Targeting B Cells and Microglia in Multiple Sclerosis With Bruton Tyrosine Kinase Inhibitors

Abstract

ImportanceCurrently, disease-modifying therapies for multiple sclerosis (MS) use 4 mechanisms of action: immune modulation, suppressing immune cell proliferation, inhibiting immune cell migration, or cellular depletion. Over the last decades, the repertoire substantially increased because of the conceptual progress that not only T cells but also B cells play an important pathogenic role in MS, fostered by the empirical success of B cell–depleting antibodies against the surface molecule CD20. Notwithstanding this advance, a continuous absence of B cells may harbor safety risks, such as a decline in the endogenous production of immunoglobulins. Accordingly, novel B cell–directed MS therapies are in development, such as inhibitors targeting Bruton tyrosine kinase (BTK).ObservationsBTK is centrally involved in the B cell receptor–mediated activation of B cells, one key requirement in the development of autoreactive B cells, but also in the activation of myeloid cells, such as macrophages and microglia. Various compounds in development differ in their binding mode, selectivity and specificity, relative inhibitory concentration, and potential to enter the central nervous system. The latter may be important in assessing whether BTK inhibition is a promising strategy to control inflammatory circuits within the brain, the key process that is assumed to drive MS progression. Accordingly, clinical trials using BTK inhibitors are currently conducted in patients with relapsing-remitting MS as well as progressive MS, so far generating encouraging data regarding efficacy and safety.Conclusions and RelevanceWhile the novel approach of targeting BTK is highly promising, several questions remain unanswered, such as the long-term effects of using BTK inhibitors in the treatment of inflammatory CNS disease. Potential changes in circulating antibody levels should be evaluated and compared with B cell depletion. Also important is the potential of BTK inhibitors to enter the CNS, which depends on the given compound. Remaining questions involve where BTK inhibitors fit in the landscape of MS therapeutics. A comparative analysis of their distinct properties is necessary to identify which inhibitors may be used in relapsing vs progressive forms of MS as well as to clarify which agent may be most suitable for sequential use after anti-CD20 treatment.

BTK inhibition limits microglia-perpetuated CNS inflammation and promotes myelin repair

“…Currently, six BTK inhibitors are being tested for the treatment of MS. While all are small molecules, they differ in their distinct characteristics, such as their mode of binding [ 7 , 11 ]. At present evobrutinib is the only BTK inhibitor to show reduce slowly expanding lesions (SEL) volume in a dose-dependent manner in patients with relapsing MS, with a significant reduction observed with evobrutinib 75 mg twice daily [ 3 ].…”

“…Thus, therapeutic targeting of chronically activated microglia may be particularly desirable [ 11 , 16 , 25 , 37 ] and inhibition of the enzyme Bruton´s tyrosine kinase (BTK) may be one promising strategy to do so. BTK is centrally involved in various immune-receptor pathways (for example downstream of the B cell receptor, Fc receptor, toll-like receptor) and mediates the activation and function of B cells, macrophages, and microglia [ 7 , 34 , 35 ]. Accordingly, therapeutic inhibition of BTK provides a dual mode of action, targeting both innate and adaptive immune processes.…”

Bruton tyrosine kinase inhibitors in multiple sclerosis: evidence and expectations

“…Although the novel approach of targeting BTK is highly promising, several questions remain unanswered, such as the long-term effects of using BTK inhibitors for the treatment of MS [67 ▪ ]. Moreover, it remains unclear whether the high concentrations of BTK inhibitors used in vitro are achievable in vivo in the brain of patients with MS [35 ▪ ].…”

“…Thus, BTK inhibitors under investigation in clinical trials differ in their pharmacologic properties (such as pharmacodynamics, selectivity, mode of binding, target occupancy, inhibitory potency, and CNS) which could lead to differences in their efficacy and safety profiles [35 ▪ ,43,62 ▪ ]. Results from phase 3 clinical trials will be essential to draw conclusions regarding differences in efficacy and safety of BTK inhibitors and to understand in which MS patients these therapies should be when optimally used to maximize clinical outcomes [62 ▪ ,67 ▪ ,71 ▪ ]. ‘With accumulating evidence and experience, we will arrive at a “best in class’ molecule - and a door into the CNS – that will transform that long and winding road, perhaps, into a straight and steady path to treatment of progression in MS” [62 ▪ ].…”

Central nervous system demyelinating diseases: glial cells at the hub of pathology

“…BTK translocation is linked with NFkB and NFAT activation ( 179 ). Although this class was initially proposed as B-cell targeting therapy without cell-line depletion, as BTK plays a role in B-cell receptor activation, this type of molecule has a role in development of myeloid cell line and may also modulate microglial NFkB pathway ( 180 ). Particularly, BTK seems to play a significant role in microglial proliferation when these cells are exposed to anti-MOG antibodies ( 181 ).…”