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Lookup NU author(s): Professor Nick ReynoldsORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
© The Author(s) 2026. Background: Therapeutic proteins such as adalimumab can elicit an antibody response. How dosing regimens impact immunogenicity remains ill-understood, especially with respect to the frequency of dosing. Objective: We aimed to investigate the relationship between single versus multiple adalimumab doses and immunogenicity, in terms of anti-drug antibody production and skewing towards the non-inflammatory immunoglobulin G4 (IgG4) subclass. Methods: Immunoglobulin M, immunoglobulin G, and IgG4 anti-drug antibodies were analyzed in retrospective cohorts of healthy individuals and patients with rheumatoid arthritis, psoriatic arthritis, spondyloarthritis, or psoriasis, receiving one or multiple doses of adalimumab, using optimized drug-tolerant assays, newly developed in the case of IgG4. Results: A single dose of adalimumab proved highly immunogenic, while repeated dosing, resulting in prolonged exposure to high antigen concentrations, led to attenuation of the anti-drug antibody response. Immunoglobulin G4 anti-drug antibodies developed earlier than previously reported with drug-sensitive assays, appearing as early as week 3, even after a single dose of adalimumab. Skewing towards IgG4 was nevertheless stronger with repeated dosing. Conclusions: Repeated high-dose adalimumab exposure can limit both the magnitude and inflammatory potential of the antibody response. These results highlight drug exposure as a factor modulating the immunogenicity of biologics.
Author(s): Valk AM, van Strien J, Derksen N, Kos D, Castellon Teixell J, Janssen J, Loeff FC, Dijk L, Leeuw M, Smith C, Tsakok T, Warren R, Reynolds NJ, Griffiths CEM, Barker J, Rissman R, ten Voorde W, Jacobse J, Alvarez D, van Ham M, Wolbink G, ten Brinke A, Rispens T
Publication type: Article
Publication status: Published
Journal: BioDrugs
Year: 2026
Volume: 40
Pages: 747-757
Print publication date: 01/07/2026
Online publication date: 17/06/2026
Acceptance date: 29/03/2026
Date deposited: 16/07/2026
ISSN (print): 1173-8804
ISSN (electronic): 1179-190X
Publisher: Springer Nature
URL: https://doi.org/10.1007/s40259-026-00792-y
DOI: 10.1007/s40259-026-00792-y
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