TY - JOUR

T1 - A nanobody recognizes a unique conserved epitope and potently neutralizes SARS-CoV-2 omicron variants

AU - Modhiran, Naphak

AU - Lauer, Simon Malte

AU - Amarilla, Alberto A.

AU - Hewins, Peter

AU - Lopes van den Broek, Sara Irene

AU - Low, Yu Shang

AU - Thakur, Nazia

AU - Liang, Benjamin

AU - Nieto, Guillermo Valenzuela

AU - Jung, James

AU - Paramitha, Devina

AU - Isaacs, Ariel

AU - Sng, Julian D.J.

AU - Song, David

AU - Jørgensen, Jesper Tranekjær

AU - Cheuquemilla, Yorka

AU - Bürger, Jörg

AU - Andersen, Ida Vang

AU - Himelreichs, Johanna

AU - Jara, Ronald

AU - MacLoughlin, Ronan

AU - Miranda-Chacon, Zaray

AU - Chana-Cuevas, Pedro

AU - Kramer, Vasko

AU - Spahn, Christian

AU - Mielke, Thorsten

AU - Khromykh, Alexander A.

AU - Munro, Trent

AU - Jones, Martina L.

AU - Young, Paul R.

AU - Chappell, Keith

AU - Bailey, Dalan

AU - Kjaer, Andreas

AU - Herth, Matthias Manfred

AU - Jurado, Kellie Ann

AU - Schwefel, David

AU - Rojas-Fernandez, Alejandro

AU - Watterson, Daniel

N1 - Publisher Copyright: © 2023

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - Decision science

KW - Information system model

KW - Public health

U2 - 10.1016/j.isci.2023.107085

DO - 10.1016/j.isci.2023.107085

M3 - Journal article

C2 - 37361875

AN - SCOPUS:85163012283

VL - 26

JO - iScience

JF - iScience

SN - 2589-0042

IS - 7

M1 - 107085

ER -