Clinical implications of natalizumab Fab-arm exchange in patients with multiple sclerosis

Natalizumab, a monoclonal antibody used to treat multiple sclerosis, can undergo Fab-arm exchange (FAE) with endogenous IgG4, resulting in a monovalent form with reduced avidity and presumed lower potency than the parental bivalent form. Levels of bivalent and monovalent natalizumab depend on the ratio of endogenous IgG4 to total natalizumab, which varies substantially between individuals. The clinical relevance of natalizumab FAE remains unknown. This study investigated the potential clinical implications of bivalent and monovalent natalizumab levels regarding progressive multifocal leukoencephalopathy (PML), extended interval dosing (EID) and wearing-off symptoms, using multiple cohorts of natalizumab-treated patients. Seven natalizumab-associated PML cases were each matched to two controls. Contrary to the hypothesis that higher bivalent levels might increase PML risk, cases showed a trend toward lower bivalent natalizumab levels, although definite conclusions were limited by small sample size. In patients receiving EID, both total and bivalent natalizumab levels decreased compared to standard interval dosing, with a greater median individual decrease in bivalent natalizumab than in total natalizumab (94% versus 78%). Notably, in more than half of patients receiving EID, bivalent natalizumab levels fell below the quantification limit (<0.1 µg/mL). Finally, patients experiencing wearing-off symptoms during natalizumab treatment had lower bivalent natalizumab levels, although this warrants validation in larger cohorts.