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Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Bruton's Tyrosine Kinase Inhibition in the Treatment of Preclinical Models and Multiple Sclerosis

Author(s): Anja Steinmaurer, Isabella Wimmer, Thomas Berger, Paulus S Rommer and Johann Sellner*

Volume 28, Issue 6, 2022

Published on: 01 July, 2021

Page: [437 - 444] Pages: 8

DOI: 10.2174/1381612827666210701152934

Price: $65


Significant progress has been made to understand the immunopathogenesis of multiple sclerosis (MS) over recent years. Successful clinical trials with CD20-depleting monoclonal antibodies have corroborated the fundamental role of B cells in the pathogenesis of MS and reinforced the notion that cells of the B cell lineage are an attractive treatment target. Therapeutic inhibition of Bruton's tyrosine kinase (BTK), an enzyme involved in B cell and myeloid cell activation and function, is regarded as a next-generation approach that aims to attenuate both errant innate and adaptive immune functions. Moreover, brain-penetrant BTK inhibitors may impact compartmentalized inflammation and neurodegeneration within the central nervous system by targeting brain-resident B cells and microglia, respectively. Preclinical studies in animal models of MS corroborated an impact of BTK inhibition on meningeal inflammation and cortical demyelination. Notably, BTK inhibition attenuated the antigen-presenting capacity of B cells and the generation of encephalitogenic T cells. Evobrutinib, a selective oral BTK inhibitor, has been tested recently in a phase 2 study of patients with relapsing-remitting MS. The study met the primary endpoint of a significantly reduced cumulative number of Gadolinium-enhancing lesions under treatment with evobrutinib compared to placebo treatment. Thus, the results of ongoing phase 2 and 3 studies with evobrutinib, fenobrutinib, and tolebrutinib in relapsing-remitting and progressive MS are eagerly awaited. This review article introduces the physiological role of BTK, summarizes the pre-clinical and trial evidence, and addresses the potential beneficial effects of BTK inhibition in MS.

Keywords: Multiple sclerosis, immunopathogenesis, B cell, Bruton's tyrosine kinase, disease-modifying therapy, immunomodulation, demyelination.

