Bruton’s Tyrosine Kinase Inhibitors: A New Generation of Promising Agents for Multiple Sclerosis Therapy

García‐Merino, Antonio

doi:10.3390/cells10102560

Cited by 31 publications

(37 citation statements)

References 90 publications

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“…Multiple sclerosis is an autoimmune disorder caused by the action of environmental factors in genetically predisposed hosts. The B cells in the brain play a central role in antigen presentation, cytokine secretion and antibody production, and in the pathogenesis of the disease [ 118 ]. In response, BTKis can penetrate to the brain and spine, reducing inflammation and neurodegeneration within the central nervous system, and target the microglia of brain-resident B cells; they can also attenuate B-cell:T-cell interactions [ 119 ].…”

Section: Multiple Sclerosismentioning

confidence: 99%

Bruton’s Kinase Inhibitors for the Treatment of Immunological Diseases: Current Status and Perspectives

Robak

2022

JCM

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The use of Bruton’s tyrosine kinase (BTK) inhibitors has changed the management of patients with B-cell lymphoid malignancies. BTK is an important molecule that interconnects B-cell antigen receptor (BCR) signaling. BTK inhibitors (BTKis) are classified into three categories, namely covalent irreversible inhibitors, covalent reversible inhibitors, and non-covalent reversible inhibitors. Ibrutinib is the first covalent, irreversible BTK inhibitor approved in 2013 as a breakthrough therapy for chronic lymphocytic leukemia patients. Subsequently, two other covalent, irreversible, second-generation BTKis, acalabrutinib and zanubrutinib, have been developed for lymphoid malignancies to reduce the ibrutinib-mediated adverse effects. More recently, irreversible and reversible BTKis have been under development for immune-mediated diseases, including autoimmune hemolytic anemia, immune thrombocytopenia, multiple sclerosis, pemphigus vulgaris, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s disease, and chronic spontaneous urticaria, among others. This review article summarizes the preclinical and clinical evidence supporting the role of BTKis in various autoimmune, allergic, and inflammatory conditions.

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Section: Multiple Sclerosismentioning

confidence: 99%

Bruton’s Kinase Inhibitors for the Treatment of Immunological Diseases: Current Status and Perspectives

Robak

2022

JCM

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“…NFAT stimulates immune cell effector functions, for example by initiating cytokine production and release. Similar to IP3, DAG can act as a second messenger and activate protein kinase C (PKC) and, together with Syk, engage the mitogen-activated protein kinase (MAPK) pathway and increase survival and accelerate proliferation [47,49,50]. Its prominent place in the BCR signaling cascade, relaying incoming, extracellular signals into cellular Besides the well-studied relevance of BTK in the BCR signaling cascade, it is also involved in the signaling of Fc receptors, and therefore the recognition of specific antigens by immunoglobulins.…”

Section: Pathology and Pathomechanisms Of Progressive Multiple Sclerosismentioning

confidence: 99%

Bruton’s Tyrosine Kinase Inhibitors in Multiple Sclerosis: Pioneering the Path Towards Treatment of Progression?

2022

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In multiple sclerosis (MS) persisting disability can derive from acute relapses or, alternatively, from slow and steady deterioration, termed chronic progression. Emerging data suggest that the latter process occurs largely independent from relapse activity or development of new central nervous system (CNS) inflammatory lesions. Pathophysiologically, acute relapses develop as a consequence of de novo CNS infiltration of immune cells, while MS progression appears to be driven by a CNStrapped inflammatory circuit between CNS-established hematopoietic cells as well as CNS-resident cells, such as microglia, astrocytes, and oligodendrocytes. Within the last decades, powerful therapies have been developed to control relapse activity in MS. All of these agents were primarily designed to systemically target the peripheral immune system and/or to prevent CNS infiltration of immune cells. Based on the above described dichotomy of MS pathophysiology, it is understandable that these agents only exert minor effects on progression and that novel targets within the CNS have to be utilized to control MS progression independent of relapse activity. In this regard, one promising strategy may be the inhibition of the enzyme Bruton's tyrosine kinase (BTK), which is centrally involved in the activation of B cells as well as myeloid cells, such as macrophages and microglia. In this review, we discuss where and to what extent BTK is involved in the immunological and molecular cascades driving MS progression. We furthermore summarize all mechanistic, preclinical, and clinical data on the various BTK inhibitors (evobrutinib, tolebrutinib, fenebrutinib, remibrutinib, orelabrutinib, BIIB091) that are currently in development for treatment of MS, with a particular focus on the potential ability of either drug to control MS progression.Anastasia Geladaris and Sebastian Torke contributed equally and are listed in alphabetical order.

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“…Bruton tyrosine kinase (BTK) translocates from the cytosol to the cell membrane when an antigen binds to the B cell receptor (BCR). Afterward, BTK activates a pathway involved in BCR signaling and differentiation and survival of B cells (reviewed in [ 172 ]). BTK inhibitors (BTKi) are small molecules that have been recently researched for the treatment of MS [ 173 ].…”

Section: Effects Of Ms Therapies On B Cell Migrationmentioning

confidence: 99%

Breaching Brain Barriers: B Cell Migration in Multiple Sclerosis

et al. 2022

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Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) known for the manifestation of demyelinated lesions throughout the CNS, leading to neurodegeneration. To date, not all pathological mechanisms that drive disease progression are known, but the clinical benefits of anti-CD20 therapies have put B cells in the spotlight of MS research. Besides their pathological effects in the periphery in MS, B cells gain access to the CNS where they can contribute to disease pathogenesis. Specifically, B cells accumulate in perivascular infiltrates in the brain parenchyma and the subarachnoid spaces of the meninges, but are virtually absent from the choroid plexus. Hence, the possible migration of B cells over the blood–brain-, blood–meningeal-, and blood–cerebrospinal fluid (CSF) barriers appears to be a crucial step to understanding B cell-mediated pathology. To gain more insight into the molecular mechanisms that regulate B cell trafficking into the brain, we here provide a comprehensive overview of the different CNS barriers in health and in MS and how they translate into different routes for B cell migration. In addition, we review the mechanisms of action of diverse therapies that deplete peripheral B cells and/or block B cell migration into the CNS. Importantly, this review shows that studying the different routes of how B cells enter the inflamed CNS should be the next step to understanding this disease.

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Bruton’s Tyrosine Kinase Inhibitors: A New Generation of Promising Agents for Multiple Sclerosis Therapy

Cited by 31 publications

References 90 publications

Bruton’s Kinase Inhibitors for the Treatment of Immunological Diseases: Current Status and Perspectives

Bruton’s Kinase Inhibitors for the Treatment of Immunological Diseases: Current Status and Perspectives

Bruton’s Tyrosine Kinase Inhibitors in Multiple Sclerosis: Pioneering the Path Towards Treatment of Progression?

Breaching Brain Barriers: B Cell Migration in Multiple Sclerosis

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