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Journal Article

Neutralization of SARS-CoV-2 by highly potent, hyperthermostable, and mutation-tolerant nanobodies

MPS-Authors
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Güttler,  T.
Department of Cellular Logistics, MPI for biophysical chemistry, Max Planck Society;

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Aksu,  M.
Department of Cellular Logistics, MPI for Biophysical Chemistry, Max Planck Society;

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Gregor,  K.
Department of Cellular Logistics, MPI for Biophysical Chemistry, Max Planck Society;

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Rees,  R.
Department of Cellular Logistics, MPI for Biophysical Chemistry, Max Planck Society;

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Taxer,  W.
Department of Cellular Logistics, MPI for Biophysical Chemistry, Max Planck Society;

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Rymarenko,  O.
Department of Cellular Logistics, MPI for Biophysical Chemistry, Max Planck Society;

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Schünemann,  J.
Department of Cellular Logistics, MPI for biophysical chemistry, Max Planck Society;

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Dienemann,  C.
Department of Molecular Biology, MPI for Biophysical Chemistry, Max Planck Society;

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Gunkel,  P.
Department of Cellular Logistics, MPI for Biophysical Chemistry, Max Planck Society;

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Mussil,  B.
Department of Cellular Logistics, MPI for Biophysical Chemistry, Max Planck Society;

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Krull,  J.
Department of Cellular Logistics, MPI for Biophysical Chemistry, Max Planck Society;

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Teichmann,  U.
Animal Facility, MPI for Biophysical Chemistry, Max Planck Society;

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Cordes,  V.
Department of Cellular Logistics, MPI for Biophysical Chemistry, Max Planck Society;

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Görlich,  D.
Department of Cellular Logistics, MPI for biophysical chemistry, Max Planck Society;

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Citation

Güttler, T., Aksu, M., Dickmanns, A., Stegmann, K. M., Gregor, K., Rees, R., et al. (2021). Neutralization of SARS-CoV-2 by highly potent, hyperthermostable, and mutation-tolerant nanobodies. EMBO Journal, 40(19): e107985. doi:10.15252/embj.2021107985.


Cite as: https://hdl.handle.net/21.11116/0000-0009-7512-F
Abstract
Monoclonal anti-SARS-CoV-2 immunoglobulins represent a treatment option for COVID-19. However, their production in mammalian cells is not scalable to meet the global demand. Single-domain (VHH) antibodies (also called nanobodies) provide an alternative suitable for microbial production. Using alpaca immune libraries against the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein, we isolated 45 infection-blocking VHH antibodies. These include nanobodies that can withstand 95°C. 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. The best VHH trimers neutralize even at 40 ng per liter. 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. We also demonstrate neutralization of the Beta strain at low-picomolar VHH concentrations. We further discovered VHH antibodies that enforce native folding of the RBD in the E. coli cytosol, where its folding normally fails. Such “fold-promoting” nanobodies may allow for simplified production of vaccines and their adaptation to viral escape-mutations.