Structural basis for broad neutralization of human antibody against Omicron sublineages and evasion by XBB variant.

The continuous emergence of SARS-CoV-2 variants, particularly the newly circulating Omicron XBB subvariants, has led to a significant reduction in the neutralizing potency and breadth of antibodies. In this study, we report a SARS-CoV-2 human neutralizing antibody, 1G11, which potently and broadly neutralizes diverse variants, including Omicron subvariants BA.4/5 and BF.7, but is evaded by the recently emerged BQ.1.1 and XBBs. Cryo-electron microscopy structure analysis of the 1G11 in complex with the BA.4/5 spike trimer reveals that 1G11, a Class 3 nAb, recognizes an epitope similar to those of S309 and LY-CoV1404. Structurally, the mutations K444T and V445P in BQ.1.1 and XBB subvariants are found to disrupt the interface between 1G11 and the spike protein, resulting in antibody evasion. 1G11 is further demonstrated to mediate neutralization through multiple mechanisms, including receptor binding blockage, interspike cross-linking, Fc-mediated ADCC and ADCP. Collectively, these findings provide insights into a better understanding of neutralizing antibody evasion and highlight the potential for broad neutralization by structure-based modification of available antibodies. [ABSTRACT FROM AUTHOR]