Suppression of Glomerulonephritis in Lupus‐Prone NZB × NZW Mice by RN486, a Selective Inhibitor of Bruton's Tyrosine Kinase

Abstract

Objective. Bruton's tyrosine kinase (BTK) plays a critical role in B cell development and function. We recently described a selective BTK inhibitor, RN486, that blocks B cell receptor (BCR) and Fc␥ receptor signaling and is efficacious in animal models of arthritis. The aim of this study was to examine the potential efficacy of BTK in systemic lupus erythematosus (SLE), using an NZB ؋ NZW mouse model of spontaneous SLE.Methods. Mice received RN486 or its vehicle (administered in chow) at a final concentration of 30 mg/kg for 8 weeks, starting at 32 weeks of age.Results

Selective Inhibition of BTK Prevents Murine Lupus and Antibody-Mediated Glomerulonephritis

“…Consistent with our findings, Mina-Osorio (40) demonstrate that treatment of NZBxW_F1 mice with RN486, which is a reversible selective inhibitor of BTK, prevents the development of severe proteinuria and renal pathology. In addition, splenic plasma cell numbers were significantly reduced and the accumulation of IgG anti-dsDNA autoantibodies was halted upon initiation of treatment with RN486 (40). The two compounds differ, however, in their respective impact on total splenic IgG ASCs and B cell numbers.…”

“…A similar report detailing the impact of treatment of NZBxW_F1 mice with a BTK inhibitor was published while this manuscript was in review (40). Consistent with our findings, Mina-Osorio (40) demonstrate that treatment of NZBxW_F1 mice with RN486, which is a reversible selective inhibitor of BTK, prevents the development of severe proteinuria and renal pathology.…”

Enhanced Expression of Bruton’s Tyrosine Kinase in B Cells Drives Systemic Autoimmunity by Disrupting T Cell Homeostasis

“…To date, several studies investigating the efficacy of BTK inhibitors in rodent models for autoimmune diseases, including SLE and rheumatoid arthritis, have shown a beneficial effect on disease progression (25)(26)(27)(28)(29). Although effects of BTK can partly be explained by direct effects on B cells and autoantibody production, BTK inhibition clearly affects other cell types, including monocytes, macrophages, and mast cells-for example, through disruption of FcR signaling in myeloid cells.…”

“…B cells overexpressing BTK are selectively hyperresponsive to BCR stimulation, showing enhanced Ca 2+ influx and NF-kB activation and resistance to Fas-mediated apoptosis in vitro, and are not effectively eliminated in vivo when autoreactive (21). A pathogenic role for BTK in rheumatic diseases is further emerging from mouse studies demonstrating that smallmolecule BTK inhibitors prevent or ameliorate lupus nephritis and experimental arthritis (25)(26)(27)(28)(29)(30)(31). However, BTK inhibitors are likely to have effects beyond BCR signaling, because BTK functions downstream of many receptors, including chemokine and TLRs, and is also expressed in myeloid cells (32).…”

Which B-cell subset should we target in lupus?

“…Third, the effects of chronic BLyS/BAFF/APRIL blockade on long-lived PCs are currently unknown (since expression of the corresponding BR3/TACI/BCMA receptors has not been studied) but are not excluded by the fact that CD20 CD138 plasmacytoid cells are progressively depleted by belimumab therapy 21. Fourth, Bruton tyrosine kinase inhibitors have been shown to progressively deplete CD138 PCs in the spleen of NZB/W nephritic mice 22. Finally, at least from a theoretical viewpoint, Blimp1 pathway inhibitors could be useful.…”