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).
| Original language | English |
|---|---|
| Pages (from-to) | 1845-1854 |
| Number of pages | 10 |
| Journal | Nature Biotechnology |
| Volume | 40 |
| Issue number | 12 |
| Early online date | 21 Jul 2022 |
| DOIs | |
| Publication status | Published - Dec 2022 |
Bibliographical note
Funding Information:We thank the Centre for AIDS Reagents (National Institute for Biological Standards and Control) for providing VeroE6/TMPRSS2 cells. The authors thank G. Zimmer for the gift of the recombinant VSV (Institute of Virology and Immunology, CH-3147 Mittelhäusern, Switzerland, Vetsuisse Faculty, University of Bern, CH-3012 Bern, Switzerland). The expression plasmid for the SARS-CoV-2 spike protein was kindly provided by G. Torriani and I. Eckerle (Department of Medicine, University of Geneva, Switzerland). We would like to thank S. van der Werf for the supply of 2019-nCoV/IDF0372/2020 (National Reference Centre for Respiratory Viruses hosted by Institut Pasteur (Paris, France)). Strain 2019-nCoV/IDF0372/2020 was generously provided by X. Lescure and Y. Yazdanpanah from the Bichat Hospital. We thank W. Lee, former board member of Molecular Partners, and the virology group at Gilead Sciences for their helpful input during the discovery phase of ensovibep. S.R. and J.M. were supported by the Swiss Federal Office for Civil Protection (grants 353008564/Stm, 353008218/Stm and 353008560/Stm). D.L.H. is funded by the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement (842333) and holds an EMBO non-stipendiary long-term fellowship (ALTF 1172-2018). Cryo-EM data processing was carried out on the Dutch national e-infrastructure with the support of the SURF Cooperative using grant EINF-398. Lentivirus pseudotype investigations were performed independently by investigators at the US Food and Drug Administration, Center for Biologics Evaluation and Research, as part of Therapeutics Research Team for the US government COVID-19 response efforts. The work was supported by US government research funds. If not stated differently, all other work was funded by Molecular Partners.
Funding Information:
We thank the Centre for AIDS Reagents (National Institute for Biological Standards and Control) for providing VeroE6/TMPRSS2 cells. The authors thank G. Zimmer for the gift of the recombinant VSV (Institute of Virology and Immunology, CH-3147 Mittelhäusern, Switzerland, Vetsuisse Faculty, University of Bern, CH-3012 Bern, Switzerland). The expression plasmid for the SARS-CoV-2 spike protein was kindly provided by G. Torriani and I. Eckerle (Department of Medicine, University of Geneva, Switzerland). We would like to thank S. van der Werf for the supply of 2019-nCoV/IDF0372/2020 (National Reference Centre for Respiratory Viruses hosted by Institut Pasteur (Paris, France)). Strain 2019-nCoV/IDF0372/2020 was generously provided by X. Lescure and Y. Yazdanpanah from the Bichat Hospital. We thank W. Lee, former board member of Molecular Partners, and the virology group at Gilead Sciences for their helpful input during the discovery phase of ensovibep. S.R. and J.M. were supported by the Swiss Federal Office for Civil Protection (grants 353008564/Stm, 353008218/Stm and 353008560/Stm). D.L.H. is funded by the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement (842333) and holds an EMBO non-stipendiary long-term fellowship (ALTF 1172-2018). Cryo-EM data processing was carried out on the Dutch national e-infrastructure with the support of the SURF Cooperative using grant EINF-398. Lentivirus pseudotype investigations were performed independently by investigators at the US Food and Drug Administration, Center for Biologics Evaluation and Research, as part of Therapeutics Research Team for the US government COVID-19 response efforts. The work was supported by US government research funds. If not stated differently, all other work was funded by Molecular Partners.
Publisher Copyright:
© 2022, The Author(s).
Keywords
- Animals
- Antibodies, Monoclonal/therapeutic use
- Antibodies, Neutralizing
- COVID-19
- Combined Antibody Therapeutics
- Cricetinae
- Cryoelectron Microscopy
- Designed Ankyrin Repeat Proteins
- Humans
- SARS-CoV-2/genetics