Background/Purpose:  Bruton’s Tyrosine Kinase (BTK), a non-receptor tyrosine kinase is involved in intracellular signaling pathways downstream of several receptors, including the B cell receptor (BCR), Fcγ receptors (FcγR) and receptor activator of NF-κB (RANK). An aberrant activation of signaling pathway mediated by these receptors are reported to be associated with a progression of several autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Therefore, BTK inhibitor would be a potential therapeutic option for the treatment of RA and SLE. TAS5315 is a highly potent and selective BTK inhibitor and its inhibitory activity (IC₅₀) against anti-IgM-induced phosphorylation of BTK is 0.15 nmol/L. Here we describe the potential efficacy of TAS5315 in animal models of RA and SLE.

Methods: In vitro biochemical assay was performed using available kinase assay panels. In macrophages, the expression of inflammatory factors induced by IgG was measured with ELISA assay. To establish collagen-induced arthritis, male DBA/1 mice were injected on day-27 and-6 with an emulsion of complete Freund’s adjuvant and bovine type II collagen. On day 0, mice were randomized into treatment groups. TAS5315 was administrated orally once daily for 15 consecutive days. Disease severity was evaluated by clinical score of paw swelling. In MRL/lpr lupus model, mice were randomized into treatment groups at 14 weeks. TAS5315 was administrated orally once daily from 14 to 20 weeks. At the end of treatment period, spleen and lymph nodes were extracted to measure their weights, and kidneys were extracted to analyze the histopathological changes. The serum levels of anti-dsDNA antibody and proteinuria were also measured at the end of treatment period.

Results: TAS5315 selectively inhibited the enzyme activity of BTK and had less off target inhibition against other kinases. In cell-based functional assay, TAS5315 significantly inhibited FcγR-mediated TNF-α production by macrophages in a dose dependent manner (IC₅₀= 47.2 nM). In established mouse CIA model,TAS5315 dose-dependently decreased the clinical score in arthritic mice compared with that in vehicle-treated mice. TAS5315-treated mice had a marked reduction in the levels of TNF-α, IL-1β and IL-6 in synovial fluid and MMP3 in plasma. In MRL/lpr lupus model, TAS5315-treated mice showed the improvement for several inflammatory responses, such as lymphadenopathy, splenomegaly and the incidence of glomerulonephritis. TAS5315-treated mice also showed lower serum levels of blood urea nitrogen (BUN) and anti-dsDNA antibodies than vehicle-treated mice.

Conclusion: Our study demonstrates that a novel BTK inhibitor, TAS5315, shows significant efficacy by inhibiting inflammation in both RA and SLE models. These data suggest that TAS5315 could be a promising therapeutic agent for human autoimmune disease including RA and SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tas5315-a-novel-brutons-tyrosine-kinase-inhibitor-demonstrates-anti-inflammatory-effect-in-autoimmune-disease-models/