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Affinity of human IgG subclasses to mouse Fc gamma receptors.

ABSTRACT: Human IgG is the main antibody class used in antibody therapies because of its efficacy and longer half-life, which are completely or partly due to Fc?R-mediated functions of the molecules. Preclinical testing in mouse models are frequently performed using human IgG, but no detailed information on binding of human IgG to mouse Fc?Rs is available. The orthologous mouse and human Fc?Rs share roughly 60-70% identity, suggesting some incompatibility. Here, we report binding affinities of all mouse and human IgG subclasses to mouse Fc?R. Human IgGs bound to mouse Fc?R with remarkably similar binding strengths as we know from binding to human ortholog receptors, with relative affinities IgG3>IgG1>IgG4>IgG2 and Fc?RI>>Fc?RIV>Fc?RIII>Fc?RIIb. This suggests human IgG subclasses to have similar relative Fc?R-mediated biological activities in mice.

SUBMITTER: Dekkers G

PROVIDER: S-EPMC5524164 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Affinity of human IgG subclasses to mouse Fc gamma receptors.

Dekkers Gillian G Bentlage Arthur E H AEH Stegmann Tamara C TC Howie Heather L HL Lissenberg-Thunnissen Suzanne S Zimring James J Rispens Theo T Vidarsson Gestur G

mAbs 20170502 5

Human IgG is the main antibody class used in antibody therapies because of its efficacy and longer half-life, which are completely or partly due to FcγR-mediated functions of the molecules. Preclinical testing in mouse models are frequently performed using human IgG, but no detailed information on binding of human IgG to mouse FcγRs is available. The orthologous mouse and human FcγRs share roughly 60-70% identity, suggesting some incompatibility. Here, we report binding affinities of all mouse a ...[more]

PMID: 28463043

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Project description:The neonatal Fc receptor (FcRn) is a key membrane protein that plays an integral role in serum immunoglobulin (IgG) recycling, which extends the half-life of antibody. In addition, FcRn is known to traffic antigen-bound immunoglobulins (Ag-IgGs), and to interact with immune complexes to facilitate the antigen cross-presentation of peptides derived from the immune complexes in antigen-presenting cells (APCs). Studies on the IgG-FcRn molecular interactions have primarily focused on the Fc region, and only recently have shown the potential impact of the antigen-binding fragment physiochemical properties on FcRn binding. However, the effect of the antigen physiochemical properties on IgG structure as it relates to Ag-IgG-FcRn binding is not well understood. Here we used an IgG-peptide antigen complex as a model system to investigate the structural effects of the antigen's physiochemical properties on the IgG structure, and the subsequent effects of Ag-IgG-FcRn interactions. We used hydroxyl radical footprinting-mass spectrometry to investigate the structural impact on an IgG upon antigen binding, and observed that the physicochemical properties of the antigen differentially induce conformational changes in the IgG FcRn binding region. The extent of these structural changes directly correlates to the magnitude of the affinity differences between the Ag-IgG complexes and FcRn. Moreover, the antigen's physicochemical properties differentially induce structural differences within the Ag-IgG-FcRn ternary complex. We also provide electron microscopy data that shows corroborating Fab-FcRn interactions, and confirms the hypothesis of potential 2:1 FcRn:IgG binding stoichiometry. These data demonstrate antigen-induced Fc structural rearrangements affect both the affinity toward FcRn and the trimeric antigen-IgG-FcRn complex, providing novel molecular insights in the first steps toward understanding interactions of FcRn-containing large(r)-sized immune complex.

Dataset Information

Affinity of human IgG subclasses to mouse Fc gamma receptors.

Publications

Affinity of human IgG subclasses to mouse Fc gamma receptors.

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