Abstract: Posted June 25, 2025 on bioRxiv. ; International audience ; The evolutionary trajectory of SARS-CoV-2 is shaped by competing pressures for ACE2 binding, structural viability, and escape from neutralizing antibodies targeting its receptor-binding domain (RBD). Here, we present EscapeMap, a modular framework that quantifies immune selection and predicts which antibodies are more or less likely to be escaped by future viral evolution. EscapeMap integrates deep mutational scanning data for ACE2 and 31 monoclonal antibodies with a generative sequence model trained on pre-pandemic Coronaviridae. To probe escape potential, we designed RBD variants under pressure from four clinically relevant antibodies (SA55, S2E12, S309, VIR-7229). Among these designs, bearing up to 21 mutations from wildtype, 50% expressed as stable proteins. Binding assays confirm that S309 and VIR-7229 retain recognition across diverse mutation combinations. EscapeMap accurately forecasts which antibodies are vulnerable to escape by our designed sequences. Finally, by identifying negatively correlated escape routes, we prioritize antibody combinations less prone to simultaneous escape, offering a quantitative basis for guiding therapeutic strategies.
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