In vivo antibody diversification targeting a conserved coronavirus epitope
Name
jem_20241563.pdf
Description
Published version
Size
10.02 MB
Format
Adobe PDF
Checksum (MD5)
586d16f792f5819b7577c0f1182f7ead
Author(s)
Nair, Usha
Feng, Ziqi
Akauliya, Madhav
Esposito, Abigail G
Crain, Charles R
Lamperti, Edward D
Prum, Thavaleak
Warner, John E
Madungwe, Lisa
Dale, Gordon A
Date Issued
July 17, 2025
Journal
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Citation
Usha Nair, Ziqi Feng, Madhav Akauliya, Abigail G. Esposito, Charles R. Crain, Edward D. Lamperti, Thavaleak Prum, John E. Warner, Lisa Madungwe, Gordon A. Dale, Julie Boucau, Gaurav D. Gaiha, Meng Yuan, Ian A. Wilson, Facundo D. Batista; In vivo antibody diversification targeting a conserved coronavirus epitope. J Exp Med 6 October 2025; 222 (10): e20241563.
Version
Final published version
Abstract
To explore the use of human B cell receptor (BCR) knock-in mice for broadening antibody responses, we diversified CR3022, a monoclonal antibody (mAb) originally identified in a 2003 severe acute respiratory syndrome coronavirus (SARS-CoV) convalescent patient. This mAb targets a conserved epitope on the coronavirus receptor-binding domain (RBD). We took advantage of high- and low-affinity CR3022 BCR knock-in mice and immunized them with SARS-CoV-2 Wuhan RBD trimers to expand the breadth of these antibodies toward this virus. The resulting antibodies retained the ability to neutralize SARS-CoV and exhibited enhanced affinity and neutralization against the SARS-CoV-2 WA1/2020 strain, as well as the Delta (B.1.617.2) and Omicron KP.3 variants. They also showed broadened reactivity to two bat coronaviruses: WIV1 and, to a lesser potency, BtKY72. Structural analysis revealed key mutations that enhanced binding and neutralization, highlighting the importance of epitope accessibility and variant-specific conformations in antibody diversification. These findings demonstrate that human BCR-expressing mouse models can generate effective antibodies with broad neutralizing activity against viral epitopes.
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DOI of Published Version
https://doi.org/10.1084/jem.20241563
