PT  - JOURNAL ARTICLE
AU  - Marcus J. Bolton
AU  - Claudia P. Arevalo
AU  - Trevor Griesman
AU  - Shuk Hang Li
AU  - Paul Bates
AU  - Patrick C. Wilson
AU  - Scott E. Hensley
TI  - IgG3 subclass antibodies recognize antigenically drifted influenza viruses and SARS-CoV-2 variants through efficient bivalent binding
AID  - 10.1101/2022.09.27.509738
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.09.27.509738
4099  - http://biorxiv.org/content/early/2022/09/28/2022.09.27.509738.short
4100  - http://biorxiv.org/content/early/2022/09/28/2022.09.27.509738.full
AB  - The constant domains of antibodies are important for effector functions, but less is known about how they can affect binding and neutralization of viruses. Here we evaluated a panel of human influenza virus monoclonal antibodies (mAbs) expressed as IgG1, IgG2 or IgG3. We found that many influenza virus-specific mAbs have altered binding and neutralization capacity depending on the IgG subclass encoded, and that these differences result from unique bivalency capacities of the subclasses. Importantly, subclass differences in antibody binding and neutralization were greatest when the affinity for the target antigen was reduced through antigenic mismatch. We found that antibodies expressed as IgG3 bound and neutralized antigenically drifted influenza viruses more effectively. We obtained similar results using a panel of SARS-CoV-2-specific mAbs and the antigenically advanced B.1.351 strain of SARS-CoV-2. We found that a licensed therapeutic mAb retained neutralization breadth against SARS-CoV-2 variants when expressed as IgG3, but not IgG1. These data highlight that IgG subclasses are not only important for fine-tuning effector functionality, but also for binding and neutralization of antigenically drifted viruses.Significance Influenza viruses and coronaviruses undergo continuous change, successfully evading human antibodies elicited from prior infections or vaccinations. It is important to identify features that allow antibodies to bind with increased breadth. Here we examined the effect that different IgG subclasses have on monoclonal antibody binding and neutralization. We show that IgG subclass is a determinant of antibody breadth, with IgG3 affording increased neutralization of antigenically drifted variants of influenza virus and SARS-CoV-2. Future studies should evaluate IgG3 therapeutic antibodies and vaccination strategies or adjuvants that may skew antibody responses toward broadly reactive isotypes.Competing Interest StatementThe authors have declared no competing interest.