Journal Article

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

Amstutz, Patrick, Sacarcelik, Feyza, Balavenkatraman, Kamal K., Gruber, Achim D., Reichen, Christian, Schlegel, Iris, Walser, Marcel, Looser, Thamar, Knutson, Charles G., Kershaw, Olivia, Lusvarghi, Sabrina, Teixeira Alves, Luiz Gustavo, Calabro, Valérie, Comby, Marco, Schlegel, Anja, Bushe, Judith, Mayor, Jennifer, Ryter, Sarah, Abdelgawad, Azza, Watson, Randall, Schaible, Doris, Nascimento, Mariana, Steiner, Daniel, Vassell, Russell, van Kuppeveld, Frank J. M., Rothenberger, Sylvia, Moreno, Hector, Zitt, Christof, Bosch, Berend-Jan, Engler, Olivier, Fontaine, Simon, Haeuptle, Micha A., Iss, Chloé, Stumpp, Michael T., Wang, Wei, Zürcher, Alexander, Sigrist, Gabriel, Bosshart, Andreas, Neerukonda, Sabari Nath, Ramanathan, Krishnan, Neculcea, Alexandra, Kaufmann, Yvonne, Paladino, Maria, Li, Wentao, Trimpert, Jakob, Villemagne, Denis, Schiegg, Dieter, Straumann, Marcel, Du, Wenjuan, Hurdiss, Daniel L., Malvezzi, Francesca, Lyoo, Heyrhyoung, Hospodarsch, Tanja, Radom, Filip, Eschke, Kathrin, Weiss, Carol D., Cornelius, Andreas, Herrup, Rachel, Wyler, Emanuel, Wolter, Julia, Dawson, Keith M., Mangold, Susann

2022

Overview

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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/535/1258/1259 / 631/61/338/22/1295 / ACE2 / Agriculture / Angiotensin-converting enzyme 2 / Animals / Ankyrins / Antibodies, Monoclonal - therapeutic use / Antibodies, Neutralizing / Binding / Bioinformatics / Biomedical and Life Sciences / Biomedical Engineering/Biotechnology / Biomedicine / Biotechnology / Combined Antibody Therapeutics / Complementarity / Coronaviruses / COVID-19 / Cricetinae / Cryoelectron Microscopy / Designed Ankyrin Repeat Proteins / Drug resistance / Electron microscopy / Hamsters / Humans / Life Sciences / Monoclonal antibodies / Mutation / Proteins / SARS-CoV-2 - genetics / Severe acute respiratory syndrome coronavirus 2 / Spike protein / Trimers / Viral diseases