Abstract
Nanobodies offer several potential advantages over mAbs for the control of SARS-CoV-2. Their ability to access cryptic epitopes conserved across SARS-CoV-2 variants of concern (VoCs) and feasibility to engineer modular, multimeric designs, make these antibody fragments ideal candidates for developing broad-spectrum therapeutics against current and continually emerging SARS-CoV-2 VoCs. Here we describe a diverse collection of 37 anti-SARS-CoV-2 spike glycoprotein nanobodies extensively characterized as both monovalent and IgG Fc-fused bivalent modalities. The nanobodies were collectively shown to have high intrinsic affinity; high thermal, thermodynamic and aerosolization stability; broad subunit/domain specificity and cross-reactivity across existing VoCs; wide-ranging epitopic and mechanistic diversity and high and broad in vitro neutralization potencies. A select set of Fc-fused nanobodies showed high neutralization efficacies in hamster models of SARS-CoV-2 infection, reducing viral burden by up to six orders of magnitude to below detectable levels. In vivo protection was demonstrated with anti-RBD and previously unreported anti-NTD and anti-S2 nanobodies. This collection of nanobodies provides a potential therapeutic toolbox from which various cocktails or multi-paratopic formats could be built to combat multiple SARS-CoV-2 variants.
【초록키워드】 SARS-CoV-2, IgG, Efficacy, feasibility, neutralization, SARS-COV-2 infection, spike glycoprotein, SARS-CoV-2 variant, in vitro, anti-SARS-CoV-2, cross-reactivity, specificity, nanobody, SARS-CoV-2 variants, therapeutic, nanobodies, epitope, mAb, anti-RBD, candidate, anti-S2, viral burden, offer, intrinsic, shown, conserved, detectable, characterized, provide, reducing, demonstrated, magnitude, antibody fragment, thermodynamic, 【제목키워드】 neutralization, SARS-CoV-2 variant, in vitro, nanobody, in vivo, arsenal,