Protection by a broadly neutralizing monoclonal antibody to pandemic Influenza requires selective Fc receptor engagement (P4216)

Abstract

Abstract Neutralizing Abs against influenza viruses have traditionally been thought to provide protection by interfering with virus entry and/or fusion with host cells, events that rely solely on Ab variable region binding to viral spike proteins. However, the contributions of in vivo mechanisms conferred by Fc-Fc receptor (FcγR) interactions during protection by Ab remain unclear. We assessed the role of FcγRs during influenza virus neutralization in mice using mAbs directed to the HA antigen. We found that a broadly neutralizing mAb (bNAb) targeting the conserved stem region of HA confers protection to mice from lethal viral challenge, and required Fc-FcγR interactions for in vivo activity against both laboratory virus strains as well as the 2009 pandemic H1N1 virus. By contrast, a strain-specific mAb to the variable head domain of HA was equally protective both in the presence or absence of FcγR interactions. We then generated a chimeric human IgG1 Fc version of the anti-stem bNAb, modified to selectively enhance human activating FcγR engagement. We utilized FcγR-humanized mice, which express all human FcγRs on a genetic background lacking mouse FcγRs, to demonstrate augmented protection by the modified bNAb compared to wild type bNAb. Thus, Fc-FcγR interactions are required for bNAb-mediated protection and can be manipulated for optimal protection in vivo. These findings represent a general approach towards enhancing bNAb-mediated protection and warrant clinical investigation.