Bruton's tyrosine kinase inhibitor BMS-986142 in experimental models of rheumatoid arthritis enhances efficacy of agents representing clinical standard-of-care.
Kathleen M GilloolyClaudine PulicicchioMark A PattoliLihong ChengStacey SkalaElizabeth M HeimrichKim W McIntyreTracy L TaylorDaniel W KukralShailesh DudhgaonkarJignesh NagarDana BanasScott H WattersonJoseph A TinoAberra FuraJames R BurkePublished in: PloS one (2017)
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.
Keyphrases
- rheumatoid arthritis
- tyrosine kinase
- disease activity
- ankylosing spondylitis
- epidermal growth factor receptor
- high glucose
- small molecule
- clinical trial
- interstitial lung disease
- healthcare
- diabetic rats
- endothelial cells
- rheumatoid arthritis patients
- palliative care
- drug induced
- multiple sclerosis
- juvenile idiopathic arthritis
- quality improvement
- combination therapy
- poor prognosis
- chronic pain
- binding protein
- systemic lupus erythematosus
- high resolution
- mass spectrometry
- high dose
- anti inflammatory
- study protocol
- long non coding rna
- wound healing
- phase ii
- inflammatory response
- replacement therapy
- tissue engineering
- health insurance
- affordable care act