Broad and potent activity against SARS-like viruses by an engineered human monoclonal antibody

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; Hou, Yixuan; 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. We employed a directed evolution approach to engineer three severe acute respiratory syndrome coronavirus 2 (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 and neutralizes representative epidemic sarbecoviruses with high potency. Structural and biochemical studies demonstrate that ADG-2 employs a distinct angle of approach to recognize a highly conserved epitope that overlaps the receptor binding site. In immunocompetent mouse models of SARS and COVID-19, prophylactic administration 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 against clade 1 sarbecoviruses.