Mouse model recapitulating human Fcγ receptor structural and functional diversity.

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Immunoglobulin G (IgG) antibodies possess bifunctional properties, with antigen recognition by the Fab fragment and effector functions mediated by the Fc domain.
• The diversity in the Fc domain, influenced by amino acid and glycan variations, dictates cellular responses via Fc gamma receptors (FcγRs).
• Species-specific differences in FcγRs limit the study of human IgG antibodies and their interactions in animal models.

Purpose of the Study:

• To develop a preclinical model for investigating human IgG antibody functions.
• To enable detailed mechanistic analysis of human IgG antibodies and their Fc engineered variants.
• To overcome limitations in studying human FcγR biology due to species diversity.

Main Methods:

• Generation of a genetically engineered mouse model lacking murine FcγRs.
• Introduction of human FcγRs into the mouse genome via transgenes.
• Validation of human FcγR expression and function in the engineered mice.

Main Results:

• The developed mouse model successfully recapitulates the human FcγR expression profile.
• Human FcγRs in the model mediate key biological activities of human IgG antibodies, including immunomodulation, inflammation, and cytotoxicity.
• Fc engineered variants of human IgG antibodies are also effectively mediated by the human FcγRs.

Conclusions:

• The novel mouse model provides a valuable platform for studying human IgG antibody mechanisms.
• This model facilitates the mechanistic analysis of both therapeutic and pathogenic human IgG antibodies.
• It opens new avenues for understanding FcγR-mediated immune responses involving human antibodies.