An Engineered Antibody with Broad Protective Efficacy in Murine Models of SARS and COVID-19

Rappazzo, C. Garrett; Tse, Longping V.; Kaku, Chengzi I.; Wrapp, Daniel; Sakharkar, Mrunal; Huang, Deli; Deveau, Laura M.; Yockachonis, Thomas J.; Herbert, Andrew S.; Battles, Michael B.; O’Brien, Cecilia M.; Brown, Michael E.; Geoghegan, James C.; Belk, Jonathan; Peng, Linghang; Yang, Linlin; Scobey, Trevor D.; Burton, Dennis R.; Nemazee, David; Dye, John M.; Voss, James E.; Gunn, Bronwyn M.; McLellan, Jason S.; Baric, Ralph S.; Gralinski, Lisa E.; Walker, Laura M.

The recurrent zoonotic spillover of coronaviruses (CoVs) into the human population underscores the need for broadly active countermeasures. Here, we employed a directed evolution approach to engineer three SARS-CoV-2 antibodies for enhanced neutralization breadth and potency. One of the affinity-matured variants, ADG-2, displays strong binding activity to a large panel of sarbecovirus receptor binding domains (RBDs) and neutralizes representative epidemic sarbecoviruses with remarkable potency. Structural and biochemical studies demonstrate that ADG-2 employs a unique angle of approach to recognize a highly conserved epitope overlapping the receptor binding site. In murine models of SARS-CoV and SARS-CoV-2 infection, passive transfer of ADG-2 provided complete protection against respiratory burden, viral replication in the lungs, and lung pathology. Altogether, ADG-2 represents a promising broad-spectrum therapeutic candidate for the treatment and prevention of SARS-CoV-2 and future emerging SARS-like CoVs.