An Engineered Antibody with Broad Protective Efficacy in Murine Models of SARS and COVID-19
Rappazzo, C. G.; Tse, L. V.; Kaku, C. I.; Wrapp, D.; Sakharkar, M.; Huang, D.; Deveau, L. M.; Yockachonis, T. J.; Herbert, A. S.; Battles, M. B.; O'Brien, C. M.; Brown, M. E.; Geoghegan, J. C.; Belk, J.; Peng, L.; Yang, L.; Scobey, T. D.; Burton, D. R.; Nemazee, D.; Dye, J. M.; Voss, J. E.; Gunn, B. M.; McLellan, J. S.; Baric, R. S.; Gralinski, L. E.; Walker, L. M.
Show abstract
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.
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