Journal
EMBO REPORTS
Volume 23, Issue 2, Pages -Publisher
WILEY
DOI: 10.15252/embr.202153865
Keywords
human ACE-2 mouse; neutralizing nanobodies; SARS-CoV-2; therapeutics; variants of concern
Categories
Funding
- Initiative and Networking Fund of the Helmholtz Association of German Research Centers [SO-96]
- European Union [101003480-CORESMA]
- State Ministry of Baden-Wurttemberg for Economic Affairs, Labour and Tourism [FKZ 34332.62-NMI/68]
- Ministry of Science, Research and Arts of the State of Baden-Wurttemberg (COVID-19 funding)
- Deutsche Herzstiftung
- Bundesministerium fuer Bildung und Forschung (BMBF) through the Deutsches Zentrum fuer Luft-und Raumfahrt, Germany, (DLR) [01KI2077]
- Federal State of BadenWuerttemberg, Germany, MWK-Sonderfoerdermassnahme [COVID-19/AZ.:337533.-6-21/7/2]
- Projekt DEAL
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The study identified two high-affinity biparatopic nanobodies that can neutralize multiple emerging SARS-CoV-2 variants, providing protection against virus infection in vivo and demonstrating a significant reduction in disease progression.
The ongoing COVID-19 pandemic and the emergence of new SARS-CoV-2 variants of concern (VOCs) requires continued development of effective therapeutics. Recently, we identified high-affinity neutralizing nanobodies (Nbs) specific for the receptor-binding domain (RBD) of SARS-CoV-2. Taking advantage of detailed epitope mapping, we generate two biparatopic Nbs (bipNbs) targeting a conserved epitope outside and two different epitopes inside the RBD:ACE2 interface. Both bipNbs bind all currently circulating VOCs with high affinities and are capable to neutralize cellular infection with VOC B.1.351 (Beta) and B.1.617.2 (Delta) in vitro. To assess if the bipNbs NM1267 and NM1268 confer protection against SARS-CoV-2 infection in vivo, human ACE2 transgenic mice are treated intranasally before infection with a lethal dose of SARS-CoV-2 B.1, B.1.351 (Beta) or B.1.617.2 (Delta). Nb-treated mice show significantly reduced disease progression and increased survival rates. Histopathological analyses further reveal a drastically reduced viral load and inflammatory response in lungs. These data suggest that both bipNbs are broadly active against a variety of emerging SARS-CoV-2 VOCs and represent easily applicable drug candidates.
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