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. 2024 Dec:269:110380.
doi: 10.1016/j.clim.2024.110380. Epub 2024 Oct 18.

Cladribine tablets in relapsing-remitting multiple sclerosis preferentially target B-cells

Francesca Ammoscato  1 , Mohammad Wafa  2 , Justyna Skonieczna  3 , Jonathan Bestwick  4 , Rosemary Monero  5 , Michael Andrews  6 , Stefania De Trane  3 , David Holden  3 , Ashok Adams  6 , Lucia Bianchi  3 , Ben Turner  6 , Monica Marta  6 , Klaus Schmierer  2 , David Baker  3 , Gavin Giovannoni  2 , Sharmilee Gnanapavan  6
Affiliations
Free article

Cladribine tablets in relapsing-remitting multiple sclerosis preferentially target B-cells

Francesca Ammoscato et al. Clin Immunol. 2024 Dec.
Free article

Abstract

Recent studies demonstrate the efficacy of B cell-targeting therapies in managing multiple sclerosis (MS) activity, emphasizing the critical role of B cells in MS pathogenesis. CladB study aimed to quantify the temporal changes in peripheral immune cells and their activity over 96 weeks of Cladribine tablets (CladT) treatment in relapsing-remitting MS (RRMS). Ten participants (3 males, 7 females) had blood samples collected at multiple intervals (Day 0, 1, 5, then weekly for 8 weeks, biweekly for up to 24 weeks, and monthly for up to 96 weeks) for immune cell analysis, compared to a historical alemtuzumab-treated cohort. Paired cerebrospinal fluid (CSF) was also taken for various analyses, alongside clinical and brain imaging assessments. CladT depleted memory B cells, while alemtuzumab rapidly depleted T and B cells. The кFLC index decreased from 164.5 ± 227.1 to 71.3 ± 84.7 at 48 weeks (p = 0.002) and to 64.4 ± 67.3 at 96 weeks (p = 0.01). The IgG index dropped from 1.1 ± 0.5 at baseline to 0.8 ± 0.4 at 48 weeks (p = 0.014) and to 0.8 ± 0.3 at 96 weeks (p = 0.02). CSF CXCL-13 decreased from 88.6 ± 68.4 pg/mL to 39.4 ± 35.2 pg/mL at 48 weeks (p = 0.037) and 19.1 ± 11.7 pg/mL at 96 weeks (p = 0.027). CSF NfL levels were reduced at 48 weeks (p = 0.01). CladT primarily depletes memory B cells and antibody-secreting cell precursors in RRMS, leading to sustained effects on intrathecal antibody production and total IgG, and a reduction in CSF CXCL-13.

Keywords: Biomarkers; Cerebrospinal fluid; Cladribine; Multiple sclerosis; Peripheral immune cells.

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Conflict of interest statement

Declaration of competing interest FA, MA, JS, RM, JB, MA, SD, DH, AA and LB have no conflict of interest to report. BT has received honoraria, travel grants, and has been a member of advisory boards for Biogen, Merck Serono Ltd., Feltham, UK, an affiliate of Merck KGaA, Darmstadt, Germany, Novartis, Sanofi Genzyme, and Roche. MM has received travel support and speaker honoraria from Biogen Idec, Genzyme, Merck Serono Ltd., Feltham, UK, an affiliate of Merck KGaA, Darmstadt, Germany Novartis, Roche and Teva, and consultation for Celgene, Merck Serono Ltd., Feltham, UK, an affiliate of Merck KGaA, Darmstadt, Germany, Novartis and Roche. KS has received research support, through Queen Mary University of London, from Biogen, Merck Serono Ltd., Feltham, UK, an affiliate of Merck KGaA,Darmstadt, Germany and Novartis, speaking honoraria from, and/or served in an advisory role for, Biogen, EMD Serono Billerica, MA, USA, Merck Serono Ltd., Feltham, UK, an affiliate of Merck KGaA, Darmstadt, Germany, Novartis, Roche, Sanofi-Genzyme and Teva; and remuneration for teaching activities from AcadeMe, Medscape and the Neurology Academy. DB has received honoraria from the healthcare business of Merck KGaA, Darmstadt, Germany, Novartis, Sandoz and Teva. GG has received honoraria and meeting support from AbbVie Biotherapeutics, Biogen, Canbex, Ironwood, Novartis, the healthcare business of Merck KGaA, Darmstadt, Germany, Merck Serono Ltd., Feltham, UK, an affiliate of Merck KGaA, Darmstadt, Germany, Genzyme, Synthon, Teva and Vertex. He also serves as a chief editor for Multiple Sclerosis and Related Disorders. SG has received honoraria and meeting support from Biogen, Sanofi-Genzyme, the healthcare business of Merck KGaA, Darmstadt, Germany, Novartis, Roche, Teva, Neurology Academy and research funding from Merck, Sanofi-Genzyme and Takeda.

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