Emerging small-molecule treatments for multiple sclerosis: focus on B cells

Abstract

Multiple sclerosis (MS) is a major cause of disability in young adults. Following an unknown trigger (or triggers), the immune system attacks the myelin sheath surrounding axons, leading to progressive nerve cell death. Antibodies and small-molecule drugs directed against B cells have demonstrated good efficacy in slowing progression of the disease. This review focusses on small-molecule drugs that can affect B-cell biology and may have utility in disease management. The risk genes for MS are examined from the drug target perspective. Existing small-molecule therapies for MS with B-cell actions together with new drugs in development are described. The potential for experimental molecules with B-cell effects is also considered. Small molecules can have diverse actions on B cells and be cytotoxic, anti-inflammatory and anti-viral. The current B cell–directed therapies often kill B-cell subsets, which can be effective but lead to side effects and toxicity. A deeper understanding of B-cell biology and the effect on MS disease should lead to new drugs with better selectivity, efficacy, and an improved safety profile. Small-molecule drugs, once the patent term has expired, provide a uniquely sustainable form of healthcare.

Therapies for multiple sclerosis targeting B cells

“…The complex, multi-player immune pathogenesis of MS, which provides multiple sites for therapeutic intervention on one hand, and the various mechanisms by which B cells contribute to the pathogenesis of MS along with the success of anti-CD20 therapies in MS, on the other hand, propelled studies on the effects of other MS drugs on B cells. Indeed, essentially all other approved therapies for MS, some of which have been designed to target T cells, were found to have some effects on the frequency, phenotype, trafficking, function, or responses of B cells, which may contribute to their therapeutic activity (11,32,57,65-67) (Table 2).…”

“…Additional approaches with a potential to target B cells that have not yet been explored as MS treatments or have not progressed past phase-II clinical trials include the use of other B cell-targeting mAbs such as epratuzumab (anti-CD22, a negative regulator of BCR-derived activation signals), daratumumab (anti-CD38 that depletes plasmablasts and some plasma cells), LTbR-IgG (anti-lymphotoxin beta receptor that would reduce the formation of ectopic germinal centers), NNC114-0005 (anti-IL21, an important cytokine for Ab formation), otilimab (anti-GM-CSF that blocks pro-inflammatory myeloid cell response), belimumab and talabumab (anti-BAFF), VAY736 (anti-BAFF receptor), hBCMA-Fc (human BCMA fused to IgG1 Fc), and mAbs to co-stimulatory molecules that would prevent B cell activation (32,57). In addition, several small molecules that target B cell signaling (through BTK, PI3 kinase, or Janus kinases), proteasome that is involved with plasma cell differentiation, or Epstein-Barr virus, which infects B cells and is believed to be involved in MS etiology, may provide novel mechanisms of targeting B cells and possibly other cells involved in the immune pathogenesis of MS (67).…”

Approved and Emerging Disease Modifying Therapies on Neurodegeneration in Multiple Sclerosis

“…Small molecules, such as BTK inhibitors, have a higher blood-brain penetration and therefore easier administration. These inhibitors, especially those that target B-cells, may provide a more economical, convenient, and effective treatment option [ 89 ].…”

“… Laquinimod: A novel oral immunomodulatory drug with a complex mechanism of action significantly decreased BVL versus placebo (ALLEGRO trial) and versus interferon beta-1a (BRAVO trial) in RRMS cases [ 88 ]. Bruton’s tyrosine kinase (BTK) inhibitors: A class of newer agents, the BTK inhibitors block the activation of B-lymphocytes both in vivo and in vitro [ 89 ]. This class includes fenebrutinib, ibrutinib, and evobrutinib; some of them are about to start entering multicenter trials and their effect on axonal integrity is currently unknown.…”

“…Bruton’s tyrosine kinase (BTK) inhibitors: A class of newer agents, the BTK inhibitors block the activation of B-lymphocytes both in vivo and in vitro [ 89 ]. This class includes fenebrutinib, ibrutinib, and evobrutinib; some of them are about to start entering multicenter trials and their effect on axonal integrity is currently unknown.…”