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

• Main Authors: 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
• Format: Article
• Language: English
• Published: Elsevier 2021-10-01
• Series: Cell Reports
• Subjects: SARS-CoV-2; public antibody; neutralization; yeast display; B-cell; biotechnology
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124721012250
• ISSN: 2211-1247

Summary: 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.