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

Valero-Hernandez, Ester, Mathur, Jai, Baker, David, Liu, Iris Y. H., Morgan, Sarah L., Tallantyre, Emma C. ORCID: https://orcid.org/0000-0002-3760-6634, Schmierer, Klaus and Kang, Angray S. 2026. Lymphocytosis as a biomarker for natalizumab treatment response in multiple sclerosis: The link with anti-drug antibodies. Multiple Sclerosis Journal 10.1177/13524585261495351

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Abstract

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 × 109 cells/L in natalizumab vs placebo; p < 0.0001) that was absent in the persistent anti-drug antibody group (−0.12 ± 0.60 × 109 cells/L). Increases in lymphocyte counts by ⩾ 0.8 × 109 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.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine
Publisher:	SAGE Publications
ISSN:	1352-4585
Date of First Compliant Deposit:	21 October 2026
Date of Acceptance:	21 September 2026
Last Modified:	21 Oct 2026 11:15
URI:	https://orca.cardiff.ac.uk/id/eprint/190350

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