Fortuitous somatic mutations during antibody evolution endow broad neutralization against SARS-CoV-2 Omicron variants

Striking antibody evasion by emerging circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants drives the identification of broadly neutralizing antibodies (bNAbs). However, how a bNAb acquires increased neutralization breadth during antibody evolution is still elusive. Here, we identify a clonally related antibody family from a convalescent individual. One of the members, XG005, exhibits potent and broad neutralizing activities against SARS-CoV-2 variants, while the other members show significant reductions in neutralization breadth and potency, especially against the Omicron sublineages. Structural analysis visualizing the XG005-Omicron spike binding interface reveals how crucial somatic mutations endow XG005 with greater neutralization potency and breadth. A single administration of XG005 with extended half-life, reduced antibody-dependent enhancement (ADE) effect, and increased antibody product quality exhibits a high therapeutic efficacy in BA.2- and BA.5-challenged mice. Our results provide a natural example to show the importance of somatic hypermutation during antibody evolution for SARS-CoV-2 neutralization breadth and potency. [Display omitted] •XG005 antibody is a potent and broad neutralizer against SARS-CoV-2 variants•XG005 family members exhibit reduced neutralization potency and breadth•Structure analysis and comparison identify the key amino acid residues of XG005•Optimized XG005 exhibits a high therapeutic efficacy in vivo Wu et al. identify that XG005, but not its family members, is a potent and broad SARS-CoV-2 neutralizer and exhibits a high therapeutic efficacy. Structural analysis identifies the key residues of XG005. This provides a natural example to show the importance of somatic hypermutation for SARS-CoV-2 neutralization breadth and potency.