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Broadening a SARS-CoV-1 neutralizing antibody for potent SARS-CoV-2 neutralization through directed evolution

By Fangzhu Zhao, Meng Yuan, Celina Keating, Namir Shabaani, Oliver Limbo, Collin Joyce, Jordan Woehl, Shawn Barman, Alison Burns, Xueyong Zhu, Michael Ricciardi, Linghang Peng, Jessica Smith, Deli Huang, Bryan Briney, Devin Sok, David Nemazee, John Teiijaro, Ian A. Wilson, Dennis Burton, Joseph G Jardine

Posted 30 May 2021
bioRxiv DOI: 10.1101/2021.05.29.443900

The emergence of SARS-CoV-2 underscores the need for strategies to rapidly develop neutralizing monoclonal antibodies that can function as prophylactic and therapeutic agents and to help guide vaccine design. Here, we demonstrate that engineering approaches can be used to refocus an existing neutralizing antibody to a related but resistant virus. Using a rapid affinity maturation strategy, we engineered CR3022, a SARS-CoV-1 neutralizing antibody, to bind SARS-CoV-2 receptor binding domain with >1000-fold improved affinity. The engineered CR3022 neutralized SARS-CoV-2 and provided prophylactic protection from viral challenge in a small animal model of SARS-CoV-2 infection. Deep sequencing throughout the engineering process paired with crystallographic analysis of an enhanced antibody elucidated the molecular mechanisms by which engineered CR3022 can accommodate sequence differences in the epitope between SARS-CoV-1 and SARS-CoV-2. The workflow described provides a blueprint for rapid broadening of neutralization of an antibody from one virus to closely related but resistant viruses.

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