Cladribine tablets in Relapsing-Remitting Multiple Sclerosis preferentially target B-cells

Abstract

Recently it has been shown that treatments targeting B cells in multiple sclerosis (MS) are effective in controlling disease activity. B cells contribute to the pathogenesis of MS via antigen presentation, T cell activation, and antibody production. In the chronic progressive cladribine trial, some patients treated with cladribine had a significant decline in oligoclonal band number. However, the mode of action of cladribine tablets (CladT) on peripheral immune cells and its biological activity within the CNS remains to be determined further. The CladB study is a longitudinal prospective investigation of CladT treatment in relapsing-remitting MS (RRMS). Blood was sampled at Day 0, 1, 5, then once a week for 8 weeks, fortnightly up to 24 weeks, and once a month till 96 weeks for immune cells. This was compared to a historical cohort of alemtuzumab treated samples for one month. Paired cerebrospinal fluid (CSF) and blood were also taken at Day 0, 48 and 96 weeks after initiating CladT for Kappa and Lambda-free light chain (кFLC, λFLC) index, oligoclonal bands (OCBs), immunoglobulin indices, inflammatory mediators and neurofilament light chain (NfL). Participants also underwent clinical and magnetic resonance imaging brain assessments. Ten participants (3 male, 7 female, mean age 35.9 ± 10.5 (SD) and Expanded disability Status Scale 2.5 (range 0-6) at baseline were enrolled. B cells, in particular memory B cells, were heavily depleted by CladT. Alemtuzumab, conversely rapidly depleted both T and B cells. Although still present, reduction in OCB numbers were observed in 4/10 participants and кFLC index reduced from mean 164.5 ± 227.1 (SD) at baseline to 71.3 ± 84.7 at 48 weeks (p=0.002) and 64.4 ± 67.3 at 96 weeks (p=0.01). This coincided with reduction in IgG index [1.1 ± 0.5 (SD) at baseline, 0.8 ± 0.4 (p=0.014) at 48 weeks and 0.8 ± 0.3 (P=0.02) at 96 weeks] and CSF CXCL-13 [88.6± 68.4 (SD) pg/mL, 39.4 ± 35.2 mg/mL (p=0.037) at 48 weeks and 19.1 ± 11.7pg/ml at 96 weeks (p=0.027)]. CSF NfL levels were reduced at 48 weeks only (p=0.01). In conclusion, our study supports the view that CladT treatment works primarily by depleting memory B-cells and antibody-secreting cell precursors in RRMS leading to sustained effects on intrathecal antibody production and total IgG associated with a reduction in the B-cell chemoattractant CXCL-13 in the CSF.