ORIGINAL RESEARCH article
Front. Immunol.
Sec. Vaccines and Molecular Therapeutics
This article is part of the Research TopicAdvances in Immunogenicity Risk Assessment, Monitoring and Mitigation of BiologicsView all 13 articles
The Role of Large Immune Complexes in Anti-drug Antibody Development: A Case Study of Anti-SARS-CoV-2 Antibody Therapeutics and Co-administered mRNA vaccine
Provisionally accepted
Susan C. Irvin*
Zhiqiang WangSamit GangulyDeepanshu ChoudharyMinita KanagarajNina LiuFlonza IsaZhongqing Will HeHong YanVeronica Mas CasulloKenneth C. TurnerJohn D. DavisMichael RosconiAlbert Torri
Michael A. Partridge- Regeneron Pharmaceuticals, Inc., Tarrytown, United States
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The administration of therapeutic proteins may induce an anti-drug antibody (ADA) response which may impact pharmacokinetics, safety or efficacy. Numerous factors contribute to ADA development, such as patient population, drug sequence, formulation impurities, as well as drug dose and frequency. Here we report data from a natural experiment where ADA incidence for monoclonal antibodies (mAbs) casirivimab (CAS) and imdevimab (IMD), targeting the SARS-CoV-2 spike protein, was more than 3-fold higher in COVID-19 vaccinated participants compared to unvaccinated. Although ADA incidence to the mAbs was elevated in vaccinated participants, there was no increase in the strength or magnitude of the ADA response, despite these participants developing robust immunogenicity directed against the COVID-19 vaccine. In vitro studies using sedimentation velocity analytical ultracentrifugation demonstrated large complexes (ranging from 1.6 to 4 MDa) being formed between CAS+IMD and recombinant spike trimer. In addition, the substantially increased immunogenicity to CAS+IMD was only observed in participants receiving mRNA-LNP-based products, likely due to higher expression of spike protein compared to adenovirus-based products. No increase in ADA was observed in COVID-19 vaccinated participants receiving mAbs to unrelated targets, suggesting COVID-19 vaccination was not a general adjuvant. Taken together, these data suggest in participants vaccinated with mRNA-LNP-based products, the formation of large mAb-target immune complexes likely results in greater surveillance by immune cells and increased ADA development to mAbs against the same target.
Keywords: Anti-drug antibodies, COVID-19, immunecomplex, Immunogenicity, monoclonal antibodies
Received: 16 Dec 2025; Accepted: 13 Feb 2026.
Copyright: © 2026 Irvin, Wang, Ganguly, Choudhary, Kanagaraj, Liu, Isa, He, Yan, Casullo, Turner, Davis, Rosconi, Torri and Partridge. 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: Susan C. Irvin
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