HM71224, a novel Bruton’s tyrosine kinase inhibitor, suppresses B cell and monocyte activation and ameliorates arthritis in a mouse model: a potential drug for rheumatoid arthritis

Abstract

BackgroundBruton’s tyrosine kinase (Btk) is critical for activation of B cells and myeloid cells. This study aimed to characterize the effects of HM71224, a novel Btk inhibitor, both in vitro and in a mouse model of experimental arthritis.MethodsThe kinase inhibition profile of HM71224 was analyzed. The in vitro effects of HM71224 on B cells and monocytes were analyzed by examining phosphorylation of Btk and its downstream signaling molecules, along with cytokine production and osteoclast formation. The in vivo effects of HM71224 were investigated in a mouse model of collagen-induced arthritis (CIA).ResultsHM71224 irreversibly bound to and inhibited Btk (IC50 = 1.95 nM). The compound also inhibited the phosphorylation of Btk and its downstream molecules such as PLCγ2, in activated Ramos B lymphoma cells and primary human B cells in a dose-dependent manner. Furthermore, HM71224 effectively inhibited the production of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β by human monocytes, and osteoclast formation by human monocytes. Finally, HM71224 improved experimental arthritis and prevented joint destruction in a murine model of CIA.ConclusionsHM71224 inhibits Btk in B cells and monocytes and ameliorates experimental arthritis in a mouse model. Thus, HM71224 is a potential novel therapeutic agent for rheumatoid arthritis in humans.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-0988-z) contains supplementary material, which is available to authorized users.

Efficacy and Pharmacodynamic Modeling of the BTK Inhibitor Evobrutinib in Autoimmune Disease Models

“…However, even in published studies with other BTK inhibitors, autoantibody levels were only partially reduced, yet disease was fully inhibited. This suggests that BTK inhibitors may affect arthritis development by inhibiting additional B cell functions, such as inflammatory cytokine production or Ag presentation to T cells (11,57). Indeed, we found the ratio between naive and memory Th cells shifted toward a more naive phenotype in the accelerated NZB/W model.…”

“…However, in the CIA experiment, treatment started only 18 d after the first immunization with collagen, and B cell differentiation to plasma cells may already have been committed. Other BTK inhibitors have been reported to reduce anti-collagen Abs in CIA models on different background strains to various degrees (57,58). It is unclear why this is not the case with evobrutinib.…”

HM71224, a selective Bruton’s tyrosine kinase inhibitor, attenuates the development of murine lupus

“…A previous report demonstrated the benefits of BTK inhibition in mouse models of TLR7/IFN-driven lupus by affecting both BCR and FcR signaling [ 23 ]. We also have previously demonstrated that BTK inhibition by HM71224 effectively blocks not only the phosphorylation of both BTK and PLCγ2 through downstream BCR signaling in human B cells, but also FcR-stimulated cytokine production in human monocytes [ 27 ].…”

“…The selectivity toward other BMX, TEC and TXK were 0.3, 2.3 and 2.4 fold, respectively. Moreover, HM71224 completely occupied to BTK and revealed potent inhibition of BCR, FcR and TLR mediated signaling [ 27 ].…”

Intracellular B Lymphocyte Signalling and the Regulation of Humoral Immunity and Autoimmunity

“…Although B cell depletion therapy has proved to be highly effective in treating a number of autoimmune diseases including RA, MS and SSc, total ablation of B cells carries its own risks including life-threatening infections. In this respect, some recent studies have revealed that treatment of lupus mice with inhibitors of Bruton’s tyrosine kinase (BTK) can ameliorate disease [ 310 , 311 ]. Thus, targeting dysregulated signalling effectors associated with proximal or downstream of BCR, CD40, TLR or cytokine receptors could prove an effective therapeutic strategy.…”