Broad and potent activity against SARS-like viruses by an engineered human monoclonal antibody.
C Garrett RappazzoLongping V TseChengzi I KakuDaniel WrappMrunal SakharkarDeli HuangLaura M DeveauThomas J YockachonisAndrew S HerbertMichael B BattlesCecilia M O'BrienMichael E BrownJames C GeogheganJonathan BelkLinghang PengLinlin YangYixuan J HouTrevor D ScobeyDennis R BurtonDavid NemazeeJohn M DyeJames E VossBronwyn M GunnJason S MclellanRalph S BaricLisa E GralinskiLaura M WalkerPublished in: Science (New York, N.Y.) (2021)
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.