | Reduced autoantibodies, B cells, DCs, macrophages, neutrophils and activated T cells; normal numbers of naïve T cells | Reduced splenomegaly and glomerular nephritis, Reduced B cells in the kidneys despite no decrease in cellularity overall |
| Murine autoimmune arthritis Ref: (96) 2013 |
CIA | CC-292 | ND | Prevented and treated CIA |
| Glomerular nephritis (Lupus) Ref: (20) 2013 |
NZB x NZW | RN486 given for 8 weeks beginning at age 32 weeks | Reduced IgG autoantibodies, autoreactive B cells, B cell activation and splenic plasma cells, with preserved total IgG | Reduced proteinuria and glomerulosclerosis, IgG, IgM and C3 deposition, reduced macrophage infiltrations |
| Glomerular nephritis (Lupus) Ref: (128) 2013 |
NZBxW_F1 and Anti-glomerular basement membrane (GBM) antibody induced nephritis | PF-06250112, given for 12 weeks beginning at age 26 weeks | Reduced autoantibodies compared with vehicle-treated, reduced naïve B cells at high doses, reduced germinal center (GC) B cells and splenic plasma cells at all doses, reduced activated T cells with normal numbers of naïve T cells, preserved total IgG and IgA levels. | Reduced proteinuria, glomerular injury, cellular inflammatory infiltrates, IgG and C3 in the spontaneous model and prevention of proteinuria in the antibody-induced model. |
| Type 1 diabetes Ref: (26) 2014 |
Non-obese diabetic mice | Ibrutinib | Eliminated transgenic anti-insulin B cells in vitro | ND |
| Human rheumatoid arthritis and psoriatic arthritis Ref: (53) 2014 |
In vitro assays using synovial explants and human macrophages | RN486 | BTK was present in B cells, macrophages, monocytes and neutrophils in tissues. RN486 significantly inhibited IL6 production by stimulated macrophages, but only trended toward TNFα reduction. | ND |