LY-CoV555 for COVID-19

Since the emergence of SARS-CoV-2, understanding how antibodies recognize and adapt to viral evolution has been central to vaccine and therapeutic developments. To date, over 1,100 SARS-CoV-2 antibody structures, 16% of all known antibody-antigen complexes, have been resolved, marking the largest structural biology effort towards a single pathogen. Here, we present a comprehensive analysis of this landmark dataset to investigate the principles of antibody recognition and immune escape. Human immunoglobulins (IgGs) and camelid single-chain antibodies dominate the dataset, collectively mapping 99% of the receptor-binding domain surface. Despite remarkable sequence and conformational diversity, antibodies exhibit striking convergence in their paratope structures, revealing evolutionary constraints in epitope selection. Structural and functional analyses reveal near-universal immune escape of antibodies, including all clinical monoclonals, by advanced variants such as KP3.1.1. On average, over one-third of antibody epitope residues are mutated. These findings support pervasive immune escape, underscoring the need to effectively leverage multi-epitope targeting strategies to achieve durable immunity.

The rapid evolution of SARS-CoV-2 has led to the emergence of variants with increased immune evasion capabilities, posing significant challenges to antibody-based therapeutics and vaccines. In this study, we conducted a comprehensive structural and energetic analysis of SARS-CoV-2 spike receptor-binding domain (RBD) complexes with neutralizing antibodies from four distinct groups (A–D), including group A LY-CoV016, group B AZD8895 and REGN10933, group C LY-CoV555, and group D antibodies AZD1061, REGN10987, and LY-CoV1404. Using coarse-grained simplified simulation models, rapid energy-based mutational scanning, and rigorous MM-GBSA binding free energy calculations, we elucidated the molecular mechanisms of antibody binding and escape mechanisms, identified key binding hotspots, and explored the evolutionary strategies employed by the virus to evade neutralization. The residue-based decomposition analysis revealed energetic mechanisms and thermodynamic factors underlying the effect of mutations on antibody binding. The results demonstrate excellent qualitative agreement between the predicted binding hotspots and the latest experiments on antibody escape. These findings provide valuable insights into the molecular determinants of antibody binding and viral escape, highlighting the importance of targeting conserved epitopes and leveraging combination therapies to mitigate the risk of immune evasion.