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      Bruton’s Tyrosine Kinase Inhibitors: A New Therapeutic Target for the Treatment of SLE?

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          Abstract

          Systemic lupus erythematosus (SLE) is an autoimmune disease with a complex pathogenesis, which presents a great variability in its presentation and can affect almost all organs and systems. Multiple therapeutic targets have been discovered recently, but there also have been failed attempts to treat SLE using biologic agents. Bruton’s tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase expressed in several types of cells of hematopoietic origin which participate in both innate and adaptive immunity. Ibrutinib, a BTK inhibitor, is approved for the treatment of several B cell malignancies, including some types of lymphoma and leukemia. As BTK is expressed on several immune cell types, the mechanism of action of BTK also suggests the use of BTK inhibitors in the treatment of autoimmune diseases. In this review, we will summarize what is known and what has been published so far about the treatment of mouse models of SLE and the human disease, using BTK inhibitors.

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          Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals.

          Wilfried Ellmeier, Hiroshi Takayanagi, T. Koga … (2008)
          Certain autoimmune diseases result in abnormal bone homeostasis, but association of immunodeficiency with bone is poorly understood. Osteoclasts, which derive from bone marrow cells, are under the control of the immune system. Differentiation of osteoclasts is mainly regulated by signaling pathways activated by RANK and immune receptors linked to ITAM-harboring adaptors. However, it is unclear how the two signals merge to cooperate in osteoclast differentiation. Here we report that mice lacking the tyrosine kinases Btk and Tec show severe osteopetrosis caused by a defect in bone resorption. RANK and ITAM signaling results in formation of a Btk(Tec)/BLNK(SLP-76)-containing complex and PLCgamma-mediated activation of an essential calcium signal. Furthermore, Tec kinase inhibition reduces osteoclastic bone resorption in models of osteoporosis and inflammation-induced bone destruction. Thus, this study reveals the importance of the osteoclastogenic signaling complex composed of tyrosine kinases, which may provide the molecular basis for a new therapeutic strategy.
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            A role for Bruton's tyrosine kinase (Btk) in platelet activation by collagen.

            Genevieve L. Quek, J B Bolen, Jonathan S. Watson (1998)
            Bruton's tyrosine kinase (Btk) is essential for normal B-cell receptor signalling. The lack of expression of functional Btk in humans leads to the B-cell deficiency X-linked agammaglobulinaemia (XLA). We report here that Btk is also important for signalling via the collagen receptor glycoprotein VI (GPVI) in platelets. GPVI is coupled to the Fc receptor gamma chain (FcRgamma). The FcRgamma-chain contains a consensus sequence known as the immune-receptor tyrosine-based activation motif (ITAM). Tyrosine phosphorylation of the ITAM upon GPVI stimulation is the initial step in the regulation of phospholipase C gamma2 (PLCgamma2) isoforms via the tyrosine kinase p72(Syk) (Syk) in platelets. Here we show that collagen and a collagen-related peptide (CRP), which binds to GPVI but does not bind to the integrin alpha2beta1, induced Btk tyrosine phosphorylation in platelets. Aggregation, dense granule secretion and calcium mobilisation were significantly diminished but not completely abolished in platelets from XLA patients in response to collagen and CRP. These effects were associated with a reduction in tyrosine phosphorylation of PLCgamma2. In contrast, aggregation and secretion stimulated by thrombin in Btk-deficient platelets were not significantly altered. Our results demonstrate that Btk is important for collagen signalling via GPVI, but is not essential for thrombin-mediated platelet activation.
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              Selective inhibition of BTK prevents murine lupus and antibody-mediated glomerulonephritis.

              Andrew Rankin, Nilufer Seth, Sean Keegan … (2013)
              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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                Author and article information

                Journal
                Journal ID (nlm-ta): Immunotargets Ther
                Journal ID (iso-abbrev): Immunotargets Ther
                Journal ID (publisher-id): ITT
                Journal ID (pmc): itt
                Title: ImmunoTargets and Therapy
                Publisher: Dove
                ISSN (Electronic): 2253-1556
                Publication date (Electronic): 02 June 2020
                Publication date Collection: 2020
                Volume: 9
                Pages: 105-110
                Affiliations
                [1 ]Department of Internal Medicine, Hospital Universitario De Ourense , Ourense, Spain
                [2 ]Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Campania L. Vanvitelli , Naples, Italy
                [3 ]Centre for Rheumatology, Department of Medicine, University College London , London, UK
                Author notes
                Correspondence: David A Isenberg Email d.isenberg@ucl.ac.uk
                Article
                Publisher ID: 240874
                DOI: 10.2147/ITT.S240874
                PMC ID: 7276208
                PubMed ID: 32582577
                SO-VID: 8f300369-f0f4-4636-8758-77ec3c45cb0d
                Copyright © © 2020 Lorenzo-Vizcaya et al.
                License:

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                Date received : 29 February 2020
                Date accepted : 19 May 2020
                Page count
                Tables: 1, References: 39, Pages: 6
                Categories
                Subject: Review

                Keywords: lupus,bruton,tyrosine kinase,therapeutic targeting,ibrutinib,fenebrutinib
                Data availability:
                Keywords: lupus, bruton, tyrosine kinase, therapeutic targeting, ibrutinib, fenebrutinib

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