Btk-specific inhibition blocks pathogenic plasma cell signatures and myeloid cell–associated damage in IFNα-driven lupus nephritis

Katewa, Arna; Wang, Yugang; Hackney, Jason A.; Huang, Tao; Suto, Eric; Ramamoorthi, Nandhini; Austin, Cary D.; Bremer, Meire; Chen, Jacob Zhi; Crawford, James J.; Currie, Kevin S.; Blomgren, Peter; DeVoss, Jason; DiPaolo, Julie; Hau, Jonathan; Johnson, Adam R.; Lesch, Justin; DeForge, Laura; Lin, Zhonghua; Liimatta, Marya; Lubach, Joseph W.; McVay, Sami; Modrušan, Zora; Nguyen, Allen; Poon, Chungkee; Wang, Jianyong; Liu, Lichuan; Lee, Wyne P.; Wong, Harvey; Young, Wendy B.; Townsend, Michael J.; Reif, Karin

doi:10.1172/jci.insight.90111

Cited by 61 publications

(62 citation statements)

References 57 publications

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“…Autoantibodies can then deposit in the kidney, activating local cells, including macrophages, via Fc receptors. These activated cells initiate a localized inflammatory immune response which damages the kidney, leading to renal disease [16]. …”

Section: Discussionmentioning

confidence: 99%

“…A separate study by Katewa et al examined BTK inhibition in an alpha-IFN accelerated model in NZB/W mice, with a reduction in plasmablasts, autoantibodies, and renal disease [16]. Finally, Kim et al recently reported beneficial effects of HM71224, a selective BTK inhibitor, on renal disease and mortality when given prophylactically in NZB/W and MRL/lpr mice[19].…”

Section: Discussionmentioning

confidence: 99%

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BTK inhibition ameliorates kidney disease in spontaneous lupus nephritis

Chalmers

Glynn

Garcia

et al. 2018

Clinical Immunology

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Lupus nephritis is a common disease manifestation of SLE, in which immune complex deposition and macrophage activation are important contributors to disease pathogenesis. Bruton’s tyrosine kinase (BTK) plays an important role in both B cell and FcgammaR mediated myeloid cell activation. In the current study, we examined the efficacy of BI-BTK-1, a recently described irreversible BTK inhibitor, in the classical NZB×NZW F1 (NZB/W) and MRL/lpr spontaneous mouse models of SLE. NZB/W mice were randomly assigned to a treatment (0.3 mg/kg, 1 mg/kg, 3 mg/kg and 10 mg/kg) or control group and began treatment at 22 weeks of age. The experimental setup was similar in MRL/lpr mice, but with a single treated (10 mg/kg, beginning at 8–9 weeks of age) and control group. A separate experiment was performed in the MRL/lpr strain to assess the ability of BI-BTK-1 to reverse established kidney disease. Early treatment with BI-BTK-1 significantly protected NZB/W and MRL/lpr mice from the development of proteinuria, correlating with significant renal histological protection, decreased anti-DNA titers, and increased survival in both strains. BI-BTK-1 treated mice displayed a significant decrease in nephritis-associated inflammatory mediators (e.g. LCN2 and IL-6) in the kidney, combined with a significant inhibition of immune cell infiltration and accumulation. Importantly, BI-BTK-1 treatment resulted in the reversal of established kidney disease. BTK inhibition significantly reduced total B cell numbers and all B cell subsets (immature, transitional, follicular, marginal zone, and class switched) in the spleen of NZB/W mice. Overall, the significant efficacy of BIBTK-1 in ameliorating multiple pathological endpoints associated with kidney disease in two distinct murine models of spontaneous lupus nephritis provides a strong rationale for BTK inhibition as a promising treatment approach for lupus nephritis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

BTK inhibition ameliorates kidney disease in spontaneous lupus nephritis

Chalmers

Glynn

Garcia

et al. 2018

Clinical Immunology

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“…53 Btk is a nonreceptor tyrosine kinase that is a promising target for treating diseases caused by B cell dysregulation, such as B-cell malignancies and autoimmune diseases including rheumatoid arthritis and lupus. 54−58 CC-292 53 as well as drugs such as ibrutinib 59 contain an acrylamide electrophile that reacts with a conserved Cys (481) in the Btk active site. We synthesized a fluorescent probe based on CC-292 that was used to quantify levels of Btk engagement by CC-292 both in cell culture (Ramos cells) as well as in B lymphocytes obtained from rats dosed with CC-292.…”

Section: In Vivo Target Vulnerability: Chemical Tools To Quantify Tarmentioning

confidence: 99%

Drug–Target Kinetics in Drug Discovery

Tonge

2017

ACS Chem. Neurosci.

