Impact of Repeated Antigen Exposure on Humoral Tolerance: Antidrug Antibodies After Single-Dose Versus Multi-dose Adalimumab

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.

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Journal
BioDrugs
Published
2026-06-17
DOI
https://doi.org/10.1007/s40259-026-00792-y
Primary Topic
Rheumatoid Arthritis Research and Therapies
Type
article
Field-Weighted Citation Impact
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article

Impact of Repeated Antigen Exposure on Humoral Tolerance: Antidrug Antibodies After Single-Dose Versus Multi-dose Adalimumab

Floris C. Loeff, J. Janssen, Justin Jacobse, Anika M. Valk et al.
BioDrugs
Rheumatoid Arthritis Research and Therapies
article

Impact of Repeated Antigen Exposure on Humoral Tolerance: Antidrug Antibodies After Single-Dose Versus Multi-dose Adalimumab

Floris C. Loeff, J. Janssen, Justin Jacobse, Anika M. Valk, Nick J. Reynolds, C S Smith, Theo Rispens, Maureen Leeuw, Jolinde van Strien, Anja ten Brinke, Dorien Kos, Wouter ten Voorde, Lisanne Dijk, Richard Warren, Daniel Alvarez, Ninotska Derksen, Marieke van Ham, Robert Rissman, Gertjan Wolbink, Jonathan Barker, Júlia Castellon Teixell, Teresa Tsakok, Christopher E. M. Griffiths, BSTOP Study Group
article en

Abstract

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.

BioDrugs
Leiden University (NL), King's College London (GB), Guy's and St Thomas' NHS Foundation Trust (GB), Manchester Academic Health Science Centre (GB), Leiden University Medical Center (NL), Royal Victoria Infirmary (GB), Sanquin (NL), Reade (NL), Netherlands Center for Occupational Diseases (NL), Centre for Human Drug Research (NL), NIHR Manchester Biomedical Research Centre (GB), Newcastle University (GB), Vrije Universiteit Amsterdam (NL), University of Amsterdam (NL)
Dutch Arthritis Society, Manchester Biomedical Research Centre, Medical Research Council, Horizon 2020
Good health and well-being
Openalex Percentile: Top 7%
Rheumatoid Arthritis Research and Therapies
DOIOpen Access PDFOpenAlex
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