Lassmann H. The changing concepts in the neuropathology of acquired demyelinating central nervous system disorders. Curr Opin Neurol 2019; 32(3): 313-9.
[] [PMID: 30893100]
Hartung HP, Aktas O, Menge T, Kieseier BC. Immune regulation of multiple sclerosis. Handb Clin Neurol 2014; 122: 3-14.
[] [PMID: 24507511]
Sellner J, Kraus J, Awad A, Milo R, Hemmer B, Stüve O. The increasing incidence and prevalence of female multiple sclerosis--a critical analysis of potential environmental factors. Autoimmun Rev 2011; 10(8): 495-502.
[] [PMID: 21354338]
Comi G, Bar-Or A, Lassmann H, et al. Role of B cells in multiple sclerosis and related disorders. Ann Neurol 2021; 89(1): 13-23.
[] [PMID: 33091175]
Moser T, Akgün K, Proschmann U, Sellner J, Ziemssen T. The role of TH17 cells in multiple sclerosis: Therapeutic implications. Autoimmun Rev 2020; 19(10): 102647.
[] [PMID: 32801039]
Graf J, Mares J, Barnett M, et al. Targeting B Cells to Modify MS, NMOSD, and MOGAD: Part 1. Neurol Neuroimmunol Neuroinflamm 2021; 8: e918.
Lehmann-Horn K, Kinzel S, Weber MS. Deciphering the role of B cells in multiple sclerosis-towards specific targeting of pathogenic function. Int J Mol Sci 2017; 18(10): 18.
[] [PMID: 28946620]
Häusser-Kinzel S, Weber MS. The role of B cells and antibodies in multiple sclerosis, neuromyelitis optica, and related disorders. Front Immunol 2019; 10: 201.
[] [PMID: 30800132]
Findling O, Sellner J. Second-generation immunotherapeutics in multiple sclerosis: can we discard their precursors? Drug Discov Today 2021; 26(2): 416-28.
[PMID: 33248250]
Brunner C, Müller B, Wirth T. Bruton’s Tyrosine Kinase is involved in innate and adaptive immunity. Histol Histopathol 2005; 20(3): 945-55.
[PMID: 15944945]
Molica S, Gianfelici V, Levato L. Emerging bruton tyrosine kinase inhibitors for chronic lymphocytic leukaemia: one step ahead ibrutinib. Expert Opin Emerg Drugs 2020; 25(1): 25-35.
[] [PMID: 31996046]
Bond DA, Maddocks KJ. Current role and emerging evidence for bruton tyrosine kinase inhibitors in the treatment of mantle cell lymphoma. Hematol Oncol Clin North Am 2020; 34(5): 903-21.
[] [PMID: 32861286]
Grimont CN, Castillo Almeida NE, Gertz MA. Current and emerging treatments for waldenstrom macroglobulinemia. Acta Haematol 2020; 144: 1-12.
[PMID: 32810857]
Lind J, Czernilofsky F, Vallet S, Podar K. Emerging protein kinase inhibitors for the treatment of multiple myeloma. Expert Opin Emerg Drugs 2019; 24(3): 133-52.
[] [PMID: 31327278]
Di Paolo JA, Huang T, Balazs M, et al. Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis. Nat Chem Biol 2011; 7(1): 41-50.
[] [PMID: 21113169]
Torke S, Pretzsch R, Häusler D, et al. Inhibition of Bruton’s tyrosine kinase interferes with pathogenic B-cell development in inflammatory CNS demyelinating disease. Acta Neuropathol 2020; 140(4): 535-48.
[] [PMID: 32761407]
Bhargava P, Kim S, Reyes AA, et al. Imaging meningeal inflammation in CNS autoimmunity identifies a therapeutic role for BTK inhibition. Brain 2021; awab045.
[] [PMID: 33724342]
de Weers M, Verschuren MC, Kraakman ME, et al. The Bruton’s tyrosine kinase gene is expressed throughout B cell differentiation, from early precursor B cell stages preceding immunoglobulin gene rearrangement up to mature B cell stages. Eur J Immunol 1993; 23(12): 3109-14.
[] [PMID: 8258324]
Xia S, Liu X, Cao X, Xu S. T-cell expression of Bruton’s tyrosine kinase promotes autoreactive T-cell activation and exacerbates aplastic anemia. Cell Mol Immunol 2020; 17(10): 1042-52.
[] [PMID: 31431692]
Smith CI, Baskin B, Humire-Greiff P, et al. Expression of Bruton’s agammaglobulinemia tyrosine kinase gene, BTK, is selectively down-regulated in T lymphocytes and plasma cells. J Immunol 1994; 152(2): 557-65.
[PMID: 8283037]
