BRIEF RESEARCH REPORT article
Front. Immunol.
Sec. Vaccines and Molecular Therapeutics
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1677925
This article is part of the Research TopicAdvances in Immunogenicity Risk Assessment, Monitoring and Mitigation of BiologicsView all 10 articles
Towards new approach methodologies for biological therapeutics: A novel model-informed metric to assess immunogenicity risk
Provisionally accepted
Rachel Helen Rose1*
Aban Shuaib1
Manon Wigbers1Maryam Khalifa1
Andrzej Kierzek1
Piet Hein van der Graaf1,2,3- 1Certara UK Limited, Sheffield, United Kingdom
- 2Universiteit Leiden Leiden Academic Centre for Drug Research, Leiden, Netherlands
- 3Cincinnati Children's Hospital Medical Center, Cincinnati, United States
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Immunogenicity poses a significant challenge in biotherapeutics development due to the formation of anti-drug antibodies (ADA), which can alter drug pharmacokinetics (PK) and reduce efficacy. However, ADA presence does not always correlate with a clinically relevant reduction in efficacy, or in some cases can be managed by adjusting dosing regimens. Current preclinical strategies focus on predicting the propensity for ADA development, but do not assess the liability for ADA to impact PK. Quantitative systems pharmacology (QSP) models integrate knowledge of biological mechanisms with physiological and drug-specific parameters to predict ADA dynamics and their effect on PK. This study describes recent progress in using QSP models to predict the incidence of immunogenicity and the impact of ADA on PK. We report continued challenges in accurately predicting ADA incidence from available data from experimental and computational methods used in immunogenicity risk assessment. However, across 13 monoclonal antibodies and fusion proteins, the model accurately predicted ADA impact on drug concentration in ten cases, Furthermore, the ADA to drug concentration ratio was identified as a strong predictor of clinically relevant immunogenicity and drug exposure impact.
Keywords: Immunogenicity, Anti-drug antibody, Biotherapeutic, Quantitative Systems Pharmacology, pharmacokinetics, Model-informed drug development
Received: 01 Aug 2025; Accepted: 20 Oct 2025.
Copyright: © 2025 Rose, Shuaib, Wigbers, Khalifa, Kierzek and van der Graaf. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Rachel Helen Rose, rachel.rose@certara.com
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.