Summary
Understanding protective mechanisms of antibody recognition can inform vaccine and therapeutic strategies against SARS-CoV-2. We discovered a new antibody, 910-30, that targets the SARS-CoV-2 ACE2 receptor binding site as a member of a public antibody response encoded by IGHV3-53/IGHV3-66 genes. We performed sequence and structural analyses to explore how antibody features correlate with SARS-CoV-2 neutralization. Cryo-EM structures of 910-30 bound to the SARS-CoV-2 spike trimer revealed its binding interactions and ability to disassemble spike. Despite heavy chain sequence similarity, biophysical analyses of IGHV3-53/3-66 antibodies highlighted the importance of native heavy:light pairings for ACE2 binding competition and for SARS-CoV-2 neutralization. We defined paired heavy:light sequence signatures and determined antibody precursor prevalence to be ~1 in 44,000 human B cells, consistent with public antibody identification in several convalescent COVID-19 patients. These data reveal key structural and functional neutralization features in the IGHV3-53/3-66 public antibody class to accelerate antibody-based medical interventions against SARS-CoV-2.
Highlights
A molecular study of IGHV3-53/3-66 public antibody responses reveals critical heavy and light chain features for potent neutralization
Cryo-EM analyses detail the structure of a novel public antibody class member, antibody 910-30, in complex with SARS-CoV-2 spike trimer
Cryo-EM data reveal that 910-30 can both bind assembled trimer and can disassemble the SARS-CoV-2 spike
Sequence-structure-function signatures defined for IGHV3-53/3-66 class antibodies including both heavy and light chains
IGHV3-53/3-66 class precursors have a prevalence of 1:44,000 B cells in healthy human antibody repertoires
Full Text Availability
The license terms selected by the author(s) for this preprint version do not permit archiving in PMC. The full text is available from the preprint server.