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Effect of posttranslational modifications and subclass on IgG activity: from immunity to immunotherapy

Nature Immunology volume 24, pages 1244–1255 (2023)Cite this article

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A Publisher Correction to this article was published on 23 August 2023

A Publisher Correction to this article was published on 12 July 2023

This article has been updated

Abstract

Humoral immune responses are characterized by complex mixtures of polyclonal antibody species varying in their isotype, target epitope specificity and affinity. Posttranslational modifications occurring during antibody production in both the antibody variable and constant domain create further complexity and can modulate antigen specificity and antibody Fc-dependent effector functions, respectively. Finally, modifications of the antibody backbone after secretion may further impact antibody activity. An in-depth understanding of how these posttranslational modifications impact antibody function, especially in the context of individual antibody isotypes and subclasses, is only starting to emerge. Indeed, only a minute proportion of this natural variability in the humoral immune response is currently reflected in therapeutic antibody preparations. In this Review, we summarize recent insights into how IgG subclass and posttranslational modifications impact IgG activity and discuss how these insights may be used to optimize therapeutic antibody development.

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Fig. 1: IgG structure, interaction partners and impact of posttranslational modifications.
Fig. 2: IgG subclass binding to cellular FcγRs in monomeric or immune complex form.
Fig. 3: Effect of fucose residues on IgG-dependent effector functions.
Fig. 4: Effect of IgG subclass and glycosylation on therapeutic IgG activity.

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Acknowledgements

This work has been funded by grants from the German Research Foundation (TRR305-B02, CRC1181-A07, CRC1526-A07, FOR2886-B2 and FOR2953-P3) and the National Institutes of Health (NIH; U01-AI-148119 and 5U19A/142790-04) to F.N. and by grants from Cancer Research UK (A20537, DRCDDRPGM-Apr2020\100005 and A24721) and NIH (grant UO1AI148153) to M.S.C.

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  1. These authors contributed equally: Falk Nimmerjahn, Gestur Vidarsson, Mark S. Cragg.

Authors and Affiliations

  1. Division of Genetics, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany

    Falk Nimmerjahn

  2. Immunoglobulin Research Laboratory, Department of Experimental Immunohematology, Sanquin Research, Amsterdam, the Netherlands

    Gestur Vidarsson

  3. Department of Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences and Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, the Netherlands

    Gestur Vidarsson

  4. Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, University of Southampton Faculty of Medicine, Southampton, UK

    Mark S. Cragg

  5. Institute for Life Sciences, University of Southampton, Southampton, UK

    Mark S. Cragg

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F.N., G.V. and M.S.C. performed the literature research and wrote the manuscript.

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Nimmerjahn, F., Vidarsson, G. & Cragg, M.S. Effect of posttranslational modifications and subclass on IgG activity: from immunity to immunotherapy. Nat Immunol 24, 1244–1255 (2023). https://doi.org/10.1038/s41590-023-01544-8

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