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

Mina‐Osorio, Paola; LaStant, Jacob; Keirstead, Natalie D.; Whittard, Toni; Ayala, Julia; Stefanova, Stella; Garrido, Rosario; Dimaano, Nena; Hilton, Holly; Giron, Mario; Lau, Kai-Yeung; Hang, Julie Q.; Postelnek, Jennifer; Kim, Yong; Min, Soo Kee; Patel, Alka; Woods, John; Ramanujam, Meera; DeMartino, Julie A.; Narula, Satwant K.; Xu, Daigen

doi:10.1002/art.38047

Cited by 72 publications

(64 citation statements)

References 47 publications

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“…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.…”

Section: Discussionsupporting

confidence: 91%

“…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.…”

Section: Discussionsupporting

confidence: 87%

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

Rankin

Seth

Keegan

et al. 2013

The Journal of Immunology

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Autoantibody production and immune complex deposition within the kidney promote renal disease in patients with lupus nephritis. Thus, therapeutics that inhibit these pathways may be efficacious in the treatment of systemic lupus erythematosus. Bruton’s tyrosine kinase (BTK) is a critical signaling component of both BCR and FcR signaling. We sought to assess the efficacy of inhibiting BTK in the development of lupus-like disease, and in this article describe (R)-5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-[2,4-difluorophenoxy]phenyl)-1H-pyrazole-4-carboxamide (PF-06250112), a novel highly selective and potent BTK inhibitor. We demonstrate in vitro that PF-06250112 inhibits both BCR-mediated signaling and proliferation, as well as FcR-mediated activation. To assess the therapeutic impact of BTK inhibition, we treated aged NZBxW_F1 mice with PF-06250112 and demonstrate that PF-06250112 significantly limits the spontaneous accumulation of splenic germinal center B cells and plasma cells. Correspondingly, anti-dsDNA and autoantibody levels were reduced in a dose-dependent manner. Moreover, administration of PF-06250112 prevented the development of proteinuria and improved glomerular pathology scores in all treatment groups. Strikingly, this therapeutic effect could occur with only a modest reduction observed in anti-dsDNA titers, implying a critical role for BTK signaling in disease pathogenesis beyond inhibition of autoantibody production. We subsequently demonstrate that PF-06250112 prevents proteinuria in an FcR-dependent, Ab-mediated model of glomerulonephritis. Importantly, these results highlight that BTK inhibition potently limits the development of glomerulonephritis by impacting both cell- and effector molecule-mediated pathways. These data provide support for evaluating the efficacy of BTK inhibition in systemic lupus erythematosus patients.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 87%

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

Rankin

Seth

Keegan

et al. 2013

The Journal of Immunology

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

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

Corneth

Bruijn

Rip

et al. 2016

The Journal of Immunology

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Upon BCR stimulation, naive B cells increase protein levels of the key downstream signaling molecule Bruton’s tyrosine kinase (BTK). Transgenic CD19-hBtk mice with B cell–specific BTK overexpression show spontaneous germinal center formation, anti-nuclear autoantibodies, and systemic autoimmunity resembling lupus and Sjögren syndrome. However, it remains unknown how T cells are engaged in this pathology. In this study, we found that CD19-hBtk B cells were high in IL-6 and IL-10 and disrupted T cell homeostasis in vivo. CD19-hBtk B cells promoted IFN-γ production by T cells and expression of the immune-checkpoint protein ICOS on T cells and induced follicular Th cell differentiation. Crosses with CD40L-deficient mice revealed that increased IL-6 production and autoimmune pathology in CD19-hBtk mice was dependent on B–T cell interaction, whereas IL-10 production and IgM autoantibody formation were CD40L independent. Surprisingly, in Btk-overexpressing mice, naive B cells manifested increased CD86 expression, which was dependent on CD40L, suggesting that T cells interact with B cells in a very early stage of immune pathology. These findings indicate that increased BTK-mediated signaling in B cells involves a positive-feedback loop that establishes T cell–propagated autoimmune pathology, making BTK an attractive therapeutic target in autoimmune disease.

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“…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.…”

Section: Perspectives In Human Nephritismentioning

confidence: 99%

Which B-cell subset should we target in lupus?

Ferraccioli

Houssiau

2013

Ann Rheum Dis

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

Cited by 72 publications

References 47 publications

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

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

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

Which B-cell subset should we target in lupus?

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