A potent pan-sarbecovirus neutralizing antibody resilient to epitope diversification Journal Article
| Authors: | Rosen, L. E.; Tortorici, M. A.; De Marco, A.; Pinto, D.; Foreman, W. B.; Taylor, A. L.; Park, Y. J.; Bohan, D.; Rietz, T.; Errico, J. M.; Hauser, K.; Dang, H. V.; Chartron, J. W.; Giurdanella, M.; Cusumano, G.; Saliba, C.; Zatta, F.; Sprouse, K. R.; Addetia, A.; Zepeda, S. K.; Brown, J.; Lee, J.; Dellota, E. Jr; Rajesh, A.; Noack, J.; Tao, Q.; DaCosta, Y.; Tsu, B.; Acosta, R.; Subramanian, S.; de Melo, G. D.; Kergoat, L.; Zhang, I.; Liu, Z.; Guarino, B.; Schmid, M. A.; Schnell, G.; Miller, J. L.; Lempp, F. A.; Czudnochowski, N.; Cameroni, E.; Whelan, S. P. J.; Bourhy, H.; Purcell, L. A.; Benigni, F.; di Iulio, J.; Pizzuto, M. S.; Lanzavecchia, A.; Telenti, A.; Snell, G.; Corti, D.; Veesler, D.; Starr, T. N. |
| Article Title: | A potent pan-sarbecovirus neutralizing antibody resilient to epitope diversification |
| Abstract: | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution has resulted in viral escape from clinically authorized monoclonal antibodies (mAbs), creating a need for mAbs that are resilient to epitope diversification. Broadly neutralizing coronavirus mAbs that are sufficiently potent for clinical development and retain activity despite viral evolution remain elusive. We identified a human mAb, designated VIR-7229, which targets the viral receptor-binding motif (RBM) with unprecedented cross-reactivity to all sarbecovirus clades, including non-ACE2-utilizing bat sarbecoviruses, while potently neutralizing SARS-CoV-2 variants since 2019, including the recent EG.5, BA.2.86, and JN.1. VIR-7229 tolerates extraordinary epitope variability, partly attributed to its high binding affinity, receptor molecular mimicry, and interactions with RBM backbone atoms. Consequently, VIR-7229 features a high barrier for selection of escape mutants, which are rare and associated with reduced viral fitness, underscoring its potential to be resilient to future viral evolution. VIR-7229 is a strong candidate to become a next-generation medicine. © 2024 The Author(s) |
| Keywords: | immunohistochemistry; adult; controlled study; human tissue; unclassified drug; gene mutation; human cell; genetics; nonhuman; binding affinity; polymerase chain reaction; animal cell; animal; metabolism; animals; animal tissue; reverse transcription polymerase chain reaction; molecular dynamics; animal experiment; animal model; in vivo study; immunofluorescence; in vitro study; virology; monoclonal antibody; immunology; antibodies, monoclonal; chemistry; amino acid sequence; virus rna; sequence alignment; epitope; dna sequence; hydrogen bond; virus load; cross reaction; surface plasmon resonance; static electricity; virus genome; virus strain; fluorescence activated cell sorting; peripheral blood mononuclear cell; polyacrylamide gel electrophoresis; antibody dependent cellular cytotoxicity; ketamine; phylogeny; epitopes; crystallography; virus inhibition; immune evasion; neutralizing antibody; antibodies, neutralizing; limit of detection; pandemic; antibodies, viral; virus antibody; virus neutralization; size exclusion chromatography; machine learning; cross reactions; density gradient centrifugation; high throughput sequencing; bat; chiroptera; humans; human; male; article; broadly neutralizing antibody; syrian hamster; xylazine; severe acute respiratory syndrome coronavirus 2; coronavirus disease 2019; covid-19; angiotensin converting enzyme 2; sars-cov-2; angiotensin-converting enzyme 2; coronavirus spike glycoprotein; spike protein, sars-cov-2; spike glycoprotein, coronavirus; coronaviridae; sars-cov-2 omicron; memory b lymphocyte; sars-cov-2 variants; sarbecovirus; viral antibody escape; vir 7229 monoclonal antibody; cho-k1 cell line; hep-2 cell line; rhinolophus; rhinolophus cornutus; sars-cov-2 (s protein) pseudotyped vsv; vero c1008 cell line |
| Journal Title: | Cell |
| Volume: | 187 |
| Issue: | 25 |
| ISSN: | 0092-8674 |
| Publisher: | Cell Press |
| Date Published: | 2024-12-12 |
| Start Page: | 7196 |
| End Page: | 7213.e26 |
| Language: | English |
| DOI: | 10.1016/j.cell.2024.09.026 |
| PUBMED: | 39383863 |
| PROVIDER: | scopus |
| PMCID: | PMC11645210 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
