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  • Review Article
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Immunogenicity of biologic agents in rheumatology

Nature Reviews Rheumatology volume 17, pages 81–97 (2021)Cite this article

Subjects

Abstract

Biologic agents have become a core component of therapeutic strategies for many inflammatory rheumatic diseases. However, perhaps reflecting the specificity and generally high affinity of biologic agents, these therapeutics have been used by rheumatologists with less consideration of their pharmacokinetics than that of conventional synthetic DMARDs. Immunogenicity was recognized as a potential limitation to the use of biologic agents at an early stage in their development, although regulatory guidance was relatively limited and assays to measure immunogenicity were less sophisticated than today. The advent of biosimilars has sparked a renewed interest in immunogenicity that has resulted in the development of increasingly sensitive assays, an enhanced appreciation of the pharmacokinetic consequences of immunogenicity and the development of comprehensive and specific guidance from regulatory authorities. As a result, rheumatologists have a greatly improved understanding of the field in general, including the factors responsible for immunogenicity, its potential clinical consequences and the implications for everyday treatment. In some specialties, immunogenicity testing is becoming a part of routine clinical management, but definitive evidence of its cost-effectiveness in rheumatology is awaited.

Key points

  • All biologic agents are immunogenic and many pathways influence their bioavailability, including patient-specific factors, disease-specific features and genetic background.

  • The potential consequences of immunogenicity range from no clinical consequences to reduced therapeutic efficacy, infusion reactions and, rarely, serum sickness or anaphylaxis.

  • Group level pharmacokinetic models have consistently shown that anti-drug antibodies (ADAs) result in decreased serum drug concentrations and reduced efficacy.

  • The most important difference between available immunogenicity assays is the degree to which the assay is drug tolerant.

  • Coadministration of anti-proliferative and/or immunosuppressive agents such as methotrexate decreases ADA formation and maintains serum drug concentrations via various mechanisms.

  • Regular monitoring of serum drug and ADA levels has been proposed but not yet instigated into rheumatological practice, mainly owing to a lack of cost-effectiveness data.

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Fig. 1: Factors that influence the pharmacokinetics and immunogenicity of biologic agents.
Fig. 2: Consequences of immunogenicity.
Fig. 3: Immunogenicity screening assays.
Fig. 4: Therapeutic drug monitoring strategies.

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Acknowledgements

Work in the laboratory of J.G. is supported by Fundacao para a Ciencia e Tecnologia, Portugal. Work in the laboratory of J.D.I. is supported by the National Institute for Health Research Newcastle Biomedical Research Centre, based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University, UK; the Research into Inflammatory Arthritis Centre Versus Arthritis; and the Horizon 2020 Innovative Medicines Initiative 2 Rheumatherapy Cure (RT-CURE). The authors acknowledge technical support from Lisa Tait in relation to helping with the referencing in this Review.

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Authors and Affiliations

  1. Division of Immunology and Rheumatology, Stanford University, Palo Alto, CA, USA

    Vibeke Strand

  2. Research Institute for Medicines (iMed), Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal

    Joao Goncalves

  3. Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK

    John D. Isaacs

  4. Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK

    John D. Isaacs

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  1. Vibeke Strand
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  2. Joao Goncalves
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  3. John D. Isaacs
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The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Vibeke Strand.

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Competing interests

V.S. declares that she has received consulting fees from AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Celgene, Celltrion, Crescendo/Myriad, EMD Serono, Equillium, Galapagos, Genentech/Roche, Gilead, GSK, Horizon, Ichnos, Inmedix, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Samsung, Sandoz, Sanofi, Servier, Setpoint and UCB. J.G. declares that he has received financial support for research projects from AstraZeneca, Biogen and Shire (Takeda). J.G. has also received consulting fees from Amgen, Biogen, Fresenius, Novartis, Samsung Bioepis and Sanofi. J.D.I. declares that he has received research funding from Pfizer and consulting or speaker fees from AbbVie, Amgen, Merck, Roche and UCB.

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Nature Reviews Rheumatology thanks G. J. Wolbink, D. Mulleman and D. H. Yoo for their contribution to the peer review of this work.

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Glossary

Phage display

A technique whereby an antibody-variable sequence is displayed on the outside of a bacteriophage that contains the DNA encoding the variable sequence, enabling the screening and selection of bacteriophages containing the genetic sequence of interest.

Single-cell cloning

A technique whereby the antibody-encoding genetic material is extracted from a human B cell clone that produces the antibody of interest.

Idiotype

The collection of sequences (idiotopes) that form the antigen-binding site of an antibody.

Humanized antibodies

Antibodies in which the complementarity determining regions of a human antibody have been replaced with those from a mouse antibody of interest to create an antibody with the specificity of the mouse antibody in the context of a mostly human sequence.

Chimeric antibodies

Antibodies in which the variable region of a mouse antibody of interest has been genetically fused with a human constant region to create an antibody that retains the specificity of the mouse antibody in the context of a human constant region.

Fully human antibodies

Antibodies that contain only sequences derived from human genes.

Cross-reactive immunological material

An endogenous protein in the recipient that is immunologically similar to the replacement therapy.

Target-mediated drug disposition

When the binding of a drug to its target affects the pharmacokinetics of the drug.

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Strand, V., Goncalves, J. & Isaacs, J.D. Immunogenicity of biologic agents in rheumatology. Nat Rev Rheumatol 17, 81–97 (2021). https://doi.org/10.1038/s41584-020-00540-8

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