214

235

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The development of therapies for the treatment of neurological cancer faces a number of major challenges including the synthesis of small molecule agents that can penetrate the blood brain barrier (BBB). Given the likelihood that in many cases drug exposure will be lower in the CNS than in systemic circulation, it follows that strategies should be employed that can sustain target engagement at low drug concentration. Time dependent target occupancy is a function of both the drug and target concentration as well as the thermodynamic and kinetic parameters that describe the binding reaction coordinate, and sustained target occupancy can be achieved through structural modifications that increase target (re)binding and/or that decrease the rate of drug dissociation. The discovery and deployment of compounds with optimized kinetic effects requires information on the structure-kinetic relationships that modulate the kinetics of binding, and the molecular factors that control the translation of drug-target kinetics to time-dependent drug activity in the disease state. This review first introduces the potential benefits of drug-target kinetics, such as the ability to delineate both thermodynamic and kinetic selectivity, and then describes factors, such as target vulnerability, that impact the utility of kinetic selectivity. The review concludes with a description of a mechanistic PK/PD model that integrates drug-target kinetics into predictions of drug activity.

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“…Specific Btk inhibitor treatment of NZB/W F1 mice ameliorated lupus‐like disease by reversing the accumulation of germinal center and plasma B cells and lowering anti‐dsDNA autoantibodies levels . Improved glomerular pathology and function were also observed after Btk inhibition . In an inducible model of lupus nephritis, Btk inhibition decreased complement deposition in the kidneys and reduced inflammatory cytokine production .…”

Section: The X Chromosome In Autoimmunitymentioning

confidence: 97%

“…SLE is a disease often characterized by excessive B cell activity, which results in increased production of cytokines and autoantibodies that elevate inflammation and cause organ damage . Specific Btk inhibitor treatment of NZB/W F1 mice ameliorated lupus‐like disease by reversing the accumulation of germinal center and plasma B cells and lowering anti‐dsDNA autoantibodies levels . Improved glomerular pathology and function were also observed after Btk inhibition .…”

Section: The X Chromosome In Autoimmunitymentioning

confidence: 99%

When the balance is broken: X-linked gene dosage from two X chromosomes and female-biased autoimmunity

Syrett

Anguera

2019

Journal of Leukocyte Biology

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Women and men exhibit differences in innate and adaptive immunity, and women are more susceptible to numerous autoimmune disorders. Two or more X chromosomes increases the risk for some autoimmune diseases, and increased expression of some X-linked immune genes is frequently observed in female lymphocytes from autoimmune patients. Evidence from mouse models of autoimmunity also supports the idea that increased expression of X-linked genes is a feature of female-biased autoimmunity. Recent studies have begun to elucidate the correlation between abnormal X-chromosome inactivation (XCI), an essential mechanism female somatic cells use to equalize X-linked gene dosage between the sexes, and autoimmunity in lymphocytes. In this review, we highlight research describing overexpression of X-linked immunity-related genes and female-biased autoimmunity in both humans and mouse models, and make connections with our recent work elucidating lymphocyte-specific mechanisms of XCI maintenance that become altered in lupus patients. K E Y W O R D Slupus, mouse models of lupus disease, sexual dimorphism with immune disease, X-chromosome inactivation, XCI gene escape, Xist RNA important for the development of autoimmunity, and disease results from additive effects of several risk variants, which alone would be insufficient to cause disease. Yet, hundreds of loci have been associated with autoimmune diseases, and some of these immune gene variants are present in different diseases, suggesting that common J Leukoc Biol. 2019;106:919-932.

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Btk-specific inhibition blocks pathogenic plasma cell signatures and myeloid cell–associated damage in IFNα-driven lupus nephritis

Cited by 61 publications

References 57 publications

BTK inhibition ameliorates kidney disease in spontaneous lupus nephritis

BTK inhibition ameliorates kidney disease in spontaneous lupus nephritis

Drug–Target Kinetics in Drug Discovery

When the balance is broken: X-linked gene dosage from two X chromosomes and female-biased autoimmunity

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