Preemptive optimization of a clinical antibody for broad neutralization of SARS-CoV-2 variants and robustness against viral escape.

Most previously authorized clinical antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have lost neutralizing activity to recent variants due to rapid viral evolution. To mitigate such escape, we preemptively enhance AZD3152, an antibody authorized for prophylaxis in immunocompromised individuals. Using deep mutational scanning (DMS) on the SARS-CoV-2 antigen, we identify AZD3152 vulnerabilities at antigen positions F456 and D420. Through two iterations of computational antibody design that integrates structure-based modeling, machine-learning, and experimental validation, we co-optimize AZD3152 against 24 contemporary and previous SARS-CoV-2 variants, as well as 20 potential future escape variants. Our top candidate, 3152-1142, restores full potency (100-fold improvement) against the more recently emerged XBB.1.5+F456L variant that escaped AZD3152, maintains potency against previous variants of concern, and shows no additional vulnerability as assessed by DMS. This preemptive mitigation demonstrates a generalizable approach for optimizing existing antibodies against potential future viral escape.