Lymphocytosis as a biomarker for natalizumab treatment response in multiple sclerosis: The link with anti-drug antibodies

Background: Natalizumab is a high-efficacy therapy drug for multiple sclerosis that inhibits lymphocyte migration into the central nervous system, increasing lymphocyte counts in the peripheral blood. Anti-drug antibody responses may limit drug efficacy, but current guidance recommends anti-drug antibody testing only after evidence of ‘reduced efficacy’. Objective: To assess the lack of relative lymphocytosis as a biomarker of anti-drug antibody responses. Methods: Lymphocyte counts and immunogenicity data from the pivotal AFFIRM clinical trial ( n = 627 natalizumab vs n = 315 placebo) and real-world data from the Cardiff MS register ( n = 185) were analysed to assess the relationship between lymphocyte counts, anti-drug antibody responses, drug levels and disease activity. Results: Natalizumab treatment induced an absolute change in lymphocyte counts by week 12 (1.40 ± 0.92 vs −0.05 ± 0.62 × 10 9 cells/L in natalizumab vs placebo; p < 0.0001) that was absent in the persistent anti-drug antibody group (−0.12 ± 0.60 × 10 9 cells/L). Increases in lymphocyte counts by ⩾ 0.8 × 10 9 cells/L from the baseline discriminated individuals without anti-drug antibody responses with high sensitivity (≥ 84%) and specificity (≥ 91%). Conclusion: The absence of relative lymphocytosis is associated with anti-drug antibody responses and may provide a simple biomarker to prompt anti-drug antibody testing before disease breakthrough occurs.