Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Mixed IgG Fc immune complexes exhibit blended binding profiles and refine FcR affinity estimates

Zhixin Cyrillus Tan, View ORCID ProfileAnja Lux, View ORCID ProfileMarkus Biburger, Prabha Varghese, Stephen Lees, View ORCID ProfileFalk Nimmerjahn, View ORCID ProfileAaron S. Meyer
doi: https://doi.org/10.1101/2023.02.15.528730
Zhixin Cyrillus Tan
1Bioinformatics Interdepartmental Program, University of California, Los Angeles (UCLA)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Anja Lux
2Department of Genetics, Friedrich-Alexander-University of Erlangen-Nürnberg
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Anja Lux
Markus Biburger
2Department of Genetics, Friedrich-Alexander-University of Erlangen-Nürnberg
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Markus Biburger
Prabha Varghese
2Department of Genetics, Friedrich-Alexander-University of Erlangen-Nürnberg
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stephen Lees
3Department of Bioengineering, UCLA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Falk Nimmerjahn
2Department of Genetics, Friedrich-Alexander-University of Erlangen-Nürnberg
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Falk Nimmerjahn
Aaron S. Meyer
1Bioinformatics Interdepartmental Program, University of California, Los Angeles (UCLA)
3Department of Bioengineering, UCLA
4Jonsson Comprehensive Cancer Center, UCLA
5Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Aaron S. Meyer
  • For correspondence: ameyer@asmlab.org
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Immunoglobulin (Ig)G antibodies coordinate immune effector responses by selectively binding to target antigens and then interacting with various effector cells via the Fcγ receptors. The Fc domain of IgG can promote or inhibit distinct effector responses across several different immune cell types through variation based on subclass and Fc domain glycosylation. Extensive characterization of these interactions has revealed how the inclusion of certain Fc subclasses or glycans results in distinct immune responses. During an immune response, however, IgG is produced with mixtures of Fc domain properties, so antigen-IgG immune complexes are likely to almost always be comprised of a combination of Fc forms. Whether and how this mixed composition influences immune effector responses has not been examined. Here, we measured Fcγ receptor binding to immune complexes of mixed Fc domain composition. We found that the binding properties of the mixed-composition immune complexes fell along a continuum between those of the corresponding pure cases. Binding quantitatively matched a mechanistic binding model, except for several low-affinity interactions mostly involving IgG2. We found that the affinities of these interactions are different than previously reported, and that the binding model could be used to provide refined estimates of these affinities. Finally, we demonstrated that the binding model can predict effector-cell elicited platelet depletion in humanized mice, with the model inferring the relevant effector cell populations. Contrary to the previous view in which IgG2 poorly engages with effector populations, we observe appreciable binding through avidity, but insufficient amounts to observe immune effector responses. Overall, this work demonstrates a quantitative framework for reasoning about effector response regulation arising from IgG of mixed Fc composition.

Summary points

  • The binding behavior of mixed Fc immune complexes is a blend of the binding properties for each constituent IgG species.

  • An equilibrium, multivalent binding model can be generalized to incorporate immune complexes of mixed Fc composition.

  • Particularly for low-affinity IgG-Fcγ receptor interactions, immune complexes provide better estimates of affinities.

  • The FcγR binding model predicts effector-elicited cell clearance in humanized mice.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
Back to top
PreviousNext
Posted February 15, 2023.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Mixed IgG Fc immune complexes exhibit blended binding profiles and refine FcR affinity estimates
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Mixed IgG Fc immune complexes exhibit blended binding profiles and refine FcR affinity estimates
Zhixin Cyrillus Tan, Anja Lux, Markus Biburger, Prabha Varghese, Stephen Lees, Falk Nimmerjahn, Aaron S. Meyer
bioRxiv 2023.02.15.528730; doi: https://doi.org/10.1101/2023.02.15.528730
Reddit logo Twitter logo Facebook logo LinkedIn logo Mendeley logo
Citation Tools
Mixed IgG Fc immune complexes exhibit blended binding profiles and refine FcR affinity estimates
Zhixin Cyrillus Tan, Anja Lux, Markus Biburger, Prabha Varghese, Stephen Lees, Falk Nimmerjahn, Aaron S. Meyer
bioRxiv 2023.02.15.528730; doi: https://doi.org/10.1101/2023.02.15.528730

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Immunology
Subject Areas
All Articles
  • Animal Behavior and Cognition (4230)
  • Biochemistry (9123)
  • Bioengineering (6767)
  • Bioinformatics (23969)
  • Biophysics (12109)
  • Cancer Biology (9510)
  • Cell Biology (13753)
  • Clinical Trials (138)
  • Developmental Biology (7623)
  • Ecology (11675)
  • Epidemiology (2066)
  • Evolutionary Biology (15492)
  • Genetics (10632)
  • Genomics (14310)
  • Immunology (9473)
  • Microbiology (22823)
  • Molecular Biology (9086)
  • Neuroscience (48920)
  • Paleontology (355)
  • Pathology (1480)
  • Pharmacology and Toxicology (2566)
  • Physiology (3841)
  • Plant Biology (8322)
  • Scientific Communication and Education (1468)
  • Synthetic Biology (2295)
  • Systems Biology (6180)
  • Zoology (1299)