BTK inhibition limits B-cell–T-cell interaction through modulation of B-cell metabolism: implications for multiple sclerosis therapy

Abstract

Inhibition of Bruton’s Tyrosine Kinase (BTKi) is now viewed as a promising next-generation B-cell-targeting therapy for autoimmune diseases including multiple sclerosis (MS). Surprisingly little is known; however, about how BTKi influences MS disease-implicated functions of B cells. Here, we demonstrate that in addition to its expected impact on B-cell activation, BTKi attenuates B-cell:T-cell interactions via a novel mechanism involving modulation of B-cell metabolic pathways which, in turn, mediates an anti-inflammatory modulation of the B cells. In vitro, BTKi, as well as direct inhibition of B-cell mitochondrial respiration (but not glycolysis), limit the B-cell capacity to serve as APC to T cells. The role of metabolism in the regulation of human B-cell responses is confirmed when examining B cells of rare patients with mitochondrial respiratory chain mutations. We further demonstrate that both BTKi and metabolic modulation ex vivo can abrogate the aberrant activation and costimulatory molecule expression of B cells of untreated MS patients. Finally, as proof-of-principle in a Phase 1 study of healthy volunteers, we confirm that in vivo BTKi treatment reduces circulating B-cell mitochondrial respiration, diminishes their activation-induced expression of costimulatory molecules, and mediates an anti-inflammatory shift in the B-cell responses which is associated with an attenuation of T-cell pro-inflammatory responses. These data collectively elucidate a novel non-depleting mechanism by which BTKi mediates its effects on disease-implicated B-cell responses and reveals that modulating B-cell metabolism may be a viable therapeutic approach to target pro-inflammatory B cells.

Human T-bet+ B cell development is associated with BTK activity and suppressed by evobrutinib

“…The observed inhibitory effects of evobrutinib on IFN-γ-and CpG-ODNmediated class switching in B cells is relevant given their enhanced responsiveness to such signals and capacity to serve as potent antigen-presenting cells in MS (4,8,12). This is supported by the fact that the antigen-presenting cell function of B cells is reinforced by T-bet (8,44) as well as BTK (45,46), and is impaired in EAE mice following evobrutinib treatment (22).…”

BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies

“…Inhibit FcγRIII-dependent production of cytokines (e.g., TNF-α, IL-1β, and IL-6) from macrophages [ 22 ]; 3. Reduced paw swelling, histological improvement without body weight loss in CIA [ 88 , 298 ] Spebrutinib monotherapy (Phase 2a): Over 20% improvement in ACR response criteria in active RA patients with good tolerability [ 101 ] Fenebrutinib monotherapy (phase 2): Showed equivalent efficacy (36%) with adalimumab when fenebrutinib was administered at a dose of 200 mg twice daily [ 299 ] MS Ex vivo BTK inhibition helped abolish the aberrant activation and expression of costimulatory molecules on B cells from untreated MS patients [ 300 ] Tolebrutinib (phase 2b): reduced the number of new gadolinium-enhancing lesions in a dose-dependent manner in RMS patients [ 73 ] Evobrutinib (phase 2): 1. Reduced the number of enhancing MRI lesions in RMS patients at 75 mg once daily; 2.…”

“…Small molecular BTKi may be more advantageous than monoclonal antibody therapy with fewer toxicities, such as antibody response and allergic reactions. Moreover, some BTKi can penetrate the blood–brain barrier and inhibit the activation of autoreactive B cells and microglial cells in the CNS, which are the primary triggers of inflammation in MS [ 73 , 300 ]. Recently, oral administration of the brain-penetrant tolebrutinib has shown promising results in relapsing MS (RMS) patients in a phase 2b study [ 73 ].…”

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

“…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 ].…”