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

Journal of Neurology, Mar 2018

Bryan Ceronie, Benjamin M. Jacobs, David Baker, Nicolas Dubuisson, Zhifeng Mao, Francesca Ammoscato, Helen Lock, Hilary J. Longhurst, Gavin Giovannoni, Klaus Schmierer

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

Journal of Neurology https://doi.org/10.1007/s00415 Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells Bryan Ceronie 0 1 2 3 4 Benjamin M. Jacobs 0 1 2 3 4 David Baker 0 1 2 3 4 Nicolas Dubuisson 0 1 2 3 4 Zhifeng Mao 0 1 2 3 4 Francesca Ammoscato 0 1 2 3 4 Helen Lock 0 1 2 3 4 Hilary J. Longhurst 0 1 2 3 4 Gavin Giovannoni 0 1 2 3 4 Klaus Schmierer 0 1 2 3 4 0 Haematology Unit, The Royal London Hospital, Barts Health NHS Trust , London , UK 1 Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London , 4 Newark Street, London E1 2AT , UK 2 Bryan Ceronie , Benjamin M. Jacobs, and David Baker contributed equally 3 Abbreviations 5′NT 5′ Nucleotidase ADA Adenosine deaminase DCK Deoxycytidine kinase DMT Disease-modifying treatments EDSS Extended disability status scale EMA European Medicines Agency MS Multiple sclerosis PwMS People with MS , USA 4 Emergency Care and Acute Medicine Clinical Academic Group Neuroscience, The Royal London Hospital, Barts Health NHS Trust , London , UK 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. B cell; Cladribine; Disease-modifying treatment; Deoxycytidine kinase; Multiple sclerosis; Memory B cells - Gavin Giovannoni and Klaus Schmierer are joint senior authors. Introduction Multiple sclerosis (MS) is a chronic-inflammatory disorder of the central nervous system leading to accumulating disability. Historically, myelin-directed, CD4+, Th17+ cells have been considered to be the important mediators of the inflammatory process [ 1 ]. This is largely based on animal experimental autoimmune encephalitis models where T cellmediated responses are key to pathogenesis [ 2 ]. However, suppression of CD4+, Th17+ cells has only produced modest benefits in clinical trials in MS [ 3, 4 ]. Therefore, other mechanisms may play a crucial role in the disease process. Whilst animal models and in vitro studies in MS provide circumstantial evidence for the involvement of particular pathways, positive and properly conducted, negative trials provide invaluable information for understanding the cellular mechanisms that drive disease activity. Alemtuzumab, a CD52, T and B cell depleting antibody [ 5 ], ocrelizumab, a CD20-B cell depleting antibody [ 6 ] and cladribine, a lymphocyte depleting agent [ 7 ], are immune-reconstitution therapies that are amongst the most efficacious treatments for MS and can provide long-term benefit from few treatment cycles [ 4, 8, 9 ]. However, there is no clear consensus on their mode of action, particularly for cladribine [ 7, 10 ]. It is well known that lymphocytes produce many secreted proteins, rapidly proliferate in response to infections and rely on both de novo and importantly salvage pathways for nucleotide synthesis. To accommodate this requirement, lymphocytes express high levels of adenosine deaminase (ADA) protein [ 11, 12 ]. This prevents the accumulation of cytotoxic levels of deoxyadenosine triphosphate, by catalysing the deamination of adenosines to inosines [12]. Cladribine is a chlorinated analogue of deoxyadenosine that is partially resistant to ADA [ 12, 13 ]. This is phosphorylated by deoxycytidine kinase (DCK) to create lymphocyte cytotoxicity [12]. This action is countered by cytosolic 5′ nucleotidase (5′NT) enzymatic activity that dephosphorylates phosphorylated-cladribine. Lymphocytes and lymphocytic cancers, including hairy cell leukaemia for which parenteral cladribine is licensed, have a high DCK-to-5′NT ratio relative to other cell types and are susceptible to cla (...truncated)


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Bryan Ceronie, Benjamin M. Jacobs, David Baker, Nicolas Dubuisson, Zhifeng Mao, Francesca Ammoscato, Helen Lock, Hilary J. Longhurst, Gavin Giovannoni, Klaus Schmierer. Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells, Journal of Neurology, 2018, pp. 1-11, DOI: 10.1007/s00415-018-8830-y