This study revealed highly potent therapeutic nanobodies/single-domain (VHH) antibodies that neutralize SARS-CoV-2 and its emerging immune-escape mutants. SYNOPSISĮffective treatment options for SARS-CoV-2 infections/COVID-19 are still sparse. Such “fold-promoting” nanobodies may allow for simplified production of vaccines and their adaptation to viral escape-mutations. We further discovered VHH antibodies that enforce native folding of the RBD in the E. coli cytosol, where its folding normally fails. We also demonstrate neutralization of the Beta strain at low-picomolar VHH concentrations. We constructed nanobody tandems and identified nanobody monomers that tolerate the K417N/T, E484K, N501Y, and L452R immune-escape mutations found in the Alpha, Beta, Gamma, Epsilon, Iota, and Delta/Kappa lineages. The best VHH trimers neutralize even at 40 ng per liter. The most effective VHH antibody neutralizes SARS-CoV-2 at 17–50 pM concentration (0.2–0.7 µg per liter), binds the open and closed states of the Spike, and shows a tight RBD interaction in the X-ray and cryo-EM structures. These include nanobodies that can withstand 95☌. Using alpaca immune libraries against the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein, we isolated 45 infection-blocking VHH antibodies. Single-domain (VHH) antibodies (also called nanobodies) provide an alternative suitable for microbial production. However, their production in mammalian cells is not scalable to meet the global demand. Monoclonal anti-SARS-CoV-2 immunoglobulins represent a treatment option for COVID-19.
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