Recent clinical trials show promising results for the next-generation Bruton’s tyrosine kinase (BTK) inhibitor evobrutinib in the treatment of multiple sclerosis (MS). BTK has a central role in signaling pathways that govern the development of B cells. Whether and how BTK activity shapes B cells as key drivers of MS is currently unclear. In contrast to BTK protein, we found higher levels of phospho-BTK in ex vivo blood memory B cells of relapsing and secondary progressive MS patients versus controls. In these MS groups, BTK activity was induced to a lesser extent after anti-IgM stimulation. BTK positively correlated with CXCR3 expression, both of which were increased in blood B cells of clinical responders to natalizumab (anti-VLA-4 antibody) treatment. Under in vitro TFH-like conditions, BTK phosphorylation was enhanced by T-bet-inducing stimuli IFN-γ and CpG-ODN, whilst the expression of T-bet and T-bet-associated molecules CXCR3, CD21 and CD11c were affected by evobrutinib. Furthermore, evobrutinib interfered with in vitro class switching as well as memory recall responses, and disturbed CXCL10-mediated migration of CXCR3+ switched B cells through human brain endothelial monolayers. These findings demonstrate a functional link between BTK activity and disease-relevant B cells and offer valuable insights into how next-generation BTK inhibitors could modulate the clinical course in MS patients.
Liza Rijvers, Jamie van Langelaar, Laurens Bogers, Marie-José Melief, Steven C. Koetzier, Katelijn M. Blok, Annet F. Wierenga-Wolf, Helga E. De Vries, Jasper Rip, Odilia B.J. Corneth, Rudi W. Hendriks, Roland Grenningloh, Ursula Boschert, Joost Smolders, Marvin M. van Luijn