학술논문
The trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants
Document Type
Original Paper
Author
Rothenberger, Sylvia; Hurdiss, Daniel L.; Walser, Marcel; Malvezzi, Francesca; Mayor, Jennifer; Ryter, Sarah; Moreno, Hector; Liechti, Nicole; Bosshart, Andreas; Iss, Chloé; Calabro, Valérie; Cornelius, Andreas; Hospodarsch, Tanja; Neculcea, Alexandra; Looser, Thamar; Schlegel, Anja; Fontaine, Simon; Villemagne, Denis; Paladino, Maria; Schiegg, Dieter; Mangold, Susanne; Reichen, Christian; Radom, Filip; Kaufmann, Yvonne; Schaible, Doris; Schlegel, Iris; Zitt, Christof; Sigrist, Gabriel; Straumann, Marcel; Wolter, Julia; Comby, Marco; Sacarcelik, Feyza; Drulyte, Ieva; Lyoo, Heyrhyoung; Wang, Chunyan; Li, Wentao; Du, Wenjuan; Binz, H. Kaspar; Herrup, Rachel; Lusvarghi, Sabrina; Neerukonda, Sabari Nath; Vassell, Russell; Wang, Wei; Adler, Julia M.; Eschke, Kathrin; Nascimento, Mariana; Abdelgawad, Azza; Gruber, Achim D.; Bushe, Judith; Kershaw, Olivia; Knutson, Charles G.; Balavenkatraman, Kamal K.; Ramanathan, Krishnan; Wyler, Emanuel; Teixeira Alves, Luiz Gustavo; Lewis, Seth; Watson, Randall; Haeuptle, Micha A.; Zürcher, Alexander; Dawson, Keith M.; Steiner, Daniel; Weiss, Carol D.; Amstutz, Patrick; van Kuppeveld, Frank J. M.; Stumpp, Michael T.; Bosch, Berend-Jan; Engler, Olivier; Trimpert, Jakob
Source
Nature Biotechnology: The Science and Business of Biotechnology. 40(12):1845-1854
Subject
Language
English
ISSN
1087-0156
1546-1696
1546-1696
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).
Multiple variants of SARS-CoV-2 are inhibited by a trispecific DARPin.
Multiple variants of SARS-CoV-2 are inhibited by a trispecific DARPin.