PloS one, 2017-07, Vol.12 (7), p.e0181782-e0181782
2017
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- Autor(en) / Beteiligte
- Titel
- Bruton's tyrosine kinase inhibitor BMS-986142 in experimental models of rheumatoid arthritis enhances efficacy of agents representing clinical standard-of-care
- Ist Teil von
- PloS one, 2017-07, Vol.12 (7), p.e0181782-e0181782
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2017
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0181782Titel-ID: cdi_plos_journals_1923785184
- Format
- –
- Schlagworte
- Animal models, Animals, Antibody Formation - drug effects, Arthritis, Arthritis, Experimental - drug therapy, Arthritis, Experimental - immunology, Arthritis, Experimental - pathology, Autoimmune diseases, Autoimmunity, B-Lymphocytes - drug effects, B-Lymphocytes - immunology, B-Lymphocytes - pathology, Biocompatibility, Biology, Biology and Life Sciences, Biomedical materials, Bruton's tyrosine kinase, Care and treatment, Cell proliferation, Cellular signal transduction, Chief executive officers, Clinical trials, Collagen, CTLA-4 protein, Cytokines, Development and progression, Disease, Disorders, Effectiveness, Enzyme inhibitors, Etanercept, Fc receptors, Female, Generic drugs, Genetic aspects, Health aspects, Humans, Immunoglobulins, In vitro methods and tests, Inhibition, Inhibitors, Leukocytes (mononuclear), Leukocytes, Mononuclear - drug effects, Leukocytes, Mononuclear - immunology, Leukocytes, Mononuclear - pathology, Lymphocytes B, Medical research, Medicine and Health Sciences, Methotrexate, Mice, Inbred BALB C, Osteoclastogenesis, Osteoclasts - drug effects, Osteoclasts - immunology, Osteoclasts - pathology, Peripheral blood mononuclear cells, Pharmacology, Phosphotransferases, Protein Kinase Inhibitors - pharmacology, Protein Kinase Inhibitors - therapeutic use, Protein-tyrosine kinase, Protein-Tyrosine Kinases - antagonists & inhibitors, Protein-Tyrosine Kinases - immunology, R&D, RANK Ligand - immunology, Research & development, Research and Analysis Methods, Rheumatoid arthritis, Rodents, Signal transduction, Sjogren's syndrome, Standard of care, TRANCE protein, Tumor necrosis factor-TNF, Tyrosine, Tyrosine kinase inhibitors