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

• Published in: Journal of neurology Vol. 265; no. 5; pp. 1199 - 1209
• Main Authors: Ceronie, Bryan, Jacobs, Benjamin M., Baker, David, Dubuisson, Nicolas, Mao, Zhifeng, Ammoscato, Francesca, Lock, Helen, Longhurst, Hilary J., Giovannoni, Gavin, Schmierer, Klaus
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.05.2018; Springer Nature B.V
• Subjects: Administration, Oral; Adult; Alemtuzumab - adverse effects; Alemtuzumab - therapeutic use; Apoptosis - drug effects; B-Lymphocyte Subsets - drug effects; B-Lymphocyte Subsets - metabolism; CD3 antigen; Cladribine; Cladribine - adverse effects; Cladribine - therapeutic use; Cross-Sectional Studies; Cytotoxicity; Deoxycytidine kinase; Deoxycytidine Kinase - metabolism; Dose-Response Relationship, Drug; Drug development; Female; Flow cytometry; Gene expression; Humans; Immunologic Factors - adverse effects; Immunologic Factors - therapeutic use; Immunological memory; Lymph Nodes - drug effects; Lymph Nodes - metabolism; Lymph Nodes - pathology; Lymphocyte receptors; Lymphocytes B; Lymphocytes T; Lymphopenia; Lymphopenia - blood; Lymphopenia - etiology; Male; Medicine; Medicine & Public Health; Memory cells; Metabolism; Monoclonal antibodies; Multiple sclerosis; Multiple Sclerosis - blood; Multiple Sclerosis - drug therapy; Multiple Sclerosis - pathology; Neurology; Neuroradiology; Neurosciences; Nucleotidase; Original Communication; Peripheral blood; Plasma cells; RNA, Messenger - metabolism; Treatment Outcome; Disease-modifying treatment; B cell; Deoxycytidine kinase; Multiple sclerosis; Memory B cells; Cladribine
• ISSN: 0340-5354; 1432-1459; 1432-1459
• DOI: 10.1007/s00415-018-8830-y

Background The mechanism of action of oral cladribine, recently licensed for relapsing multiple sclerosis, is unknown. Objective To 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. Methods A 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. Results Cladribine 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. Conclusions Selective 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.