Bruton's tyrosine kinase inhibitor BMS-986142 in experimental models of rheumatoid arthritis enhances efficacy of agents representing clinical standard-of-care.

Kathleen M Gillooly,James R Burke,Jignesh Nagar,Aberra Fura,Elizabeth M Heimrich,Scott H Watterson,Lihong Cheng,Tracy L Taylor,Daniel W Kukral,Stacey Skala,Mark A Pattoli,Shailesh Dudhgaonkar,Dana Banas,Kim W Mcintyre,Claudine Pulicicchio,Joseph A Tino,Sakamuri V Reddy

doi:10.1371/journal.pone.0181782

Abstract

Bruton’s tyrosine kinase (BTK) regulates critical signal transduction pathways involved in the pathobiology of rheumatoid arthritis (RA) and other autoimmune disorders. BMS-986142 is a potent and highly selective reversible small molecule inhibitor of BTK currently being investigated in clinical trials for the treatment of both RA and primary Sjögren’s syndrome. In the present report, we detail the in vitro and in vivo pharmacology of BMS-986142 and show this agent provides potent and selective inhibition of BTK (IC50 = 0.5 nM), blocks antigen receptor-dependent signaling and functional endpoints (cytokine production, co-stimulatory molecule expression, and proliferation) in human B cells (IC50 ≤ 5 nM), inhibits Fcγ receptor-dependent cytokine production from peripheral blood mononuclear cells, and blocks RANK-L-induced osteoclastogenesis. Through the benefits of impacting these important drivers of autoimmunity, BMS-986142 demonstrated robust efficacy in murine models of rheumatoid arthritis (RA), including collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA). In both models, robust efficacy was observed without continuous, complete inhibition of BTK. When a suboptimal dose of BMS-986142 was combined with other agents representing the current standard of care for RA (e.g., methotrexate, the TNFα antagonist etanercept, or the murine form of CTLA4-Ig) in the CIA model, improved efficacy compared to either agent alone was observed. The results suggest BMS-986142 represents a potential therapeutic for clinical investigation in RA, as monotherapy or co-administered with agents with complementary mechanisms of action.

Highlights

Despite availability of various disease-modifying anti-rheumatic drugs (DMARDs) for the management of rheumatoid arthritis (RA), less than a fifth of DMARD-experienced patients receiving anti-tumor necrosis factor (TNF) biologic treatment achieve a 70% improvement in disease activity (American College of Rheumatology [ACR]70 response), even when co-administered with methotrexate (MTX) [1]
Bruton’s tyrosine kinase (BTK) is a key intracellular enzyme predominantly expressed in hematopoietic cells, including B cells, where it plays an essential role in B-cell receptor (BCR)-mediated activation, proliferation, cytokine production, and co-stimulatory molecule expression [5,6,7,8]
BTK is a key intracellular enzyme that regulates critical pathways involved in the pathobiology of RA and other autoimmune disorders

Summary

Introduction

Despite availability of various disease-modifying anti-rheumatic drugs (DMARDs) for the management of rheumatoid arthritis (RA), less than a fifth of DMARD-experienced patients receiving anti-tumor necrosis factor (TNF) biologic treatment achieve a 70% improvement in disease activity (American College of Rheumatology [ACR]70 response), even when co-administered with methotrexate (MTX) [1]. B cells play multiple roles in RA pathobiology, including being a source of autoantibodies and inflammatory cytokines, and as antigen-presenting cells [4]. Bruton’s tyrosine kinase (BTK) is a key intracellular enzyme predominantly expressed in hematopoietic cells, including B cells, where it plays an essential role in B-cell receptor (BCR)-mediated activation, proliferation, cytokine production, and co-stimulatory molecule expression [5,6,7,8]. Fcγ receptor IIa (FcγRIIa; cluster of differentiation [CD]32a) and FcγRIIIa (CD16) expression is increased in monocytes/macrophages from patients with RA, and these cells have been shown to produce higher levels of TNF-α and MMPs than those from healthy controls [11]. BTK has been shown to be essential in both the signal transduction pathway downstream of these activating IgG IC receptors as well as the subsequent expression of pro-inflammatory cytokines and integrins [5, 12]

Methods

Results

Conclusion