| Literature DB >> 35864170 |
Sylvia Rothenberger1,2, Daniel L Hurdiss3,4, Marcel Walser5, Francesca Malvezzi5, Jennifer Mayor1,2, Sarah Ryter1, Hector Moreno2, Nicole Liechti1, Andreas Bosshart5, Chloé Iss5, Valérie Calabro5, Andreas Cornelius5, Tanja Hospodarsch5, Alexandra Neculcea5, Thamar Looser5, Anja Schlegel5, Simon Fontaine5, Denis Villemagne5, Maria Paladino5, Dieter Schiegg5, Susanne Mangold5, Christian Reichen5, Filip Radom5, Yvonne Kaufmann5, Doris Schaible5, Iris Schlegel5, Christof Zitt5, Gabriel Sigrist5, Marcel Straumann5, Julia Wolter5, Marco Comby5, Feyza Sacarcelik5, Ieva Drulyte6, Heyrhyoung Lyoo3, Chunyan Wang3, Wentao Li3, Wenjuan Du3, H Kaspar Binz7, Rachel Herrup8, Sabrina Lusvarghi8, Sabari Nath Neerukonda8, Russell Vassell8, Wei Wang8, Julia M Adler9, Kathrin Eschke9, Mariana Nascimento9, Azza Abdelgawad9, Achim D Gruber10, Judith Bushe10, Olivia Kershaw10, Charles G Knutson11, Kamal K Balavenkatraman12, Krishnan Ramanathan13, Emanuel Wyler14, Luiz Gustavo Teixeira Alves14, Seth Lewis5, Randall Watson5, Micha A Haeuptle5, Alexander Zürcher5, Keith M Dawson5, Daniel Steiner5, Carol D Weiss8, Patrick Amstutz5, Frank J M van Kuppeveld3, Michael T Stumpp15, Berend-Jan Bosch3, Olivier Engler1, Jakob Trimpert9.
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).Entities:
Year: 2022 PMID： 35864170 DOI： 10.1038/s41587-022-01382-3
Source DB: PubMed Journal: Nat Biotechnol ISSN： 1087-0156 Impact factor: 68.164