Abstract
Introduction Cladribine (Mavenclad®) is an oral treatment for relapsing remitting MS (RRMS). P2X7R is a purinergic receptor implicated in neuroinflammatory processes.
Objective To investigate the mechanism of action of Cladribine on peripheral monocytes.
Methods This is a Phase IV, open-label, multi-centre, 3-year, translational trial. 40 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). P2X7R Pore activity was assessed using YOPRO dye uptake experiments and confocal microscopy.
Results There was evidence of reduction in monocyte count at week 1 post-cladribine commencement compared to baseline (0.55 ±0.04 vs 0.08 ± 0.0187; p=10^-6). However, unlike lymphocytes, the cytotoxic effects of cladribine on monocytes was not sustained, and the cells repopulated at 2 months. CD14loCD16+ monocytes were the sub-population most reduced at week 1 compared to baseline, 2, and 6 months (P<0.001). In vitro, Cladrabine induced a reduction in P2X7R pore activity (p<0.001). MS relapse activity decreased in the 12 months after commencement of Cladribine (p<0.001). Relapse in the last 12 months, MRI disease activity and age did not predict changes in EDSS in the 12 months subsequent to Cladribine commencement.
Conclusion This study demonstrates a novel mechanism of action for Cladribine, highlighting that it exerts its effects acutely on peripheral monocytes, and possibly via P2X7R. The laboratory data will be linked to clinical data to decipher what innate immune parameters translate to better patient outcome.
