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

• DOI: 10.1126/sciadv.adu0718
• Publication Date: 2025-03-28T18:05:49Z
• Authors: Fangqiang Zhu; Saravanan Rajan; Conor F. Hayes; Ka Yin Kwong; Andre R. Goncalves; Adam T. Zemla; Edmond Y. Lau; Yi Zhang; Yingyun Cai; John W. Goforth; Mikel Landajuela; Pavlo Gilchuk; Michael Kierny; Andrew Dippel; Bismark Amofah; Gilad Kaplan; Vanessa Cadevilla...; Christopher Moreh...; Ben Sparklin; Vancheswaran Gopa...; Kevin M. Tuffy; Amy Nguyen; Jagadish Beloor; Gustavo Kijak; Chang Liu; Aiste Dijokaite-G...; Juthathip Mongkol...; Gavin R. Screaton; Brenden K. Petersen; Thomas A. Desautels; Drew Bennett; Simone Conti; Brent W. Segelke; Kathryn T. Arrildt; Samantha Kaul; Emilia A. Grzesiak; Felipe Leno da Silva; Thomas W. Bates; Christopher G. Ea...; Svetlana Hopkins; Shivshankar Sundaram; Mark T. Esser; Joseph R. Francica; Daniel M. Faissol
• Keywords: Robustness; 2019-20 coronavirus outbreak; Antibody response

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