Cross-species cellular mapping and humanization of Fcγ receptors to advance antibody modeling
Fc receptors mediate antibody effector functions. Immunoglobulin G (IgG), the predominant antibody in circulation and in clinical use, engages diverse Fc gamma (Fcγ) receptors differentially expressed across cell types. Here, we provide a comprehensive overview of Fcγ receptor and neonatal Fc receptor (FcRn) expression in humans, macaques, and mice. This analysis revealed substantial differences in Fcγ receptor diversity, cell-specific expression, and regulatory mechanisms that compromise the translation of mouse and macaque models for antibody research. To improve preclinical modeling, we generated a mouse in which humanized Fcγ receptors (FcγRI/CD64, FcγRIIA/CD32A, FcγRIIB/CD32B, FcγRIIIA/CD16A, and FcγRIIIB/CD16B), expressed under control of human promotors, replace their murine counterparts. This model also incorporates human FcRn to improve antibody pharmacokinetics. Humanization resulted in more faithful Fcγ receptor expression. We validated receptor functionality and demonstrated how cytokines modulate their expression. Together, this cross-species Fcγ receptor atlas and humanized mouse model can improve the preclinical evaluation of antibody-based therapeutics.
Authors
- Tino Hochepied (ORCID: https://orcid.org/0000-0001-5897-2054)
- Rachel Courtois
- Sofie Voet
- Sofie De Prijck
- Ilse Rogiers (ORCID: https://orcid.org/0000-0002-6478-0814)
- Hamida Hammad (ORCID: https://orcid.org/0000-0003-3762-8603)
- Christophe Desmet (ORCID: https://orcid.org/0000-0002-5723-2449)
- Séverine Augier
- António P. Baptista (ORCID: https://orcid.org/0000-0001-8182-8982)
- Éric Vivier (ORCID: https://orcid.org/0000-0001-7022-8287)
- Joseph Jorssen (ORCID: https://orcid.org/0000-0001-6247-906X)
- Justine Van Moorleghem (ORCID: https://orcid.org/0009-0000-6967-6269)
- Katrien Van der Borght
- Fabiane Sônego
- Karel Van Damme (ORCID: https://orcid.org/0000-0002-4379-1047)
- Victor Bosteels (ORCID: https://orcid.org/0000-0001-8838-021X)
- Stijn Vanhee (ORCID: https://orcid.org/0000-0001-5305-1651)
- Alan J. Korman (ORCID: https://orcid.org/0000-0002-1142-8542)
- Seppe De Winter (ORCID: https://orcid.org/0000-0001-7907-1247)
- A.J. Stein
- Ariane Morel
- Kader Thiam
- Dorine Sichien (ORCID: https://orcid.org/0000-0002-7298-3005)
- Jinke D’Hont
- Fabio Benigni (ORCID: https://orcid.org/0000-0002-1974-5606)
- Patricia Isnard Petit
- Clint De Nolf (ORCID: https://orcid.org/0000-0002-2033-1830)
- Sophie Janssens (ORCID: https://orcid.org/0000-0003-1702-1636)
- Stijn Verwaerde (ORCID: https://orcid.org/0000-0002-1398-8746)
- Katrien Quintelier (ORCID: https://orcid.org/0000-0001-5306-5615)
- Charlotte L. Scott (ORCID: https://orcid.org/0000-0003-4914-6580)
- Anna Bujko (ORCID: https://orcid.org/0000-0001-8693-9227)
- Anna Brotcke Zumsteg
- Sjoerd Schetters (ORCID: https://orcid.org/0000-0003-2589-4226)
- Bram Van Den Eeckhout (ORCID: https://orcid.org/0000-0002-6729-8951)
- Sofie Van Gassen (ORCID: https://orcid.org/0000-0002-7119-5330)
- Caihong Wang (ORCID: https://orcid.org/0000-0003-0817-7946)
- Davide Corti (ORCID: https://orcid.org/0000-0003-4046-7222)
- Yvan Saeys (ORCID: https://orcid.org/0000-0002-0415-1506)
- Bianca Balbino
- Robin Browaeys
- Niels Vandamme
- Michael A. Schmid
- Elisabeth De Leeuw
- Qingqing Chai
- Martijn J. Schuijs
- Bart N. Lambrecht
- Flore Thielemans
- Pieter De Bleser
Institutions
- HOGENT University of Applied Sciences and Arts (BE)
- Inserm (FR)
- University of Liège (BE)
- Ghent University Hospital (BE)
- Erasmus MC (NL)
- Ghent University (BE)
- Assistance Publique Hôpitaux de Marseille (FR)
- Vir Biotechnology (Switzerland) (CH)
- Genoway (France) (FR)
- Cancer Research Institute Ghent (BE)
- Pharmasum Therapeutics (Norway) (NO)
- VIB-UGent Center for Inflammation Research (BE)
- Innate Pharma (France) (FR)
- Centre d’Immunologie de Marseille-Luminy (FR)
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- Bluebird Bio (United States) (US)
- Argenx (Belgium) (BE)
- Hôpital de la Timone (FR)
- Singer (United States) (US)
- Erasmus University Rotterdam (NL)
- KU Leuven (BE)
Publication Details
- Journal
- Science Immunology
- Published
- 2026-01-30
- DOI
- https://doi.org/10.1126/sciimmunol.ady7328
- Citations
- 1
- Primary Topic
- Monoclonal and Polyclonal Antibodies Research
- Type
- article
- Field-Weighted Citation Impact
- 31.92