Molecular parameters governing antibody FcγR signaling and effector functions in the context of HIV envelope

Antibody effector functions contribute to the immune response to pathogens and can influence the efficacy of antibodies as therapeutics. To date, however, there is limited information on the molecular parameters that govern fragment crystallizable (Fc) effector functions. In this study, using AI-assisted protein design, the influences of binding kinetics, epitope location, and stoichiometry of binding on cellular Fc effector functions were investigated using engineered HIV-1 envelope as a model antigen. For this antigen, stoichiometry of binding was found to be the primary molecular determinant of FcγRIIIa signaling, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis, while epitope location and antibodybinding kinetics, at least in the ranges investigated, were of no substantial impact. These findings are of importance for informing the development of vaccination strategies against HIV-1 and, possibly, other viral pathogens.

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Publication Details

Journal
Cell Reports
Published
2025-03-31
DOI
https://doi.org/10.1016/j.celrep.2025.115331
Citations
3
Primary Topic
Monoclonal and Polyclonal Antibodies Research
Type
article
Field-Weighted Citation Impact
4.08

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Molecular parameters governing antibody FcγR signaling and effector functions in the context of HIV envelope

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Cell Reports
Monoclonal and Polyclonal Antibodies Research
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Molecular parameters governing antibody FcγR signaling and effector functions in the context of HIV envelope

Rebecca Nedellec, Xuduo Li, Raiza Bastidas, Javier Guenaga, Lars Hangartner, Richard T. Wyatt, Gabriel Ozorowski, Max Crispin, Michael Bick, Dennis R. Burton, Eduard Puig, Wen-Hsin Lee, David Beauparlant, Andrew B. Ward, Wenwen Zhu, Iszac Burton, Thea R. Zalunardo, Keihvan Ardaghi
article en
3 citations

Abstract

Antibody effector functions contribute to the immune response to pathogens and can influence the efficacy of antibodies as therapeutics. To date, however, there is limited information on the molecular parameters that govern fragment crystallizable (Fc) effector functions. In this study, using AI-assisted protein design, the influences of binding kinetics, epitope location, and stoichiometry of binding on cellular Fc effector functions were investigated using engineered HIV-1 envelope as a model antigen. For this antigen, stoichiometry of binding was found to be the primary molecular determinant of FcγRIIIa signaling, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis, while epitope location and antibodybinding kinetics, at least in the ranges investigated, were of no substantial impact. These findings are of importance for informing the development of vaccination strategies against HIV-1 and, possibly, other viral pathogens.

Cell ReportsVol. 44(4)
Scripps Research Institute (US), International AIDS Vaccine Initiative (US), Ragon Institute of MGH, MIT and Harvard (US), University of Southampton (GB)
National Science Foundation, European Molecular Biology Organization, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, National Institutes of Health
Good health and well-being
Openalex Percentile: Top 7%
Monoclonal and Polyclonal Antibodies Research
4.08
DOIOpen Access PDFOpenAlex
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