Nanobodies that neutralize Monoclonal antibodies that bind to the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) show therapeutic promise but must be produced in mammalian cells and need to be delivered intravenously. By contrast, single-domain antibodies called nanobodies can be produced in bacteria or yeast, and their stability may enable aerosol delivery. Two papers now report nanobodies that bind tightly to spike and efficiently neutralize SARS-CoV-2 in cells. Schoof et al. screened a yeast surface display of synthetic nanobodies and Xiang et al. screened anti-spike nanobodies produced by a llama. Both groups identified highly potent nanobodies that lock the spike protein in an inactive conformation. Multivalent constructs of selected nanobodies achieved even more potent neutralization. Science , this issue p. 1473 , p. 1479 Potent neutralizers of SARS-CoV-2 are identified by screening either synthetic or llama-produced nanobodies. Cost-effective, efficacious therapeutics are urgently needed to combat the COVID-19 pandemic. In this study, we used camelid immunization and proteomics to identify a large repertoire of highly potent neutralizing nanobodies (Nbs) to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor binding domain (RBD). We discovered Nbs with picomolar to femtomolar affinities that inhibit viral infection at concentrations below the nanograms-per-milliliter level, and we determined a structure of one of the most potent Nbs in complex with the RBD. Structural proteomics and integrative modeling revealed multiple distinct and nonoverlapping epitopes and indicated an array of potential neutralization mechanisms. We bioengineered multivalent Nb constructs that achieved ultrahigh neutralization potency (half-maximal inhibitory concentration as low as 0.058 ng/ml) and may prevent mutational escape. These thermostable Nbs can be rapidly produced in bulk from microbes and resist lyophilization and aerosolization.
【초록키워드】 SARS-CoV-2, viral infection, proteomics, coronavirus, antibody, neutralization, COVID-19 pandemic, immunization, Spike protein, Receptor binding domain, stability, nanobody, multivalent, cells, RBD, therapeutic, nanobodies, Bacteria, Neutralizing, mechanisms, group, potent, yeast, Anti-spike, affinity, Concentration, microbe, Science, acute respiratory syndrome, half-maximal inhibitory concentration, complex, neutralization potency, intravenously, mammalian cell, Prevent, neutralize, selected, produced, identify, indicated, inhibit, screened, the spike protein, the RBD, inactive, nonoverlapping epitope, synthetic nanobody, 【제목키워드】 SARS-CoV-2, nanobody, neutralize,