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

• Published in: Cell reports (Cambridge) 2021-10, Vol.37 (1), p.109771-109771, Article 109771
• Main Authors: Banach, Bailey B., Cerutti, Gabriele, Fahad, Ahmed S., Shen, Chen-Hsiang, Oliveira De Souza, Matheus, Katsamba, Phinikoula S., Tsybovsky, Yaroslav, Wang, Pengfei, Nair, Manoj S., Huang, Yaoxing, Francino-Urdániz, Irene M., Steiner, Paul J., Gutiérrez-González, Matías, Liu, Lihong, López Acevedo, Sheila N., Nazzari, Alexandra F., Wolfe, Jacy R., Luo, Yang, Olia, Adam S., Teng, I-Ting, Yu, Jian, Zhou, Tongqing, Reddem, Eswar R., Bimela, Jude, Pan, Xiaoli, Madan, Bharat, Laflin, Amy D., Nimrania, Rajani, Yuen, Kwok-Yung, Whitehead, Timothy A., Ho, David D., Kwong, Peter D., Shapiro, Lawrence, DeKosky, Brandon J.
• Format: Article
• Language: English
• Subjects: 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-cell; B-Lymphocytes - immunology; Binding Sites; biotechnology; Chlorocebus aethiops; COVID-19 - immunology; COVID-19 - virology; Cryoelectron Microscopy; HEK293 Cells; Humans; immunity; 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; neutralization; Protein Binding; Protein Interaction Domains and Motifs; public antibody; SARS-CoV-2; SARS-CoV-2 - chemistry; SARS-CoV-2 - immunology; Spike Glycoprotein, Coronavirus - chemistry; Spike Glycoprotein, Coronavirus - immunology; Vero Cells; virology; yeast display
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109771

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. [Display omitted] •Paired heavy:light-chain antibody features drive potent IGHV3-53/3-66 neutralization•Cryo-EM analyses reveal 910-30 can bind and disassemble SARS-CoV-2 spike•Sequence-structure-function signatures for IGHV3-53/3-66 antibodies•Class precursor prevalence is ∼1:44,000 B cells in healthy human repertoires Banach et al. report a SARS-CoV-2 neutralizing antibody along with genetic, structural, and functional features of public antibody responses targeting SARS-CoV-2. These data reveal how structural interactions with the SARS-CoV-2 receptor-binding domain correlate with viral neutralization and demonstrate the importance of native antibody heavy:light pairings in convergent antibody responses.