Biparatopic nanobodies protect mice from lethal challenge with SARS‐CoV‐2 variants of concern
Teresa R. Wagner, Daniel Schnepf, Julius Beer, Natalia Ruétalo, Karin Klingel, Philipp D. Kaiser, Daniel Junker, Martina Sauter, Bjoern Traenkle, Desiree I. Frecot, Matthias Becker, Nicole Schneiderhan‐Marra, Annette Ohnemus, Martin Schwemmle, Michael Schindler, Ulrich Rothbauer
Abstract
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.