Potent neutralization of SARS-CoV-2 variants of concern by an antibody with an uncommon genetic signature and structural mode of spike recognition

• Published in: Cell reports (Cambridge) Vol. 37; no. 1; p. 109784
• Main Authors: Kramer, Kevin J., Johnson, Nicole V., Shiakolas, Andrea R., Suryadevara, Naveenchandra, Periasamy, Sivakumar, Raju, Nagarajan, Williams, Jazmean K., Wrapp, Daniel, Zost, Seth J., Walker, Lauren M., Wall, Steven C., Holt, Clinton M., Hsieh, Ching-Lin, Sutton, Rachel E., Paulo, Ariana, Nargi, Rachel S., Davidson, Edgar, Doranz, Benjamin J., Crowe, James E., Bukreyev, Alexander, Carnahan, Robert H., McLellan, Jason S., Georgiev, Ivelin S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.10.2021; The Author(s); Elsevier
• Subjects: Angiotensin-Converting Enzyme 2 - chemistry; Angiotensin-Converting Enzyme 2 - immunology; Animals; Antibodies, Monoclonal - immunology; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; antibody discovery; Antibody Formation; Cell Line; Chlorocebus aethiops; COVID-19; COVID-19 - genetics; COVID-19 - immunology; COVID-19 - virology; cryo-EM; Cryoelectron Microscopy; Delta variant; Epitope Mapping - methods; Epitopes - chemistry; Epitopes - immunology; High-Throughput Screening Assays - methods; Humans; LIBRA-seq; Male; Middle Aged; monoclonal antibodies biology; Protein Binding; Protein Interaction Domains and Motifs; Receptors, Antigen, B-Cell - chemistry; Receptors, Antigen, B-Cell - immunology; SARS-CoV-2; SARS-CoV-2 - chemistry; SARS-CoV-2 - genetics; SARS-CoV-2 - immunology; Spike Glycoprotein, Coronavirus - chemistry; Spike Glycoprotein, Coronavirus - immunology; Vero Cells; COVID-19; SARS-CoV-2; monoclonal antibodies biology; antibody discovery; Delta variant; cryo-EM; LIBRA-seq
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109784

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages that are more transmissible and resistant to currently approved antibody therapies poses a considerable challenge to the clinical treatment of coronavirus disease (COVID-19). Therefore, the need for ongoing discovery efforts to identify broadly reactive monoclonal antibodies to SARS-CoV-2 is of utmost importance. Here, we report a panel of SARS-CoV-2 antibodies isolated using the linking B cell receptor to antigen specificity through sequencing (LIBRA-seq) technology from an individual who recovered from COVID-19. Of these antibodies, 54042-4 shows potent neutralization against authentic SARS-CoV-2 viruses, including variants of concern (VOCs). A cryoelectron microscopy (cryo-EM) structure of 54042-4 in complex with the SARS-CoV-2 spike reveals an epitope composed of residues that are highly conserved in currently circulating SARS-CoV-2 lineages. Further, 54042-4 possesses uncommon genetic and structural characteristics that distinguish it from other potently neutralizing SARS-CoV-2 antibodies. Together, these findings provide motivation for the development of 54042-4 as a lead candidate to counteract current and future SARS-CoV-2 VOCs. [Display omitted] •LIBRA-seq identifies 54042-4, a potently neutralizing SARS-CoV-2 antibody•54042-4 maintains potent neutralization against Alpha, Beta, Gamma, and Delta VOCs•The epitope of 54042-4 is highly conserved among current SARS-CoV-2 isolates Kramer et al. demonstrate that antibody 54042-4 recognizes residues highly conserved across global SARS-CoV-2 isolates. Antibody 54042-4 potently neutralizes all known circulating variants of concern (VOCs) and could be developed as a clinical candidate to treat COVID-19 infection.