Inhibition of Bruton’s tyrosine kinase interferes with pathogenic B-cell development in inflammatory CNS demyelinating disease

Torke, Sebastian; Pretzsch, Roxanne; Häusler, Darius; Haselmayer, Philipp; Grenningloh, Roland; Boschert, Ursula; Brück, Wolfgang; Weber, Martin

doi:10.1007/s00401-020-02204-z

Cited by 71 publications

(88 citation statements)

References 27 publications

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“…A large number of experimental models support the efficacy of BTK inhibition in MS. In experimental autoimmune encephalomyelitis (EAE) mouse models of MS, evobrutinib prophylactically reduced disease severity [ 28 ], and evobrutinib treatment in mice with established symptoms resulted in reduced leptomeningeal inflammation [ 29 ]. Hereby, the numbers of meningeal B cells were reduced, but myeloid cell infiltrates appeared to persist.…”

Section: Introductionmentioning

confidence: 99%

Bruton’s Tyrosine Kinase Inhibition as an Emerging Therapy in Systemic Autoimmune Disease

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Rip

Hendriks

et al. 2021

Drugs

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Systemic autoimmune disorders are complex heterogeneous chronic diseases involving many different immune cells. A significant proportion of patients respond poorly to therapy. In addition, the high burden of adverse effects caused by “classical” anti-rheumatic or immune modulatory drugs provides a need to develop more specific therapies that are better tolerated. Bruton’s tyrosine kinase (BTK) is a crucial signaling protein that directly links B-cell receptor (BCR) signals to B-cell activation, proliferation, and survival. BTK is not only expressed in B cells but also in myeloid cells, and is involved in many different signaling pathways that drive autoimmunity. This makes BTK an interesting therapeutic target in the treatment of autoimmune diseases. The past decade has seen the emergence of first-line BTK small-molecule inhibitors with great efficacy in the treatment of B-cell malignancies, but with unfavorable safety profiles for use in autoimmunity due to off-target effects. The development of second-generation BTK inhibitors with superior BTK specificity has facilitated the investigation of their efficacy in clinical trials with autoimmune patients. In this review, we discuss the role of BTK in key signaling pathways involved in autoimmunity and provide an overview of the different inhibitors that are currently being investigated in clinical trials of systemic autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus, as well as available results from completed trials.

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Section: Introductionmentioning

confidence: 99%

Bruton’s Tyrosine Kinase Inhibition as an Emerging Therapy in Systemic Autoimmune Disease

Neys

Rip

Hendriks

et al. 2021

Drugs

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“…Similar to the BAFFR, TLR4 is thought to transduce signals through the BCR (Schweighoffer et al, 2017). BTK interacts directly with the cytoplasmic sensor NLR family pyrin domain containing 3 (NLRP3) and its adaptor ASC (apoptosis-associated speck like protein containing a caspase recruitment domain) and Halcomb et al, 2008;Lee et al, 2008a;Corneth et al, 2016;von Borstel et al, 2019;Torke et al, 2020 BCR; BAFFR; TLR Proliferation, differentiation & immunoglobulin production Wicker and Scher, 1986;Khan et al, 1995;Di Paolo et al, 2011;Haselmayer et al, 2019;von Borstel et al, 2019 Kneidinger et al, 2008;MacGlashan et al, 2011;Smiljkovic et al, 2017;Haselmayer et al, 2019 Monocyte FcγR Cytokine production (TNFα, IL-6, MCP-1, IL-1β) Chang et al, 2011;Di Paolo et al, 2011;Ren et al, 2016 Macrophage TLR2/4 Microbicidal activity (via nitric oxide (NO) production), cytokine production (TNFα, IL-1β) and M1 polarization Mukhopadhyay et al, 1999Mukhopadhyay et al, , 2002Mangla et al, 2004;Ni Gabhann et al, 2014;de Porto et al, 2019 FcγR Cytokine production (TNFα, IL-6, IL-1β, MCP-1) Chang et al, 2011;Di Paolo et al, 2011;Hartkamp et al, 2015 is, thus, involved in inflammasome and caspase-1 activation and subsequent interleukin (IL)-1β and IL-18 production (Ito et al, 2015). Engagement of triggering receptor expressed on myeloid cells-1 (TREM-1) induces BTK activation and leads to inflammatory responses (Ormsby et al, 2011).…”

Section: Pattern Recognition Receptorsmentioning

confidence: 99%

“…B cells are thought to play an important role in MS pathogenesis as shown by the clinical success of rituximab treatment (Kinzel and Weber, 2016). In experimental autoimmune encephalitis, a mouse model for MS, BTKi ameliorated disease (Torke et al, 2020). Compared with other AID and healthy controls, MS B cells did not show increased BTK protein expression or pBTK levels upon BCR stimulation (Torke et al, 2020).…”

Section: Multiple Sclerosismentioning

confidence: 99%

“…In experimental autoimmune encephalitis, a mouse model for MS, BTKi ameliorated disease (Torke et al, 2020). Compared with other AID and healthy controls, MS B cells did not show increased BTK protein expression or pBTK levels upon BCR stimulation (Torke et al, 2020). A phase II clinical trial with evobrutinib showed promising clinical results at the highest dose (Montalban et al, 2019).…”

Section: Multiple Sclerosismentioning

confidence: 99%

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Targeting Bruton’s Tyrosine Kinase in Inflammatory and Autoimmune Pathologies

Neys

Hendriks

Corneth

2021

Front. Cell Dev. Biol.

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Bruton’s tyrosine kinase (BTK) was discovered due to its importance in B cell development, and it has a critical role in signal transduction downstream of the B cell receptor (BCR). Targeting of BTK with small molecule inhibitors has proven to be efficacious in several B cell malignancies. Interestingly, recent studies reveal increased BTK protein expression in circulating resting B cells of patients with systemic autoimmune disease (AID) compared with healthy controls. Moreover, BTK phosphorylation following BCR stimulation in vitro was enhanced. In addition to its role in BCR signaling, BTK is involved in many other pathways, including pattern recognition, Fc, and chemokine receptor signaling in B cells and myeloid cells. This broad involvement in several immunological pathways provides a rationale for the targeting of BTK in the context of inflammatory and systemic AID. Accordingly, numerous in vitro and in vivo preclinical studies support the potential of BTK targeting in these conditions. Efficacy of BTK inhibitors in various inflammatory and AID has been demonstrated or is currently evaluated in clinical trials. In addition, very recent reports suggest that BTK inhibition may be effective as immunosuppressive therapy to diminish pulmonary hyperinflammation in coronavirus disease 2019 (COVID-19). Here, we review BTK’s function in key signaling pathways in B cells and myeloid cells. Further, we discuss recent advances in targeting BTK in inflammatory and autoimmune pathologies.

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“…The treatment resulted in lower levels of cytokines as well as diminished levels of auto-reactive antibodies [128,129]. In EAE, BTK inhibitors act as B cell and monocyte silencers, lowering cytokine production, impairing antigen presentation, and altering the composition of immune cells [130,131]. As BTK inhibitors dampen B cell function, four BTK inhibitors are currently tested in phase I, II, or III clinical trials for the treatment of MS: evobrutinib (M2951, MSC2364447), tolebrutinib (PRN-2246, SAR442168), fenebrutinib (BDC-0853, RG7845), and BIIB091.…”

Section: Biomarkers and Alternative Strategies To Target B Cellsmentioning

confidence: 99%

A Milestone in Multiple Sclerosis Therapy: Monoclonal Antibodies Against CD20—Yet Progress Continues

2021

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Multiple sclerosis (MS), which is a chronic inflammatory disease of the central nervous system, still represents one of the most common causes of persisting disability with an early disease onset. Growing evidence suggests B cells to play a crucial role in its pathogenesis and progression. Over the last decades, monoclonal antibodies (mabs) against the surface protein CD20 have been intensively studied as a B cell targeting therapy in relapsing MS (RMS) as well as primary progressive MS (PPMS). Pivotal studies on anti-CD20 therapy in RMS showed remarkable clinical and radiological effects, especially on acute inflammation and relapse biology. These results paved the way for further research on the implication of B cells in the pathogenesis of MS. Besides controlling relapse development in RMS, ocrelizumab (OCR) also showed clinical benefits in patients with PPMS and became the first approved drug for this disease course. In this review, we provide an overview of the current anti-CD20 mabs used or tested for the treatment of MS—namely rituximab (RTX), OCR, ofatumumab (OFA), and ublituximab (UB). Besides their effectiveness, we also discuss possible limitations and safety concerns especially in regard to long-term treatment, both for this class of drugs overall as well as for each anti-CD20 mab individually. Additionally, we elucidate to what extent anti-CD20 therapy may alter the function of other immune cells, both directly or indirectly. Finally, we cover the current knowledge on repopulation of CD20+ cells after cessation of anti-CD20 treatment and discuss future aspirations towards alternative, further developed B cell silencing therapies.

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Inhibition of Bruton’s tyrosine kinase interferes with pathogenic B-cell development in inflammatory CNS demyelinating disease

Cited by 71 publications

References 27 publications

Bruton’s Tyrosine Kinase Inhibition as an Emerging Therapy in Systemic Autoimmune Disease

Bruton’s Tyrosine Kinase Inhibition as an Emerging Therapy in Systemic Autoimmune Disease

Targeting Bruton’s Tyrosine Kinase in Inflammatory and Autoimmune Pathologies

A Milestone in Multiple Sclerosis Therapy: Monoclonal Antibodies Against CD20—Yet Progress Continues

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