Impact of Immune Complex Size and Glycosylation on IgG Binding to Human FcγRs
Abstract
IgG molecules are widely used as therapeutic agents either in the form of intact Abs or as Fc fusion proteins. Although efficient binding of the IgG Fc fragment to cellular FcγRs may be essential to achieve a high cytolytic activity, it may be advantageous for other applications to limit or abolish this interaction. Genetic or biochemical approaches have been used to generate these non–FcγR-binding IgG variants. By using soluble versions of FcγRs and monomeric versions of these altered IgG molecules, it was demonstrated that these IgG variants no longer bind to FcγRs. Importantly, however, these assays do not reflect the physiologic interaction of IgG with low-affinity cellular FcγRs occurring in the form of multimeric immune complexes. In this study, we investigated how the size of an immune complex can affect the interaction of normal and various versions of potentially non–FcγR-binding IgG variants with cellular FcγRs. We show that neither the D265A mutation nor EndoS treatment resulting in IgG molecules with only one N-acetylglucosamine and a fucose residue was fully able to abolish the interaction of all IgG subclasses with cellular FcγRs, suggesting that IgG subclass–specific strategies are essential to fully interfere with human FcγR binding.
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The reduced affinity to FcγRs might be required to increase safety, for example in the context of neutralizing antibodies used for inflammatory cytokine targeting.
“This reduced affinity might be required to increase safety, for example in the context of neutralizing antibodies used for inflammatory cytokine targeting (Lux et al., 2013).”
From Therapeutic glycoprotein production in mammalian cells (2017) · cites this paper as Lux et al., 2013
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- Authors
- Lux, A., Yu, X., Scanlan, C. N., & Nimmerjahn, F.
- Affiliations
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- University of Oxford (GB)
- Department of Biochemistry, University of Oxford , Oxford OX1 3QU,
- Corresponding author
- Lux, Anja
- Nimmerjahn, Falk
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-04
- Volume
- 190
- Issue
- 8
- Pages
- 4315-4323
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2162952238
- Cited by
- 272
- References
- 3
- Citations by year
- 2026: 13 · 2025: 14 · 2024: 18 · 2023: 21 · 2022: 22 · 2021: 21 · 2020: 26 · 2019: 26 · 2018: 18 · 2017: 21 · 2016: 20 · 2015: 23 · 2014: 22 · 2013: 7
- FWCI
- 18.59
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Southampton
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Keywords
- IgG, Fc gamma receptor, glycosylation, N-acetylglucosamine, fucose, IgG subclasses, Fc fusion protein, antibody-drug conjugates
- MeSH terms
- Alleles, Animals, Antigen-Antibody Complex, Binding Sites, Antibody, Cell Line, Glycoside Hydrolases, Glycosylation, Cricetinae, Humans, Immunoglobulin G, Mutation, Recombinant Proteins, CHO Cells, Receptors, IgG, Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase, Mice, HEK293 Cells
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