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The trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants

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Item Type:Article
Title:The trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants
Creators Name:Rothenberger, S. and Hurdiss, D.L. and Walser, M. and Malvezzi, F. and Mayor, J. and Ryter, S. and Moreno, H. and Liechti, N. and Bosshart, A. and Iss, C. and Calabro, V. and Cornelius, A. and Hospodarsch, T. and Neculcea, A. and Looser, T. and Schlegel, A. and Fontaine, S. and Villemagne, D. and Paladino, M. and Schiegg, D. and Mangold, S. and Reichen, C. and Radom, F. and Kaufmann, Y. and Schaible, D. and Schlegel, I. and Zitt, C. and Sigrist, G. and Straumann, M. and Wolter, J. and Comby, M. and Sacarcelik, F. and Drulyte, I. and Lyoo, H. and Wang, C. and Li, W. and Du, W. and Binz, H.K. and Herrup, R. and Lusvarghi, S. and Neerukonda, S.N. and Vassell, R. and Wang, W. and Adler, J.M. and Eschke, K. and Nascimento, M. and Abdelgawad, A. and Gruber, A.D. and Bushe, J. and Kershaw, O. and Knutson, C.G. and Balavenkatraman, K.K. and Ramanathan, K. and Wyler, E. and Teixeira Alves, L.G. and Lewis, S. and Watson, R. and Haeuptle, M.A. and Zürcher, A. and Dawson, K.M. and Steiner, D. and Weiss, C.D. and Amstutz, P. and van Kuppeveld, F.J.M. and Stumpp, M.T. and Bosch, B.J. and 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
Publisher:Nature Publishing Group
Page Range:1845-1854
Date:December 2022
Official Publication:https://doi.org/10.1038/s41587-022-01382-3

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