tetano
Editor, Senior Moderator
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[SUP] #[/SUP][SUP] 1 [/SUP], Longping V Tse[SUP] #[/SUP][SUP] 2 [/SUP], Chengzi I Kaku[SUP] 1 [/SUP], Daniel Wrapp[SUP] 3 [/SUP], Mrunal Sakharkar[SUP] 1 [/SUP], Deli Huang[SUP] 4 [/SUP], Laura M Deveau[SUP] 1 [/SUP], Thomas J Yockachonis[SUP] 5 [/SUP], Andrew S Herbert[SUP] 6 7 [/SUP], Michael B Battles[SUP] 1 [/SUP], Cecilia M O'Brien[SUP] 6 7 [/SUP], Michael E Brown[SUP] 1 [/SUP], James C Geoghegan[SUP] 1 [/SUP], Jonathan Belk[SUP] 1 [/SUP], Linghang Peng[SUP] 4 [/SUP], Linlin Yang[SUP] 4 [/SUP], Yixuan Hou[SUP] 2 [/SUP], Trevor D Scobey[SUP] 2 [/SUP], Dennis R Burton[SUP] 4 8 9 10 [/SUP], David Nemazee[SUP] 4 [/SUP], John M Dye[SUP] 6 [/SUP], James E Voss[SUP] 4 [/SUP], Bronwyn M Gunn[SUP] 5 [/SUP], Jason S McLellan[SUP] 3 [/SUP], Ralph S Baric[SUP] 11 12 [/SUP], Lisa E Gralinski[SUP] 11 [/SUP], Laura M Walker[SUP] 13 14 [/SUP]
Affiliations
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.
. 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[SUP] #[/SUP][SUP] 1 [/SUP], Longping V Tse[SUP] #[/SUP][SUP] 2 [/SUP], Chengzi I Kaku[SUP] 1 [/SUP], Daniel Wrapp[SUP] 3 [/SUP], Mrunal Sakharkar[SUP] 1 [/SUP], Deli Huang[SUP] 4 [/SUP], Laura M Deveau[SUP] 1 [/SUP], Thomas J Yockachonis[SUP] 5 [/SUP], Andrew S Herbert[SUP] 6 7 [/SUP], Michael B Battles[SUP] 1 [/SUP], Cecilia M O'Brien[SUP] 6 7 [/SUP], Michael E Brown[SUP] 1 [/SUP], James C Geoghegan[SUP] 1 [/SUP], Jonathan Belk[SUP] 1 [/SUP], Linghang Peng[SUP] 4 [/SUP], Linlin Yang[SUP] 4 [/SUP], Yixuan Hou[SUP] 2 [/SUP], Trevor D Scobey[SUP] 2 [/SUP], Dennis R Burton[SUP] 4 8 9 10 [/SUP], David Nemazee[SUP] 4 [/SUP], John M Dye[SUP] 6 [/SUP], James E Voss[SUP] 4 [/SUP], Bronwyn M Gunn[SUP] 5 [/SUP], Jason S McLellan[SUP] 3 [/SUP], Ralph S Baric[SUP] 11 12 [/SUP], Lisa E Gralinski[SUP] 11 [/SUP], Laura M Walker[SUP] 13 14 [/SUP]
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.