Lindvall JM, Blomberg KE, Väliaho J, et al. Bruton’s tyrosine kinase: cell biology, sequence conservation, mutation spectrum, siRNA modifications, and expression profiling. Immunol Rev 2005; 203: 200-15.
[] [PMID: 15661031]
Tsukada S, Saffran DC, Rawlings DJ, et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell 1993; 72(2): 279-90.
[] [PMID: 8425221]
Vetrie D, Vorechovský I, Sideras P, et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature 1993; 361(6409): 226-33.
[] [PMID: 8380905]
Bruton OC. Agammaglobulinemia. Pediatrics 1952; 9(6): 722-8.
[PMID: 14929630]
Campana D, Farrant J, Inamdar N, Webster AD, Janossy G. Phenotypic features and proliferative activity of B cell progenitors in X-linked agammaglobulinemia. J Immunol 1990; 145(6): 1675-80.
[PMID: 2391416]
Nomura K, Kanegane H, Karasuyama H, et al. Genetic defect in human X-linked agammaglobulinemia impedes a maturational evolution of pro-B cells into a later stage of pre-B cells in the B- cell differentiation pathway. Blood 2000; 96(2): 610-7.
[PMID: 10887125]
Ponader S, Burger JA. Bruton’s tyrosine kinase: from X-linked agammaglobulinemia toward targeted therapy for B-cell malignancies. J Clin Oncol 2014; 32(17): 1830-9.
[] [PMID: 24778403]
Lackey AE, Ahmad F. X-linked Agammaglobulinemia. StatPearls: Treasure Island (FL) Stat- Pearls: Treasure Island (FL) 2020.
Kersseboom R, Kil L, Flierman R, et al. Constitutive activation of Bruton’s tyrosine kinase induces the formation of autoreactive IgM plasma cells. Eur J Immunol 2010; 40(9): 2643-54.
[] [PMID: 20623551]
Kendall PL, Moore DJ, Hulbert C, Hoek KL, Khan WN, Thomas JW. Reduced diabetes in btk-deficient nonobese diabetic mice and restoration of diabetes with provision of an anti-insulin IgH chain transgene. J Immunol 2009; 183(10): 6403-12.
[] [PMID: 19841184]
Dal Porto JM, Gauld SB, Merrell KT, Mills D, Pugh-Bernard AE, Cambier J. B cell antigen receptor signaling 101. Mol Immunol 2004; 41(6-7): 599-613.
[] [PMID: 15219998]
Rawlings DJ, Scharenberg AM, Park H, et al. Activation of BTK by a phosphorylation mechanism initiated by SRC family kinases. Science 1996; 271(5250): 822-5.
[] [PMID: 8629002]
Petro JB, Rahman SM, Ballard DW, Khan WN. Bruton’s tyrosine kinase is required for activation of IkappaB kinase and nuclear factor kappaB in response to B cell receptor engagement. J Exp Med 2000; 191(10): 1745-54.
[] [PMID: 10811867]
Takata M, Kurosaki T. A role for Bruton’s tyrosine kinase in B cell antigen receptor-mediated activation of phospholipase C-gamma 2. J Exp Med 1996; 184(1): 31-40.
[] [PMID: 8691147]
Genevier HC, Callard RE. Impaired Ca2+ mobilization by X-linked agammaglobulinaemia (XLA) B cells in response to ligation of the B cell receptor (BCR). Clin Exp Immunol 1997; 110(3): 386-91.
[] [PMID: 9409640]
Rip J, Van Der Ploeg EK, Hendriks RW, Corneth OBJ. The role of bruton’s tyrosine kinase in immune cell signaling and systemic autoimmunity. Crit Rev Immunol 2018; 38(1): 17-62.
[] [PMID: 29717662]
Weber ANR, Bittner Z, Liu X, Dang TM, Radsak MP, Brunner C. Bruton’s tyrosine kinase: An emerging key player in innate immunity. Front Immunol 2017; 8: 1454.
[] [PMID: 29167667]
Jefferies CA, Doyle S, Brunner C, et al. Bruton’s tyrosine kinase is a Toll/interleukin-1 receptor domain-binding protein that participates in nuclear factor kappaB activation by Toll-like receptor 4. J Biol Chem 2003; 278(28): 26258-64.
[] [PMID: 12724322]
Kenny EF, Quinn SR, Doyle SL, Vink PM, van Eenennaam H, O’Neill LA. Bruton’s tyrosine kinase mediates the synergistic signalling between TLR9 and the B cell receptor by regulating calcium and calmodulin. PLoS One 2013; 8(8): e74103.
[] [PMID: 23967355]
Ito M, Shichita T, Okada M, et al. Bruton’s tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury. Nat Commun 2015; 6: 7360.
