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

Area of Science:

• Virology
• Immunology
• Structural Biology

Background:

• The emergence of SARS-CoV-2 necessitates rapid development of neutralizing monoclonal antibodies for prophylaxis and therapy.
• Existing antibodies may target related viruses but require adaptation for new viral strains.

Purpose of the Study:

• To engineer a SARS-CoV-1 neutralizing antibody (CR3022) to effectively neutralize SARS-CoV-2.
• To investigate the molecular mechanisms enabling antibody adaptation to related viruses.

Main Methods:

• Rapid affinity maturation of CR3022 to enhance binding to the SARS-CoV-2 receptor binding domain.
• In vitro neutralization assays and in vivo prophylactic protection studies in a small animal model.
• Deep sequencing and crystallographic analysis to elucidate antibody-epitope interactions.

Main Results:

• Engineered CR3022 exhibited >1000-fold increased affinity for SARS-CoV-2.
• The engineered antibody demonstrated neutralization of SARS-CoV-2 and provided prophylactic protection.
• Structural and sequencing data revealed mechanisms for accommodating epitope sequence differences.

Conclusions:

• Antibody engineering can refocus existing antibodies to neutralize newly emerged, related viruses.
• This workflow provides a blueprint for rapidly broadening antibody neutralization capabilities.
• The engineered CR3022 serves as a potential therapeutic candidate and guides vaccine design.