Contributions
Abstract: EP1583
Type: Poster Sessions
Abstract Category: Therapy - Immunomodulation/Immunosuppression
Objective: To determine the mechanism by which cladribine leads to long-lasting depletion of memory B lymphocytes in people with multiple sclerosis (pwMS).
Background: Cladribine is a synthetic purine nucleoside analogue with high efficacy in relapsing MS. Cladribine is selectively toxic towards lymphocytes in vivo, and leads to long-lasting memory B cell depletion. Here, we explore the mechanistic basis of this apparent cell type-specific toxicity.
Results: Cladribine was toxic to stimulated and unstimulated lymphocytes in a dose-dependent and deoxycytidine kinase (DCK)-dependent manner over a physiological dosing range (0 - 1x105 nM). Toxicity was most pronounced for naive B cells, followed by memory B cells, followed by T cells. High DCK expression and low ADA expression correlated with susceptibility to cladribine-induced cell death.
Conclusions: Cladribine kills all lymphocyte subsets in vitro with a predilection for naïve B cells. Depletion of the circulating naïve B cell pool removes the precursors for the generation of new memory cells. This 'roadblock' mechanism may explain delayed reconstitution of the memory B cell pool in pwMS following treatment with cladribine. A high DCK:ADA expression ratio appears to partly determine the cell type-specific toxicity of cladribine.
Disclosure: Competing interests: Dr Baker reports being a founder and consultant to Canbex Therapeutics and receiving research funds from Canbex Therapeutics, Sanofi-Genzyme, and Takeda in the past 3 years. Prof Giovannoni reports receiving fees for participation in the advisory board for AbbVie Biotherapeutics, Biogen, Canbex, Ironwood, Novartis, Merck, Inc, Merck Serono, Roche, Sanofi Genzyme, Synthon, Teva, and Vertex; speaker fees from AbbVie, Biogen, Bayer HealthCare, Genzyme, Merck Serono, Sanofi-Aventis, and Teva; and research support from Biogen, Genzyme, Ironwood, Merck, Inc, Merck Serono, and Novartis. Dr Schmierer reports being a principal investigator of trials sponsored by Novartis, Roche, Teva, and Medday; involved in trials sponsored by Biogen, Sanofi-Genzyme, BIAL, Cytokinetics, and Canbex; and receiving speaking honoraria for lecturing and advisory activity and/or meeting support from Biogen, Merck, Inc, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. All authors with the exception of TX have presented at the ECTRIMS annual congress on one or more occasions.
Abstract: EP1583
Type: Poster Sessions
Abstract Category: Therapy - Immunomodulation/Immunosuppression
Objective: To determine the mechanism by which cladribine leads to long-lasting depletion of memory B lymphocytes in people with multiple sclerosis (pwMS).
Background: Cladribine is a synthetic purine nucleoside analogue with high efficacy in relapsing MS. Cladribine is selectively toxic towards lymphocytes in vivo, and leads to long-lasting memory B cell depletion. Here, we explore the mechanistic basis of this apparent cell type-specific toxicity.
Results: Cladribine was toxic to stimulated and unstimulated lymphocytes in a dose-dependent and deoxycytidine kinase (DCK)-dependent manner over a physiological dosing range (0 - 1x105 nM). Toxicity was most pronounced for naive B cells, followed by memory B cells, followed by T cells. High DCK expression and low ADA expression correlated with susceptibility to cladribine-induced cell death.
Conclusions: Cladribine kills all lymphocyte subsets in vitro with a predilection for naïve B cells. Depletion of the circulating naïve B cell pool removes the precursors for the generation of new memory cells. This 'roadblock' mechanism may explain delayed reconstitution of the memory B cell pool in pwMS following treatment with cladribine. A high DCK:ADA expression ratio appears to partly determine the cell type-specific toxicity of cladribine.
Disclosure: Competing interests: Dr Baker reports being a founder and consultant to Canbex Therapeutics and receiving research funds from Canbex Therapeutics, Sanofi-Genzyme, and Takeda in the past 3 years. Prof Giovannoni reports receiving fees for participation in the advisory board for AbbVie Biotherapeutics, Biogen, Canbex, Ironwood, Novartis, Merck, Inc, Merck Serono, Roche, Sanofi Genzyme, Synthon, Teva, and Vertex; speaker fees from AbbVie, Biogen, Bayer HealthCare, Genzyme, Merck Serono, Sanofi-Aventis, and Teva; and research support from Biogen, Genzyme, Ironwood, Merck, Inc, Merck Serono, and Novartis. Dr Schmierer reports being a principal investigator of trials sponsored by Novartis, Roche, Teva, and Medday; involved in trials sponsored by Biogen, Sanofi-Genzyme, BIAL, Cytokinetics, and Canbex; and receiving speaking honoraria for lecturing and advisory activity and/or meeting support from Biogen, Merck, Inc, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. All authors with the exception of TX have presented at the ECTRIMS annual congress on one or more occasions.