Table 4.
New candidates for therapeutic agents targeting rheumatoid FLS*
| Efficacy in animal model | Development stage | Potential adverse effects | |
|---|---|---|---|
| Targeting specific surface molecule | |||
| Cadherin-11 antagonistic antibodies | Cadherin-11-Fc fusion protein and anti- cadherin-11 monoclonal antibody ameliorated K/BxN serum transfer arthritis activity (115). | RG6125: (SDP051 formerly, Roche): completed phase I trial in RA (115) | Not reported |
| Cell cycle inhibitors | |||
| Cyclin-dependent kinase (CDK) inhibitor | Pan-CDK inhibitor (118) and selective CDK 4/6 inhibitor (117) suppressed arthritis dose dependently in murine CIA model. Immune response to type II collagen was not impaired. Synergistic anti-arthritic effect with cytokine blockade (Etanercept, IL-6 blocker) |
Palbociclib: (selective CDK 4/6 inhibitor, Pfizer) approved by the U.S. FDA for the treatment of metastatic breast cancer. | Neutropenia Gastrointestinal adverse Events (152) |
| Epigenetic regulators | |||
| SSAT-1 inhibitor | Diminazene aceturate restored DNA methylation and reduced the adhesion ability, MMP1 production, and invasiveness of rheumatoid FLS in SCID mice model (124). | Diminazene aceturate: the drug of choice for treatment animal Trypanosomiasis (153). | Not reported |
| Histone deacetylase inhibitor | Givinostat (125), SAHA, MS-275 (154), Trichostatin A (155) ameliorated synovial inflammation and joint destruction in murine arthritis model. MS-275 and SAHA decreased serum IL-6 and IL-1beta level (156). MS-275 suppressed cytokine-induced metalloproteinase expression in cartilage cells (157). |
Givinostat: showed therapeutic benefit with excellent safety profile on phase II, open-label trial in JIA (126) SAHA (Vorinostat): approved by U.S. FDA for the treatment of cutaneous T cell lymphoma. MS-275 (Entinostat): being studied phase II trial on Hodgkin’s lymphoma, breast cancer, and lung cancer. |
Self-limited respiratory or gastrointestinal disturbances, QTc prolongation (126) Fatigue, diarrhea, nausea, anorexia, anemia and thrombocytopenia (158) Nausea, anorexia, thrombocytopenia, anemia, neutropenia, hypophosphatemia (159, 160) |
CDK=cyclin-dependent kinase; CIA=collagen induced arthritis; IL=interleukin; FLS=fibroblast-like synoviocytes; MMP=matrix metalloproteinase; JIA=juvenile idiopathic arthritis; QTc=corrected QT interval; RA=rheumatoid arthritis; SAHA=suberoylanilide hydroxamic acid; SCID=severe combined immunodeficiency; SSAT-1=Spermidine/spermine N1-acetyltransferase 1
*
For reference detail, see Supplementary references.