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Cited by 286Monoclonal and Polyclonal Antibodies ResearchT-cell and B-cell ImmunologyImmunodeficiency and Autoimmune Disorders

Competition for FcRn-mediated transport gives rise to short half-life of human IgG3 and offers therapeutic potential

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Stapleton, Nigel M., Andersen, Jan Terje, Stemerding, Annette M., Bjarnarson, Stefania P., Verheul, Ruurd C., Gerritsen, Jacoline, Zhao, Yixian, Kleijer, Marion +5 more·2011·Nature Communications
DOI 10.1038/ncomms1608PMC PMC3247843
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Abstract

Human IgG3 displays the strongest effector functions of all IgG subclasses but has a short half-life for unresolved reasons. Here we show that IgG3 binds to IgG-salvage receptor (FcRn), but that FcRn-mediated transport and rescue of IgG3 is inhibited in the presence of IgG1 due to intracellular competition between IgG1 and IgG3. We reveal that this occurs because of a single amino acid difference at position 435, where IgG3 has an arginine instead of the histidine found in all other IgG subclasses. While the presence of R435 in IgG increases binding to FcRn at neutral pH, it decreases binding at acidic pH, affecting the rescue efficiency—but only in the presence of H435–IgG. Importantly, we show that in humans the half-life of the H435-containing IgG3 allotype is comparable to IgG1. H435–IgG3 also gave enhanced protection against a pneumococcal challenge in mice, demonstrating H435–IgG3 to be a candidate for monoclonal antibody therapies. The half-life of IgG is regulated by binding to the neonatal Fc receptor and, in the case of IgG3, is reduced compared to other IgG proteins. In this study, a mutation in IgG3 is shown to reduce binding to the neonatal Fc receptor, which can be competitively blocked by IgG1.

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Authors
Stapleton, N. M., Andersen, J. T., Stemerding, A. M., Bjarnarson, S. P., Verheul, R. C., Gerritsen, J., Zhao, Y., Kleijer, M., Sandlie, I., de Haas, M., Jonsdottir, I., van der Schoot, C. E., & Vidarsson, G.
Affiliations
  • Amsterdam UMC Location University of Amsterdam (NL)
  • Oslo University Hospital (NO)
  • University Medical Center Utrecht (NL)
  • Utrecht University (NL)
  • University of Oslo (NO)
Corresponding author
Vidarsson, Gestur
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2011-12-20
Volume
2
Issue
1
Pages
599-599
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms1608
PMC
PMC3247843
OpenAlex
W2018187711
Cited by
286
References
54
Citations by year
2026: 10 · 2025: 19 · 2024: 30 · 2023: 27 · 2022: 22 · 2021: 27 · 2020: 15 · 2019: 25 · 2018: 16 · 2017: 21 · 2016: 15 · 2015: 19 · 2014: 17 · 2013: 16 · 2012: 6
FWCI
9.55
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion)
  • NORA - Norwegian Open Research Archives (submittedVersion, cc-by-nc-nd)
  • Hirsla (Landspítali University Hospital) (submittedVersion)
Funders
  • Landsteiner Foundation for Blood Transfusion Research
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (015.001.083)
  • Norges Forskningsråd (179573)
  • Helse Sør-Øst RHF (39375)
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 › Immunodeficiency and Autoimmune Disorders
Keywords
IgG3, IgG1, neonatal Fc receptor, antibody half-life, monoclonal antibody therapy, effector function
MeSH terms
Agammaglobulinemia, Animals, Antibodies, Monoclonal, Arginine, Binding, Competitive, Disease Models, Animal, Half-Life, Histidine, Humans, Hydrogen-Ion Concentration, Immunoglobulin G, Pneumococcal Infections, Protein Binding, Receptors, Fc, Streptococcus pneumoniae, Histocompatibility Antigens Class I, Amino Acid Substitution, Protein Transport, Cell Line, Tumor, Mice, Molecular Targeted Therapy

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