Abstract
Introduction Cladribine (Mavenclad®) is an oral treatment for relapsing remitting MS (RRMS). In RRMS clinical trials, Cladribine has been shown to reduce brain atrophy, relapse rates, and new lesions on MRI. Cladribine is thought to produce its beneficial effects through its lymphocytic actions.
Objective To investigate the mechanism of action of Cladribine on peripheral innate immune cells, in particular monocytes.
Methods This is a Phase IV, open-label, multi-centre, 3-year, translational trial. Forty RRMS patients commencing Cladribine were prospectively recruited into this study. Peripheral monocytes were isolated from whole blood using negative selection, and stained with the following markers for flow cytometric analysis (CD14, CD16, HLADR, CD11b, P2X7R, DAPI). Blood samples and clinical information were collected at: T0 (prior to cladribine commencement), week 1, week 8, week 26, and week 52.
Results There was evidence of reduction in monocyte count at week 1 compared to prior to treatment (0.55 ±0.04 vs 0.08 ± 0.0187; p=10^-6). However, unlike lymphocytes, the cytotoxic effects of cladribine on monocytes were not sustained, and the cells repopulated at 2 months post-cladribine treatment. Extended analysis of monocyte subtypes showed a reduction in the ‘non-classical’ monocyte (CD14-CD16+) subset at 1-week post-cladribine treatment. However, this was not reflected in the ‘classical’ (CD14+CD16-) and ‘intermediate’ (CD14+CD16+) monocyte populations.
Conclusion This study demonstrates a novel mechanism of action for Cladribine, highlighting that it exerts its effects acutely on peripheral monocytes. The laboratory data will be linked to clinical data to decipher what innate immune parameters translate to better patient outcome.
