Article
Author: Chen, Li ; Benzeno, Sharon ; Alter, Galit ; Gilbert, Amy E ; Sherwood, Anna ; Baldo, Lance ; Linkem, Charles ; Keitany, Gladys J ; Wilkins, Courtney ; Garrett, Meghan E ; Ebert, Peter ; Al-Asadi, Hussein ; Yusko, Erik ; Liang, Yu ; Harris, Rebecca ; Carbo, Adria ; Musa, Andrea ; Dines, Jennifer N ; Klinger, Mark ; Ching, Travers ; Liu, Chuanxin ; Rubin, Benjamin E R ; Tracy, Jeff ; Brown, Ryan ; Robins, Harlan S ; Guan, Jonathan ; Wang, Jiao ; Popov, Dimitry ; Atyeo, Caroline ; Day, Austin ; Li, Lianqu ; Moore, Amanda J ; Eggers, Erica ; Howie, Bryan ; Lescano, Ninnia
TruAB Discovery is an approach that integrates cellular immunology, high-throughput immunosequencing, bioinformatics, and computational biology in order to discover naturally occurring human antibodies for prophylactic or therapeutic use. We adapted our previously described pairSEQ technology to pair B cell receptor heavy and light chains of SARS-CoV-2 spike protein-binding antibodies derived from enriched antigen-specific memory B cells and bulk antibody-secreting cells. We identified approximately 60,000 productive, in-frame, paired antibody sequences, from which 2,093 antibodies were selected for functional evaluation based on abundance, isotype and patterns of somatic hypermutation. The exceptionally diverse antibodies included RBD-binders with broad neutralizing activity against SARS-CoV-2 variants, and S2-binders with broad specificity against betacoronaviruses and the ability to block membrane fusion. A subset of these RBD- and S2-binding antibodies demonstrated robust protection against challenge in hamster and mouse models. This high-throughput approach can accelerate discovery of diverse, multifunctional antibodies against any target of interest.