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

• DOI: 10.1126/scisignal.abk3516
• Publication Date: 2023-08-15T17:58:05Z
• Authors: Fangzhu Zhao; Meng Yuan; Celina Keating; Namir Shaabani; Oliver Limbo; Collin Joyce; Jordan Woehl; Shawn Barman; Alison Burns; Quoc Tran; Xueyong Zhu; Michael Ricciardi; Linghang Peng; Jessica Smith; Deli Huang; Bryan Briney; Devin Sok; David Nemazee; John R. Teijaro; Ian A. Wilson; Dennis R. Burton; Joseph G. Jardine
• Keywords: Antibody-dependent enhancement; Coronavirus

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) underscores the need for strategies to rapidly develop neutralizing monoclonal antibodies that can function as prophylactic and therapeutic agents help guide vaccine design. Here, we demonstrate engineering approaches be used refocus an existing antibody neutralizes one virus but not a related virus. Through rapid affinity maturation strategy, engineered CR3022, SARS-CoV-1–neutralizing antibody, bind receptor binding domain SARS-CoV-2 with >1000-fold increased affinity. CR3022 neutralized provided protection from viral challenge in small animal model infection. Deep sequencing throughout process paired crystallographic analysis elucidated molecular mechanisms by which accommodate sequence differences epitopes between SARS-CoV-1 SARS-CoV-2. This workflow provides blueprint broadening neutralization closely resistant viruses.