Broadly neutralizing hemagglutinin stalk–specific antibodies require FcγR interactions for protection against influenza virus in vivo

By D. DiLillo, G. Tan, P. Palese, J. Ravetch. Nature Medicine, 2014

757 citations recorded by the source corpus.

Neutralizing antibodies against influenza viruses have traditionally been thought to provide protection exclusively through their variable region; the contributions of mechanisms conferred by the Fc domain remain controversial. We investigated the in vivo contributions of Fc interactions with their cognate receptors for a collection of neutralizing anti-influenza antibodies. Whereas five broadly neutralizing monoclonal antibodies (bNAbs) targeting the conserved stalk region of hemagglutinin (HA) required interactions between the antibody Fc and Fc receptors for IgG (FcγRs) to confer protection from lethal H1N1 challenge, three strain-specific monoclonal Abs (mAbs) against the variable head domain of HA were equally protective in the presence or absence of FcγR interactions. Although all antibodies blocked infection, only anti-stalk bNAbs were capable of mediating cytotoxicity of infected cells, which accounts for their FcγR dependence. Immune complexes generated with anti–HA stalk mAb efficiently interacted with FcγRs, but anti–HA head immune complexes did not. These results suggest that FcγR binding capacity by anti-HA antibodies was dependent on the interaction of the cognate Fab with antigen. We exploited these disparate mechanisms of mAb-mediated protection to reengineer an anti-stalk bNAb to selectively enhance FcγR engagement to augment its protective activity. These findings reveal a previously uncharacterized property of bNAbs and guide an approach toward enhancing mAb-mediated antiviral therapeutics.

Subfields: Epidemiology, Immunology, Radiology, Nuclear Medicine and Imaging

View Paper: https://www.semanticscholar.org/paper/2aaf1968e38c42d663bf237dca0022cf75422a8a

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Citations in the corpus

Neutralizing and protective human monoclonal antibodies recognizing the N-terminal domain of the SARS-CoV-2 spike protein (2021, background): “IgG interactions with Fcg receptors and complement contribute to antibody-dependent viral clearance during many infections, including HIV-1, Ebola, influenza, and chikungunya viruses (DiLillo et al., 2014; Fox et al., 2019; Halper-Stromberg et al., 2014; Lu et al., 2016).”
Antibody Structure and Function: The Basis for Engineering Therapeutics (2019, background): “The molecule was designed to have an active Fc region to utilize ADCC activity that could contribute to in vivo activity [554].”
Structure and Function Analysis of an Antibody Recognizing All Influenza A Subtypes (2016, background): “Anti-stem antibodies are less potent at direct viral neutralization as compared to antihead antibodies, but were shown to induce potent antibodydependent cellular cytotoxicity (ADCC) of infected cells in vitro and in vivo (Corti et al., 2011; Dilillo et al., 2016; DiLillo et al., 2014), while anti-h”