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| Item Type: | Article |
|---|---|
| Title: | The trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants |
| Creators: |
Rothenberger, S.  ORCID: https://orcid.org/0000-0001-8633-2994, Hurdiss, D.L., Walser, M., Malvezzi, F., Mayor, J., Ryter, S., Moreno, H., Liechti, N. ORCID: https://orcid.org/0000-0003-4354-2419, Bosshart, A., Iss, C., Calabro, V., Cornelius, A., Hospodarsch, T., Neculcea, A., Looser, T., Schlegel, A., Fontaine, S., Villemagne, D. ORCID: https://orcid.org/0000-0002-4465-364X, Paladino, M., Schiegg, D., Mangold, S., Reichen, C., Radom, F., Kaufmann, Y., Schaible, D., Schlegel, I., Zitt, C., Sigrist, G., Straumann, M., Wolter, J., Comby, M., Sacarcelik, F., Drulyte, I., Lyoo, H. ORCID: https://orcid.org/0000-0001-5806-9463, Wang, C., Li, W., Du, W., Binz, H.K. ORCID: https://orcid.org/0000-0003-0702-2280, Herrup, R., Lusvarghi, S. ORCID: https://orcid.org/0000-0003-1793-0450, Neerukonda, S.N., Vassell, R., Wang, W., Adler, J.M. ORCID: https://orcid.org/0000-0001-8147-0351, Eschke, K., Nascimento, M., Abdelgawad, A., Gruber, A.D., Bushe, J. ORCID: https://orcid.org/0000-0001-6103-3277, Kershaw, O., Knutson, C.G., Balavenkatraman, K.K., Ramanathan, K., Wyler, E. ORCID: https://orcid.org/0000-0002-9884-1806, Teixeira Alves, L.G. ORCID: https://orcid.org/0000-0002-5822-4168, Lewis, S., Watson, R., Haeuptle, M.A., Zürcher, A., Dawson, K.M. ORCID: https://orcid.org/0000-0002-1770-291X, Steiner, D., Weiss, C.D. ORCID: https://orcid.org/0000-0002-9965-1289, Amstutz, P., van Kuppeveld, F.J.M., Stumpp, M.T. ORCID: https://orcid.org/0000-0001-7356-2061, Bosch, B.J. ORCID: https://orcid.org/0000-0002-3864-232X, Engler, O. ORCID: https://orcid.org/0000-0002-8404-1496 and Trimpert, J. ORCID: https://orcid.org/0000-0003-1616-0810
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| Abstract: | The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with potential resistance to existing drugs emphasizes the need for new therapeutic modalities with broad variant activity. Here we show that ensovibep, a trispecific DARPin (designed ankyrin repeat protein) clinical candidate, can engage the three units of the spike protein trimer of SARS-CoV-2 and inhibit ACE2 binding with high potency, as revealed by cryo-electron microscopy analysis. The cooperative binding together with the complementarity of the three DARPin modules enable ensovibep to inhibit frequent SARS-CoV-2 variants, including Omicron sublineages BA.1 and BA.2. In Roborovski dwarf hamsters infected with SARS-CoV-2, ensovibep reduced fatality similarly to a standard-of-care monoclonal antibody (mAb) cocktail. When used as a single agent in viral passaging experiments in vitro, ensovibep reduced the emergence of escape mutations in a similar fashion to the same mAb cocktail. These results support further clinical evaluation of ensovibep as a broad variant alternative to existing targeted therapies for Coronavirus Disease 2019 (COVID-19). |
| Keywords: | Monoclonal Antibodies, Neutralizing Antibodies, COVID-19, Combined Antibody Therapeutics, Cricetinae, Cryoelectron Microscopy, Designed Ankyrin Repeat Proteins, SARS-CoV-2, Animals |
| Source: | Nature Biotechnology |
| ISSN: | 1087-0156 |
| Publisher: | Nature Publishing Group |
| Volume: | 40 |
| Number: | 12 |
| Page Range: | 1845-1854 |
| Date: | December 2022 |
| Official Publication: | https://doi.org/10.1038/s41587-022-01382-3 |
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