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

Bailey B Banach; Gabriele Cerutti; Ahmed S Fahad; Chen-Hsiang Shen; Matheus Oliveira De Souza; Phinikoula S Katsamba; Yaroslav Tsybovsky; Pengfei Wang; Manoj S Nair; Yaoxing Huang; Irene M Francino-Urdániz; Paul J Steiner; Matías Gutiérrez-González; Lihong Liu; Sheila N López Acevedo; Alexandra F Nazzari; Jacy R Wolfe; Yang Luo; Adam S Olia; I-Ting Teng; Jian Yu; Tongqing Zhou; Eswar R Reddem; Jude Bimela; Xiaoli Pan; Bharat Madan; Amy D Laflin; Rajani Nimrania; Kwok-Yung Yuen; Timothy A Whitehead; David D Ho; Peter D Kwong; Lawrence Shapiro; Brandon J DeKosky

doi:10.1016/j.celrep.2021.109771

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.

Authors

Bailey B Banach¹, Gabriele Cerutti², Ahmed S Fahad³, Chen-Hsiang Shen⁴, Matheus Oliveira De Souza³, Phinikoula S Katsamba², Yaroslav Tsybovsky⁵, Pengfei Wang⁶, Manoj S Nair⁶, Yaoxing Huang⁶, Irene M Francino-Urdániz⁷, Paul J Steiner⁷, Matías Gutiérrez-González³, Lihong Liu⁶, Sheila N López Acevedo³, Alexandra F Nazzari⁴, Jacy R Wolfe³, Yang Luo⁶, Adam S Olia⁴, I-Ting Teng⁴, Jian Yu⁸, Tongqing Zhou⁴, Eswar R Reddem², Jude Bimela², Xiaoli Pan³, Bharat Madan³, Amy D Laflin³, Rajani Nimrania³, Kwok-Yung Yuen⁹, Timothy A Whitehead⁷, David D Ho⁶, Peter D Kwong¹⁰, Lawrence Shapiro¹¹, Brandon J DeKosky¹²

Affiliations

¹ Bioengineering Graduate Program, University of Kansas, Lawrence, KS 66045, USA.
² Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA.
³ Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66045, USA.
⁴ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
⁶ Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
⁷ Department of Chemical and Biological Engineering, University of Colorado, Boulder, CO 80305, USA.
⁸ Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
⁹ State Key Laboratory for Emerging Infectious Diseases, Department of Microbiology, Carol Yu Centre for Infection, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Microbiology, Queen Mart Hospital, Hong Kong Special Administrative Region, China; Department of Clinical Microbiology and Infection Control, University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
¹⁰ Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
¹¹ Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA. Electronic address: lss8@columbia.edu.
¹² Bioengineering Graduate Program, University of Kansas, Lawrence, KS 66045, USA; Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66045, USA; Department of Chemical Engineering, University of Kansas, Lawrence, KS 66045, USA. Electronic address: dekosky@ku.edu.

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding