Paired heavy- and light-chain signatures contribute to potent SARS-CoV-2 neutralization in public antibody responses

Cell Rep. 2021 Oct 5;37(1):109771. doi: 10.1016/j.celrep.2021.109771. Epub 2021 Sep 28.

Abstract

Understanding mechanisms of protective antibody recognition can inform vaccine and therapeutic strategies against SARS-CoV-2. We report a monoclonal antibody, 910-30, targeting the SARS-CoV-2 receptor-binding site for ACE2 as a member of a public antibody response encoded by IGHV3-53/IGHV3-66 genes. Sequence and structural analyses of 910-30 and related antibodies explore how class recognition features correlate with SARS-CoV-2 neutralization. Cryo-EM structures of 910-30 bound to the SARS-CoV-2 spike trimer reveal binding interactions and its ability to disassemble spike. Despite heavy-chain sequence similarity, biophysical analyses of IGHV3-53/3-66-encoded antibodies highlight the importance of native heavy:light pairings for ACE2-binding competition and SARS-CoV-2 neutralization. We develop paired heavy:light class sequence signatures and determine antibody precursor prevalence to be ∼1 in 44,000 human B cells, consistent with public antibody identification in several convalescent COVID-19 patients. These class signatures reveal genetic, structural, and functional immune features that are helpful in accelerating antibody-based medical interventions for SARS-CoV-2.

Keywords: B-cell; SARS-CoV-2; biotechnology; immunity; neutralization; public antibody; virology; yeast display.

Publication types

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

MeSH terms

  • Aged
  • Angiotensin-Converting Enzyme 2 / chemistry
  • Angiotensin-Converting Enzyme 2 / immunology*
  • Animals
  • Antibodies, Monoclonal / chemistry*
  • Antibodies, Monoclonal / genetics
  • Antibodies, Monoclonal / immunology*
  • Antibodies, Monoclonal / ultrastructure
  • Antibodies, Neutralizing / immunology
  • Antibodies, Viral / immunology
  • Antibody Formation
  • B-Lymphocytes / immunology
  • Binding Sites
  • COVID-19 / immunology*
  • COVID-19 / virology*
  • Chlorocebus aethiops
  • Cryoelectron Microscopy
  • HEK293 Cells
  • Humans
  • Immunoglobulin Heavy Chains / chemistry
  • Immunoglobulin Heavy Chains / genetics
  • Immunoglobulin Heavy Chains / immunology
  • Immunoglobulin Heavy Chains / ultrastructure
  • Immunoglobulin Light Chains / chemistry
  • Immunoglobulin Light Chains / genetics
  • Immunoglobulin Light Chains / immunology
  • Immunoglobulin Light Chains / ultrastructure
  • Male
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • SARS-CoV-2 / chemistry
  • SARS-CoV-2 / immunology*
  • Spike Glycoprotein, Coronavirus / chemistry
  • Spike Glycoprotein, Coronavirus / immunology*
  • Vero Cells

Substances

  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Immunoglobulin Heavy Chains
  • Immunoglobulin Light Chains
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2