Inhibition of Bruton´s tyrosine kinase as a novel therapeutic approach in multiple sclerosis

Torke, Sebastian; Weber, Martin

doi:10.1080/13543784.2020.1807934

Cited by 40 publications

(50 citation statements)

References 76 publications

(44 reference statements)

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“…Bruton's tyrosine kinase (BTK) is a cytoplasmic kinase expressed on cells of the hematopoietic lineage, except for T cells, natural killer (NK) cells and plasma cells, and contributes to signal transductions from B-cell receptor (BCR) to the PI3K, MAPK and NF-κB pathways, thus regulating B-cell survival, activation, proliferation, and differentiation to plasma cells [66,67]. Several BTK inhibitors have been proposed for the treatment of hematological malignancies and dysimmune disorders [66,68].…”

Section: Therapies Currently Under Investigation and Future Perspectivesmentioning

confidence: 99%

Anti-CD20 therapies for multiple sclerosis: current status and future perspectives

et al. 2021

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Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disease affecting the central nervous system (CNS), often characterized by the accumulation of irreversible clinical disability over time. During last years, there has been a dramatic evolution in several key concepts of immune pathophysiology of MS and in the treatment of this disease. The demonstration of the strong efficacy and good safety profile of selective B-cell-depleting therapies (such as anti-CD20 monoclonal antibodies) has significantly expanded the therapeutic scenario for both relapsing and progressive MS patients with the identification of a new therapeutic target. The key role of B cells in triggering MS disease has been also pointed out, determining a shift from the traditional view of MS activity as largely being ‘T-cell mediated’ to the notion that MS-related pathological processes involve bi-directional interactions between several immune cell types, including B cells, both in the periphery and in the CNS. This review provides an updated overview of the involvement of B cells in the immune pathophysiology and pathology of MS. We summarize the rationale regarding the use of anti-CD20 therapies and the results of the main randomized controlled trials and observational studies investigating the efficacy and safety profile of rituximab, ocrelizumab, ofatumumab and ublituximab. Suggestions regarding vaccinations and management of MS patients during COVID-19 pandemic with anti-CD20 therapies are also discussed. Finally, therapies under investigation and future perspectives of anti-CD20 therapies are taken into consideration.

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Section: Therapies Currently Under Investigation and Future Perspectivesmentioning

confidence: 99%

Anti-CD20 therapies for multiple sclerosis: current status and future perspectives

et al. 2021

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“…Despite the evidence of the beneficial effect in MS of anti-inflammatory agents [ 9 , 49 ], currently no clinical trials regarding the use of irreversible BtkIs in this pathology are reported.…”

Section: Btk Inhibitorsmentioning

confidence: 99%

Btk Inhibitors: A Medicinal Chemistry and Drug Delivery Perspective

Brullo

Villa

Tasso

et al. 2021

IJMS

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In the past few years, Bruton’s tyrosine Kinase (Btk) has emerged as new target in medicinal chemistry. Since approval of ibrutinib in 2013 for treatment of different hematological cancers (as leukemias and lymphomas), two other irreversible Btk inhibitors have been launched on the market. In the attempt to overcome irreversible Btk inhibitor limitations, reversible compounds have been developed and are currently under evaluation. In recent years, many Btk inhibitors have been patented and reported in the literature. In this review, we summarized the (ir)reversible Btk inhibitors recently developed and studied clinical trials and preclinical investigations for malignancies, chronic inflammation conditions and SARS-CoV-2 infection, covering advances in the field of medicinal chemistry. Furthermore, the nanoformulations studied to increase ibrutinib bioavailability are reported.

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“…Several clinical trials are studying the effects of other BTK inhibitors such as evobrutinib, tirabrutinib (also called ONO/GS-4059) and AC0058TA for the treatment of systemic lupus erythematosus (SLE) and relapsing multiple sclerosis (MS) (www. clinicaltrials.gov) (3,112,(118)(119)(120). In addition, preclinical evidence has shown that ibrutinib effectively ameliorates disease symptoms in patient samples or animal models of SLE, MS, systemic sclerosis (SSc), neuropathy with anti-myelin-associated glycoprotein (MAG), type 2 diabetes (T2D) and obesity (118,119,(121)(122)(123)(124)(125).…”

Section: Autoimmune Diseasesmentioning

confidence: 99%

“…clinicaltrials.gov) (3,112,(118)(119)(120). In addition, preclinical evidence has shown that ibrutinib effectively ameliorates disease symptoms in patient samples or animal models of SLE, MS, systemic sclerosis (SSc), neuropathy with anti-myelin-associated glycoprotein (MAG), type 2 diabetes (T2D) and obesity (118,119,(121)(122)(123)(124)(125). Such ongoing clinical studies and preclinical evidence demonstrate the immunosuppressive effects of BTK inhibitors in autoimmune diseases and warrant further considerations of new clinical trials on BTK inhibitors as therapeutic agents for these autoimmune diseases.…”

Section: Autoimmune Diseasesmentioning

confidence: 99%

Clinical Trials of the BTK Inhibitors Ibrutinib and Acalabrutinib in Human Diseases Beyond B Cell Malignancies

et al. 2021

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The BTK inhibitors ibrutinib and acalabrutinib are FDA-approved drugs for the treatment of B cell malignances. Both drugs have demonstrated clinical efficacy and safety profiles superior to chemoimmunotherapy regimens in patients with chronic lymphocytic leukemia. Mounting preclinical and clinical evidence indicates that both ibrutinib and acalabrutinib are versatile and have direct effects on many immune cell subsets as well as other cell types beyond B cells. The versatility and immunomodulatory effects of both drugs have been exploited to expand their therapeutic potential in a wide variety of human diseases. Over 470 clinical trials are currently registered at ClinicalTrials.gov to test the efficacy of ibrutinib or acalabrutinib not only in almost every type of B cell malignancies, but also in hematological malignancies of myeloid cells and T cells, solid tumors, chronic graft versus host disease (cGHVD), autoimmune diseases, allergy and COVID-19 (http:www.clinicaltrials.gov). In this review, we present brief discussions of the clinical trials and relevant key preclinical evidence of ibrutinib and acalabrutinib as monotherapies or as part of combination therapies for the treatment of human diseases beyond B cell malignancies. Adding to the proven efficacy of ibrutinib for cGVHD, preliminary results of clinical trials have shown promising efficacy of ibrutinib or acalabrutinib for certain T cell malignancies, allergies and severe COVID-19. However, both BTK inhibitors have no or limited efficacy for refractory or recurrent solid tumors. These clinical data together with additional pending results from ongoing trials will provide valuable information to guide the design and improvement of future trials, including optimization of combination regimens and dosing sequences as well as better patient stratification and more efficient delivery strategies. Such information will further advance the precise implementation of BTK inhibitors into the clinical toolbox for the treatment of different human diseases.

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Inhibition of Bruton´s tyrosine kinase as a novel therapeutic approach in multiple sclerosis

Cited by 40 publications

References 76 publications

Anti-CD20 therapies for multiple sclerosis: current status and future perspectives

Anti-CD20 therapies for multiple sclerosis: current status and future perspectives

Btk Inhibitors: A Medicinal Chemistry and Drug Delivery Perspective

Clinical Trials of the BTK Inhibitors Ibrutinib and Acalabrutinib in Human Diseases Beyond B Cell Malignancies

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