Table 3.
Studies, clinical trials and approved therapeutic targeting of cytokines and signalling pathways in B cells for treating autoimmune diseases
| Targeted signalling molecule/pathway | Agent used | Structure of agent | Biological effects on B lymphocytes | Disease/status | Reference |
|---|---|---|---|---|---|
| JAK1/JAK2/JAK3 and to a lesser extent TYK2 | Tofacitinib | Chemical inhibitor | Inhibits the JAK/STAT pathway and blocks cytokine signalling | Approved for treating RA in many countries but not yet in the EU | [302] |
| JAK1/JAK2 | Baricitinib | Chemical inhibitor | Inhibits the JAK/STAT pathway and blocks cytokine signalling | RA in phase III clinical trials | [302] |
| JAK3 | Decernotinib (VX-509) | Chemical inhibitor | Inhibits the JAK/STAT pathway and blocks cytokine signalling | RA in phase II clinical trials | [302] |
| Pan-JAK | Peficitinib (ASP015 K) | Chemical inhibitor | Inhibits the JAK/STAT pathway and blocks cytokine signalling | RA in phase II clinical trials | [302] |
| JAK1 | Filgotinib (GLPG-0634) | Chemical inhibitor | Inhibits the JAK/STAT pathway and blocks cytokine signalling | RA in phase II clinical trials | [302] |
| JAK1 | ABT-494 | Chemical inhibitor | Inhibits the JAK/STAT pathway and blocks cytokine signalling | RA in phase II clinical trials | [302] |
| JAK1/JAK2 | INCB039110 | Chemical inhibitor | Inhibits the JAK/STAT pathway and blocks cytokine signalling | RA in phase II clinical trials | [302] |
| JAK/SYK | R333 | Chemical inhibitor | Inhibits the JAK/STAT pathway and blocks cytokine signalling | Discoid lupus in phase II clinical trials | [303] |
| JAK1 | GSK2586184 | Chemical inhibitor | Inhibits the JAK/STAT pathway and blocks cytokine signalling | SLE in phase II clinical trials | [303] |
| JAK1 | GLG0778 | Chemical inhibitor | Inhibits the JAK/STAT pathway and blocks cytokine signalling | SLE in phase II clinical trials | [303] |
| SYK | Fostamatinib | Chemical inhibitor | Inhibits SYK and blocks BCR and FcγR signalling | Clinical trials concluded that it is effective in treating RA; however, its clinical application is precluded due to unexpected side effects | [304] |
| BLyS (BAFF) | Atacicept | Recombinant fusion protein (TACI-Ig) | Blocks BLyS/APRIL binding and reduces survival and the number of some B cell subsets | Reduced B cell and plasma cell numbers and SLE disease activity but phase II/III trial stopped due to low blood Ab levels and pneumonia | [305] |
| Belimumab | Fully human monoclonal Ab (mAb) | Inhibits BLyS binding to membrane receptors; promotes apoptosis of B lymphocytes | Approved for treating SLE. However, patients with active lupus nephritis are excluded. Use for active lupus nephritis at phase III clinical trials. Sjögren’s syndrome phase III clinical trials |
[305] | |
| Briobacept (BR3-Fc) | Recombinant fusion protein | Inhibits BLyS binding to its receptor and promotes apoptosis | SLE clinical trials did not show sufficient efficacy | [305] | |
| Blisibimod (AMG-623) | Peptide-Fc fusion protein with 4 BLyS binding domains | Inhibits BLyS binding to its receptors and promotes apoptosis | SLE clinical trial is in phase III | [305] | |
| IL-6 | Sirukumab | Fully human mAb | Reduces B lymphocyte proliferation and differentiation | Clinical trials concluded its effectiveness in inhibiting progression of joint damage and improved signs and symptoms of disease in RA | [306] |
| IL-6R | Tocilizumab | Humanized mAb | Blocks B lymphocyte differentiation and reduces Ab production | Clinical trials concluded its effectiveness as a therapy for treating early RA | [307] |
| IFNα | Rontalizumab | Humanized mAb | Inhibits B lymphocyte activation and Ab production | Clinical trials concluded its effectiveness in treating SLE | [307] |
| Sifalimumab | Fully human mAb | Inhibits B lymphocyte activation and Ab production | Clinical trials concluded its effectiveness in treating SLE | [308] | |
| TLR4 | NI-0101 | Humanized mAb | Inhibits signalling through TLR4 | In phase I clinical trial for treating RA | [309] |
| TLR7/8/9 | Chloroquine | Chemical TLR7/8/9 antagonist | Reduces endosomal acidification and inhibits signalling through TLR | A mainstay therapy for SLE | [308] |
| TLR7/8/9 | IMO-8400 | Chemical TLR7/8/9 antagonist | Inhibits signalling through TLR7/8/9 | In phase I clinical trials for SLE | [308] |
| TLR7-RLR9 | IMO-3100 | Chemical TLR7/9 antagonist | Inhibits signalling through TLR7/9 | SLE clinical trial is in phase I | [308] |
The table summarizes available information on the use of therapeutic agents to target signalling pathways in B lymphocytes in clinical trials and in practice