[] [PMID: 26059659]
Mukhopadhyay S, George A, Bal V, Ravindran B, Rath S. Bruton’s tyrosine kinase deficiency in macrophages inhibits nitric oxide generation leading to enhancement of IL-12 induction. J Immunol 1999; 163(4): 1786-92.
[PMID: 10438910]
Ní Gabhann J, Hams E, Smith S, et al. Btk regulates macrophage polarization in response to lipopolysaccharide. PLoS One 2014; 9(1): e85834.
[] [PMID: 24465735]
Prinz M, Jung S, Priller J. Microglia biology: one century of evolving concepts. Cell 2019; 179(2): 292-311.
[] [PMID: 31585077]
Fiebich BL, Batista CRA, Saliba SW, Yousif NM, de Oliveira ACP. Role of Microglia TLRs in Neurodegeneration. Front Cell Neurosci 2018; 12: 329.
[] [PMID: 30333729]
Whyburn LR, Halcomb KE, Contreras CM, Lowell CA, Witte ON, Satterthwaite AB. Reduced dosage of Bruton’s tyrosine kinase uncouples B cell hyperresponsiveness from autoimmunity in lyn-/- mice. J Immunol 2003; 171(4): 1850-8.
[] [PMID: 12902486]
Keaney J, Gasser J, Gillet G, Scholz D, Kadiu I. Inhibition of bruton’s tyrosine kinase modulates microglial phagocytosis: Therapeutic implications for Alzheimer’s disease. J Neuroimmune Pharmacol 2019; 14(3): 448-61.
[] [PMID: 30758770]
Martin E, Aigrot MS, Grenningloh R, et al. Bruton’s tyrosine kinase inhibition promotes myelin repair. Brain Plast 2020; 5(2): 123-33.
[] [PMID: 33282676]
Schutt SD, Fu J, Nguyen H, et al. Inhibition of BTK and ITK with ibrutinib is effective in the prevention of chronic graft-versus-host disease in mice. PLoS One 2015; 10(9): e0137641.
[] [PMID: 26348529]
Dubovsky JA, Flynn R, Du J, et al. Ibrutinib treatment ameliorates murine chronic graft-versus-host disease. J Clin Invest 2014; 124(11): 4867-76.
[] [PMID: 25271622]
Burger JA, Wiestner A. Targeting B cell receptor signalling in cancer: preclinical and clinical advances. Nat Rev Cancer 2018; 18(3): 148-67.
[] [PMID: 29348577]
Wen T, Wang J, Shi Y, et al. Inhibitors targeting Bruton’s tyrosine kinase in cancers: drug development advances. Leukemia 2020.
[PMID: 33122850]
Estupiñán HY, Berglöf A, Zain R, Smith CIE. Comparative analysis of BTK inhibitors and mechanisms underlying adverse effects. Front Cell Dev Biol 2021; 9: 630942.
[] [PMID: 33777941]
Ondrisova L, Mraz M. Genetic and non-genetic mechanisms of resistance to BCR signaling inhibitors in B cell malignancies. Front Oncol 2020; 10: 591577.
[] [PMID: 33154951]
Delgado J, Josephson F, Camarero J, et al. The European medicines agency review of acalabrutinib for the treatment of adult patients with chronic lymphocytic leukemia. Oncologist 2021; 26(3): 242-9.
Kriegsmann K, Kriegsmann M, Witzens-Harig M. Acalabrutinib, A second-generation bruton’s tyrosine kinase inhibitor. Recent Results Cancer Res 2018; 212: 285-94.
[] [PMID: 30069636]
Awan FT, Schuh A, Brown JR, et al. Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. Blood Adv 2019; 3(9): 1553-62.
[] [PMID: 31088809]
Tam CS, Opat S, D’Sa S, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood 2020; 136(18): 2038-50.
[] [PMID: 32731259]
Estupiñán HY, Wang Q, Berglöf A, et al. BTK gatekeeper residue variation combined with cysteine 481 substitution causes super-resistance to irreversible inhibitors acalabrutinib, ibrutinib and zanubrutinib. Leukemia 2021; 35(5): 1317-29.
[] [PMID: 33526860]
Lipsky A, Lamanna N. Managing toxicities of bruton tyrosine kinase inhibitors. Hematology (Am Soc Hematol Educ Program) 2020; 2020(1): 336-45.
[] [PMID: 33275698]
Lasica M, Tam CS. Management of Ibrutinib Toxicities: a Practical Guide. Curr Hematol Malig Rep 2020; 15(3): 177-86.
[] [PMID: 32415406]
Caldwell RD, Qiu H, Askew BC, et al. Discovery of evobrutinib: An oral, potent, and highly selective, Covalent Bruton’s tyrosine kinase (BTK) inhibitor for the treatment of immunological diseases. J Med Chem 2019; 62(17): 7643-55.
