A nanobody recognizes a unique conserved epitope and potently neutralizes SARS-CoV-2 omicron variants

• Published in: iScience Vol. 26; no. 7; p. 107085
• Main Authors: Modhiran, Naphak, Lauer, Simon Malte, Amarilla, Alberto A., Hewins, Peter, Lopes van den Broek, Sara Irene, Low, Yu Shang, Thakur, Nazia, Liang, Benjamin, Nieto, Guillermo Valenzuela, Jung, James, Paramitha, Devina, Isaacs, Ariel, Sng, Julian D.J., Song, David, Jørgensen, Jesper Tranekjær, Cheuquemilla, Yorka, Bürger, Jörg, Andersen, Ida Vang, Himelreichs, Johanna, Jara, Ronald, MacLoughlin, Ronan, Miranda-Chacon, Zaray, Chana-Cuevas, Pedro, Kramer, Vasko, Spahn, Christian, Mielke, Thorsten, Khromykh, Alexander A., Munro, Trent, Jones, Martina L., Young, Paul R., Chappell, Keith, Bailey, Dalan, Kjaer, Andreas, Herth, Matthias Manfred, Jurado, Kellie Ann, Schwefel, David, Rojas-Fernandez, Alejandro, Watterson, Daniel
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.07.2023; Elsevier
• Subjects: Decision science; Information system model; Public health; Information system model; Decision science; Public health
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2023.107085

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) Omicron variant sub-lineages spread rapidly worldwide, mostly due to their immune-evasive properties. This has put a significant part of the population at risk for severe disease and underscores the need for effective anti-SARS-CoV-2 agents against emergent strains in vulnerable patients. Camelid nanobodies are attractive therapeutic candidates due to their high stability, ease of large-scale production, and potential for delivery via inhalation. Here, we characterize the receptor binding domain (RBD)-specific nanobody W25 and show superior neutralization activity toward Omicron sub-lineages in comparison to all other SARS-CoV2 variants. Structure analysis of W25 in complex with the SARS-CoV2 spike glycoprotein shows that W25 engages an RBD epitope not covered by any of the antibodies previously approved for emergency use. In vivo evaluation of W25 prophylactic and therapeutic treatments across multiple SARS-CoV-2 variant infection models, together with W25 biodistribution analysis in mice, demonstrates favorable pre-clinical properties. Together, these data endorse W25 for further clinical development. [Display omitted] •The nanobody W25 efficiently neutralizes SARS-CoV2 omicron sub-lineages•A dimeric W25-Fc fusion shows enhanced neutralization activity•W25 binds a unique conserved SARS-CoV2 spike RBD epitope•W25 protects K18-huACE2 mice from Wuhan and Omicron SARS-CoV-2 infections Public health; Information system model; Decision science