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| Item Type: | Article |
|---|---|
| Title: | The trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants |
| Creators Name: | Rothenberger, S., Hurdiss, D.L., Walser, M., Malvezzi, F., Mayor, J., Ryter, S., Moreno, H., Liechti, N., Bosshart, A., Iss, C., Calabro, V., Cornelius, A., Hospodarsch, T., Neculcea, A., Looser, T., Schlegel, A., Fontaine, S., Villemagne, D., 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., Wang, C., Li, W., Du, W., Binz, H.K., Herrup, R., Lusvarghi, S., Neerukonda, S.N., Vassell, R., Wang, W., Adler, J.M., Eschke, K., Nascimento, M., Abdelgawad, A., Gruber, A.D., Bushe, J., Kershaw, O., Knutson, C.G., Balavenkatraman, K.K., Ramanathan, K., Wyler, E., Teixeira Alves, L.G., Lewis, S., Watson, R., Haeuptle, M.A., Zürcher, A., Dawson, K.M., Steiner, D., Weiss, C.D., Amstutz, P., van Kuppeveld, F.J.M., Stumpp, M.T., Bosch, B.J., Engler, O. and Trimpert, J. |
| 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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