Bruton tyrosine kinase inhibitors for multiple sclerosis

Abstract

Current therapies for multiple sclerosis (MS) reduce both relapses and relapse-associated worsening of disability, which is assumed to be mainly associated with transient infiltration of peripheral immune cells into the central nervous system (CNS). However, approved therapies are less effective at slowing disability accumulation in patients with MS, in part owing to their lack of relevant effects on CNS-compartmentalized inflammation, which has been proposed to drive disability. Bruton tyrosine kinase (BTK) is an intracellular signalling molecule involved in the regulation of maturation, survival, migration and activation of B cells and microglia. As CNS-compartmentalized B cells and microglia are considered central to the immunopathogenesis of progressive MS, treatment with CNS-penetrant BTK inhibitors might curtail disease progression by targeting immune cells on both sides of the blood-brain barrier. Five BTK inhibitors that differ in selectivity, strength of inhibition, binding mechanisms and ability to modulate immune cells within the CNS are currently under investigation in clinical trials as a treatment for MS. This Review describes the role of BTK in various immune cells implicated in MS, provides an overview of preclinical data on BTK inhibitors and discusses the (largely preliminary) data from clinical trials.

Fig. 1. Bruton tyrosine kinase signalling pathways in B cells, macrophages and microglia.

Bruton tyrosine kinase (BTK) mediates signalling from the B cell receptor (BCR) in B cells and IgG Fc receptor III (FcγRIII, also known as CD16) in macrophages and microglia to downstream elements crucial to immune cell function. a, BCR activation leads to the formation and activation of a signalling complex in which BTK is linked with 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase-γ2 (PLCγ2) through the scaffold protein SLP65 (Src homology 2 domain-containing leukocyte protein of 65 kDa). Phosphorylation of PLCγ2 by BTK triggers several downstream signalling pathways, including inositol 1,4,5-triphosphate (IP₃) receptor (IP3R)-dependent calcium mobilization (green), cytoskeletal remodelling (light blue) and activation of nuclear factor of activated T cells (NFAT; green), nuclear factor (NF)-κB (olive green) and RAS GTPase pathways (red). b, FcγRIII activation recruits and activates Lck/Yes-related novel protein tyrosine kinase (LYN) and spleen tyrosine kinase (SYK), which phosphorylate linker for the activation of T cells family member 1 (LAT) and establish a signalling complex comprising BTK and PLCγ2. In turn, PLCγ2 is responsible for generating diacylglycerol and IP₃, two secondary messengers that control cellular effector responses via protein kinase Cβ (PKC-β) and intracellular Ca²⁺ release, respectively. Diacylglycerol interacts with a scaffold complex comprising B cell leukaemia and/or lymphoma 10 (BCL10), B cell adaptor for phosphoinositide-3-kinase (BCAP) and caspase recruitment domain-containing protein 11 (CARD11). ER, endoplasmic reticulum; ERK, extracellular signal-regulated protein kinase; ITAM, immunoreceptor tyrosine-based activation motif; MALT1, mucosa-associated lymphoid tissue lymphoma translocation protein 1; PI3K, phosphoinositide 3-kinase; PtdIns(4,5)P₂, phosphatidylinositol 4,5-bisphosphate; PtdIns(3,4,5)P₃, phosphatidylinositol (3,4,5)-trisphosphate; TRAF6, tumour necrosis factor receptor-associated factor 6; WASP, Wiskott–Aldrich syndrome protein. Adapted from refs. ^,, Springer Nature.

Fig. 2. Putative mechanism of action of Bruton tyrosine kinase inhibitors in multiple sclerosis.

Bruton tyrosine kinase (BTK) inhibitors directly modulate the functions of B cells and myeloid cells (including macrophages and microglia) and therefore target both adaptive and innate mechanisms that contribute to the immunopathology of multiple sclerosis on both sides of the blood–brain barrier (BBB). Although BTK inhibitors do not modulate T cell function directly, they can interfere with deleterious B cell–T cell interactions (not shown). CNS, central nervous system.