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.

doi:10.1101/2020.11.17.385500

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bioRxiv · 10.1101/2020.11.17.385500

An Engineered Antibody with Broad Protective Efficacy in Murine Models of SARS and COVID-19

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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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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.. 2020-11-17. An Engineered Antibody with Broad Protective Efficacy in Murine Models of SARS and COVID-19. https://doi.org/10.1101/2020.11.17.385500

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