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. This study reports on two highly efficient RBD‐specific biparatopic nanobodies that bind and neutralize SARS‐CoV‐2 and its currently circulating variants of concern in vitro and in vivo , underscoring the potential of nanobodies to prevent or treat SARS‐CoV‐2 infection.
【저자키워드】 immunology, Therapeutics, SARS‐CoV‐2, variants of concern, Microbiology, Virology & Host Pathogen Interaction, human ACE‐2 mouse, neutralizing nanobodies, Molecular Biology of Disease, 【초록키워드】 pandemic, VoC, B.1.351, Infection, Delta, B.1.617.2, in vitro, COVID‐19, SARS‐CoV‐2, human ACE2, Disease progression, Epitopes, Viral, nanobody, Viral load, mice, RBD, Lungs, VOCs, nanobodies, Beta, Neutralizing, epitope mapping, in vivo, epitope, cellular, Inflammatory response, dose, B.1, (Beta, lethal dose, drug candidates, These data, increased survival, high affinity, transgenic mice, treat, SARS‐CoV‐2 infection, circulating, receptor‐binding domain, Prevent, effective, neutralize, conserved, significantly, intranasally, generate, reduced, treated, variety, analysis, active against, Taking, circulating variant, 【제목키워드】 SARS‐CoV‐2, nanobody, mice, PROTECT,