Conversion of a Viral Glycan Shield into a Binding Anchor via Causal-Driven Antibody Optimization

Authors

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.

Abstract

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.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 28 Jun 2026.

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