Genetic and structural basis for SARS-CoV-2 variant neutralization by a two-antibody cocktail

Area of Science:

• Immunology
• Structural Biology
• Virology

Background:

• Understanding SARS-CoV-2 spike glycoprotein recognition is crucial for developing effective therapeutics.
• The receptor-binding domain (RBD) is a key target for neutralizing antibodies.

Purpose of the Study:

• To determine the structural and genetic basis of neutralization by human monoclonal antibodies AZD8895 and AZD1061.
• To define the molecular interactions between these antibodies and the SARS-CoV-2 RBD.
• To map antibody binding sites and identify potential viral escape mechanisms.

Main Methods:

• X-ray crystallography to determine antibody-RBD complex structures.
• Deep mutational scanning to map antibody binding sites.
• Neutralization escape selection experiments to identify escape mutations.
• Analysis of antibody germ line-encoded features.

Main Results:

• Detailed structures of AZD8895 and AZD1061 in complex with the SARS-CoV-2 RBD were determined.
• Unique structural features, including an 'aromatic cage' in AZD8895 and a long LCDR1 in AZD1061, were identified.
• Crucial binding residues were mapped, and potential viral escape positions were identified.
• Both antibodies demonstrated strong neutralizing activity against SARS-CoV-2 and RBD-mutated variants.

Conclusions:

• Germ line-encoded antibody features are essential for recognizing the SARS-CoV-2 spike RBD.
• The antibody cocktail AZD7442 exhibits broad neutralizing activity against SARS-CoV-2 and its variants.
• These findings provide a molecular basis for designing next-generation antibody therapeutics.