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Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells

B. Ceronie,B. Jacobs,D. Baker,N. Dubuisson,Z. Mao,F. Ammoscato,H. Lock,H. Longhurst,G. Giovannoni,K. Schmierer

Published 2018 in Journal of Neurology

ABSTRACT

BackgroundThe mechanism of action of oral cladribine, recently licensed for relapsing multiple sclerosis, is unknown.ObjectiveTo determine whether cladribine depletes memory B cells consistent with our recent hypothesis that effective, disease-modifying treatments act by physical/functional depletion of memory B cells.MethodsA cross-sectional study examined 40 people with multiple sclerosis at the end of the first cycle of alemtuzumab or injectable cladribine. The relative proportions and absolute numbers of peripheral blood B lymphocyte subsets were measured using flow cytometry. Cell-subtype expression of genes involved in cladribine metabolism was examined from data in public repositories.ResultsCladribine markedly depleted class-switched and unswitched memory B cells to levels comparable with alemtuzumab, but without the associated initial lymphopenia. CD3+ T cell depletion was modest. The mRNA expression of metabolism genes varied between lymphocyte subsets. A high ratio of deoxycytidine kinase to group I cytosolic 5′ nucleotidase expression was present in B cells and was particularly high in mature, memory and notably germinal centre B cells, but not plasma cells.ConclusionsSelective B cell cytotoxicity coupled with slow repopulation kinetics results in long-term, memory B cell depletion by cladribine. These may offer a new target, possibly with potential biomarker activity, for future drug development.

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