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Biparatopic nanobodies protect mice from lethal challenge with SARS‐CoV‐2 variants of concern
Author(s) -
Wagner Teresa R,
Schnepf Daniel,
Beer Julius,
Ruetalo Natalia,
Klingel Karin,
Kaiser Philipp D,
Junker Daniel,
Sauter Martina,
Traenkle Bjoern,
Frecot Desiree I,
Becker Matthias,
SchneiderhanMarra Nicole,
Ohnemus Annette,
Schwemmle Martin,
Schindler Michael,
Rothbauer Ulrich
Publication year - 2021
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202153865
Subject(s) - epitope , virology , biology , genetically modified mouse , in vivo , transgene , covid-19 , pandemic , in vitro , drug development , immunology , antibody , drug , disease , infectious disease (medical specialty) , medicine , gene , pharmacology , genetics , pathology
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.