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Science
. 2021 Jan 25;eabf4830.
doi: 10.1126/science.abf4830. Online ahead of print.
Broad and potent activity against SARS-like viruses by an engineered human monoclonal antibody
C Garrett Rappazzo # 1 , Longping V Tse # 2 , Chengzi I Kaku 1 , Daniel Wrapp 3 , Mrunal Sakharkar 1 , Deli Huang 4 , Laura M Deveau 1 , Thomas J Yockachonis 5 , Andrew S Herbert 6 7 , Michael B Battles 1 , Cecilia M O'Brien 6 7 , Michael E Brown 1 , James C Geoghegan 1 , Jonathan Belk 1 , Linghang Peng 4 , Linlin Yang 4 , Yixuan Hou 2 , Trevor D Scobey 2 , Dennis R Burton 4 8 9 10 , David Nemazee 4 , John M Dye 6 , James E Voss 4 , Bronwyn M Gunn 5 , Jason S McLellan 3 , Ralph S Baric 11 12 , Lisa E Gralinski 11 , Laura M Walker 13 14
Affiliations
- PMID: 33495307
- DOI: 10.1126/science.abf4830
Abstract
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 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 high potency. Structural and biochemical studies demonstrate that ADG-2 employs a distinct angle of approach to recognize a highly conserved epitope overlapping 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.