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

ABSTRACT

Introduction

B cells have increasingly come under the spotlight as mediators of inflammatory central nervous system (CNS) demyelinating diseases such as multiple sclerosis (MS). B cell depletion via the targeting of the surface molecule CD20 has proven to be highly effective; however, continuous absence of an integral component of the immune system may cause safety concerns over time. Declining humoral competence and potential immune system impairments are key issues, and moreover, unselective removal of B cells reduces immune system control functions which should preferably be maintained in inflammatory CNS disease.

Areas covered

This paper illuminates the novel approach of specific interference with B cell signaling by targeting Bruton´s tyrosine kinase (BTK). We discuss the role of BTK within the B cell receptor (BCR) signaling cascade and BTK inhibition as a promising strategy to control inflammatory CNS disease which crucially excludes immune-cell depletion. We searched PubMed or clinicaltrials.gov for the terms ‘BTK inhibition’ or ‘Bruton´s Tyrosine Kinase’ or ‘anti-CD20ʹ and ‘Multiple Sclerosis’

Expert opinion

BTK inhibition has shown effectiveness in preclinical models of CNS disease and MS clinical trials. Further studies are necessary to differentiate this approach from B cell depletion and to position it in the armamentarium of therapeutics.

KEYWORDS:

• Multiple sclerosis
• experimental autoimmune encephalomyelitis
• Bruton´s tyrosine kinase
• BTKi
• evobrutinib
• ibrutinib

Article highlights

• BTK is expressed in various subsets of cells of hematopoietic origin

• BTK is centrally placed in immune receptor signaling

• BTK inhibitors have been used in B cell malignancies and autoimmune disease

• BTK inhibition is an emerging approach to target pathogenic antigen-presenting cells

• The inhibitor evobrutinib successfully reduced clinical activity in a phase II trial in RRMS

This box summarizes key points contained in the article.

Declaration of interest

S Torke has received travel support from EMD Serono. MS Weber receives research support from the National Multiple Sclerosis Society (NMSS; PP 1660), the Deutsche Forschungsgemeinschaft (DFG; WE 3547/5-1), from Novartis, TEVA, Biogen-Idec, Roche, Merck and the ProFutura Programm of the Universitätsmedizin Göttingen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.