Structural insights into human monoclonal antibodies with pan-coronavirus reactivity

Human monoclonal antibodies from convalescent individuals that target the SARS-CoV-2 spike protein have been deployed as therapeutics against SARS-CoV-2. However, the emergence of SARS-CoV-2 variants have diminished the efficacy of almost all antiviral monoclonal antibodies. Moreover, most SARS-CoV-2 specific antibodies are inactive against divergent sarbecoviruses and the larger Orthocoronavirinae subfamily. Thus, continued development of immunotherapies resilient to SARS-CoV-2 viral evolution, and capable of recognizing zoonotic coronaviruses with spillover potential is necessary. Using coldspot-guided antibody discovery, a screening approach that focuses on portions of the virus spike glycoprotein that are both functionally relevant and averse to change, we identified human neutralizing antibodies to highly conserved viral epitopes. We identified and structurally-characterized neutralizing antibodies to the fusion peptide, to the stem helix near the heptad repeat 2 region and to subdomain 1 of the spike glycoprotein, that are broadly cross-reactive and protective in vivo. Collectively, our data adds to the growing body of evidence suggesting the potential use of broadly neutralizing antibodies for prophylaxis or therapy against emerging SARS-CoV-2 VOC and future zoonotic spillover events. C.O.B. is supported by the Howard Hughes Medical Institute Hanna Gray Fellowship and is a Chan Zuckerberg Biohub investigator.