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

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.

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Güttler, T.1, Author              
Aksu, M.2, Author              
Dickmanns, A., Author
Stegmann, K. M., Author
Gregor, K.2, Author              
Rees, R.2, Author              
Taxer, W.2, Author              
Rymarenko, O.2, Author              
Schünemann, J.1, Author              
Dienemann, C.3, Author              
Gunkel, P.2, Author              
Mussil, B.2, Author              
Krull, J.2, Author              
Teichmann, U.4, Author              
Groß, U., Author
Cordes, V.2, Author              
Dobbelstein, M., Author
Görlich, D.1, Author              
Affiliations:
1Department of Cellular Logistics, MPI for biophysical chemistry, Max Planck Society, ou_578574              
2Department of Cellular Logistics, MPI for Biophysical Chemistry, Max Planck Society, ou_578574              
3Department of Molecular Biology, MPI for Biophysical Chemistry, Max Planck Society, ou_1863498              
4Animal Facility, MPI for Biophysical Chemistry, Max Planck Society, ou_2355695              

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 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.

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Language(s): eng - English
 Dates: 2021-08-092021-10-01
 Publication Status: Published in print
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 Rev. Type: Peer
 Identifiers: DOI: 10.15252/embj.2021107985
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Title: EMBO Journal
Source Genre: Journal
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Pages: 26 Volume / Issue: 40 (19) Sequence Number: e107985 Start / End Page: - Identifier: -