Modular basis for potent SARS-CoV-2 neutralization by a prevalent VH1-2-derived antibody class

Cell Rep. 2021 Apr 6;35(1):108950. doi: 10.1016/j.celrep.2021.108950. Epub 2021 Mar 19.

Abstract

Antibodies with heavy chains that derive from the VH1-2 gene constitute some of the most potent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing antibodies yet identified. To provide insight into whether these genetic similarities inform common modes of recognition, we determine the structures of the SARS-CoV-2 spike in complex with three VH1-2-derived antibodies: 2-15, 2-43, and H4. All three use VH1-2-encoded motifs to recognize the receptor-binding domain (RBD), with heavy-chain N53I-enhancing binding and light-chain tyrosines recognizing F486RBD. Despite these similarities, class members bind both RBD-up and -down conformations of the spike, with a subset of antibodies using elongated CDRH3s to recognize glycan N343 on a neighboring RBD-a quaternary interaction accommodated by an increase in RBD separation of up to 12 Å. The VH1-2 antibody class, thus, uses modular recognition encoded by modular genetic elements to effect potent neutralization, with the VH-gene component specifying recognition of RBD and the CDRH3 component specifying quaternary interactions.

Keywords: COVID-19; RBD; SARS-CoV-2; multi-donor antibody class; neutralizing antibody; quaternary recognition; spike.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antibodies, Neutralizing* / genetics
  • Antibodies, Neutralizing* / immunology
  • Antibodies, Viral* / genetics
  • Antibodies, Viral* / immunology
  • COVID-19* / genetics
  • COVID-19* / immunology
  • HEK293 Cells
  • Humans
  • Immunoglobulin Variable Region* / genetics
  • Immunoglobulin Variable Region* / immunology
  • SARS-CoV-2 / immunology*

Substances

  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Immunoglobulin Variable Region