Conversion of a Viral Glycan Shield into a Binding Anchor via Causal-Driven Antibody Optimization
Wang, X.; Zhang, G.; Hu, M.; Han, J.; Shang, C.; Zhang, L.; Chen, Z.; Huang, P.; Wang, W.; Zhao, X.; Dong, Y.; Zhao, Y.; Lv, P.; Zai, X.; Jin, R.; Wang, H.; Wei, C.; Li, X.; Yan, L.; Lou, Z.; Ren, H.; Xu, J.; Chi, X.
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Therapeutic antibodies are challenged by rapidly evolving pathogens that exploit glycosylation to shield epitopes. SARS-CoV-2 JN.1 exemplifies this, escaping antibodies through the N354-linked glycan. However, targeting glycosylated epitopes remains vacant, as scarce and heterogeneous glycan structures render existing approaches ineffective. Here, we introduce the Antibody Evolution Nexus with Causal-Driven Simulation (AENCS), integrating molecular simulation with causal inference. Applying AENCS to restore S309 efficacy against JN.1, we identified ACC01, exhibiting [~]24-fold improved neutralization. With limited prior knowledge of the N354 glycosylation site, ACC01 stabilized this glycan conformation, facilitating the determination of its cryo-EM structure. Causal dissection revealed how this glycan shield is functionally inverted into a binding anchor through multi-layered interactions. This mechanistic conversion, combined with the conservation of N354 glycosylation, enabled ACC01 to maintain potent activity against the latest variant NB.1.8.1. Collectively, AENCS demonstrates causal-driven antibody engineering can illuminate cryptic glycosylated epitopes, providing viable paradigms for exploring this vacant frontier.
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