[] [PMID: 31368705]
Nam HY, Nam JH, Yoon G, et al. Ibrutinib suppresses LPS-induced neuroinflammatory responses in BV2 microglial cells and wild-type mice. J Neuroinflammation 2018; 15(1): 271.
[] [PMID: 30231870]
Mangla A, Khare A, Vineeth V, et al. Pleiotropic consequences of Bruton tyrosine kinase deficiency in myeloid lineages lead to poor inflammatory responses. Blood 2004; 104(4): 1191-7.
[] [PMID: 15117762]
Svensson L, Abdul-Majid KB, Bauer J, Lassmann H, Harris RA, Holmdahl R. A comparative analysis of B cell-mediated myelin oligodendrocyte glycoprotein-experimental autoimmune encephalomyelitis pathogenesis in B cell-deficient mice reveals an effect on demyelination. Eur J Immunol 2002; 32(7): 1939-46.
[<1939::AID-IMMU1939>3.0.CO;2-S] [PMID: 12115614]
Montalban X, Arnold DL, Weber MS, et al. Placebo-controlled trial of an oral BTK inhibitor in multiple sclerosis. N Engl J Med 2019; 380(25): 2406-17.
[] [PMID: 31075187]
Kerschbaumer A, Smolen JS, Herkner H, Stefanova T, Chwala E, Aletaha D. Efficacy outcomes in phase 2 and phase 3 randomized controlled trials in rheumatology. Nat Med 2020; 26(6): 974-80.
[] [PMID: 32313250]
Liu J, Chen C, Wang D, Zhang J, Zhang T. Emerging small- molecule inhibitors of the Bruton’s tyrosine kinase (BTK): Current development. Eur J Med Chem 2021; 217: 113329.
[] [PMID: 33740548]
Vermersch P, Benrabah R, Schmidt N, et al. Masitinib treatment in patients with progressive multiple sclerosis: a randomized pilot study. BMC Neurol 2012; 12: 36.
[] [PMID: 22691628]
Lassmann H. Pathogenic mechanisms associated with different clinical courses of multiple sclerosis. Front Immunol 2019; 9: 3116.
[] [PMID: 30687321]
Rommer PS, Sellner J. Repurposing multiple sclerosis drugs: a review of studies in neurological and psychiatric conditions. Drug Discov Today 2019; 24(7): 1398-404.
[] [PMID: 31100209]
Sellner J, Rommer PS. Multiple sclerosis and SARS-CoV-2 vaccination: considerations for immune-depleting therapies. Vaccines (Basel) 2021; 9(2): 9.
[] [PMID: 33525459]
Sormani MP, De Rossi N, Schiavetti I, et al. Disease modifying therapies and Covid-19 severity in Multiple Sclerosis. Ann Neurol 2021; 89(4): 780-9.
Zabalza A, Cárdenas-Robledo S, Tagliani P, et al. COVID-19 in multiple sclerosis patients: susceptibility, severity risk factors and serological response. Eur J Neurol 2020; 28(10): 3384-95.
[PMID: 33340215]
Lester SN, Li K. Toll-like receptors in antiviral innate immunity. J Mol Biol 2014; 426(6): 1246-64.
[] [PMID: 24316048]
Mdkhana B, Saheb Sharif-Askari N, Ramakrishnan RK, Goel S, Hamid Q, Halwani R. Nucleic acid-sensing pathways during SARS-CoV-2 infection: expectations versus reality. J Inflamm Res 2021; 14: 199-216.
[] [PMID: 33531826]
Roschewski M, Lionakis MS, Sharman JP, et al. Inhibition of Bruton tyrosine kinase in patients with severe COVID-19. Sci Immunol 2020; 5(48): 5.
[] [PMID: 32503877]
Rada M, Qusairy Z, Massip-Salcedo M, et al. Relevance of the bruton tyrosine kinase as a target for COVID-19 therapy. Mol Cancer Res 2020.
[PMID: 33328281]
Zrzavy T, Kollaritsch H, Rommer PS, et al. Vaccination in multiple sclerosis: friend or foe? Front Immunol 2019; 10: 1883.
[] [PMID: 31440255]
Sellner J, M Jenkins T, J von Oertzen T, et al. Primary prevention of COVID-19: Advocacy for vaccination from a neurological perspective. Eur J Neurol 2021.
[] [PMID: 33386655]
Hauer L, Perneczky J, Sellner J. A global view of comorbidity in multiple sclerosis: a systematic review with a focus on regional differences, methodology, and clinical implications. J Neurol 2020.
[] [PMID: 32719975]

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