The trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants
-
Published:2022-07-21
Issue:12
Volume:40
Page:1845-1854
-
ISSN:1087-0156
-
Container-title:Nature Biotechnology
-
language:en
-
Short-container-title:Nat Biotechnol
Author:
Rothenberger SylviaORCID, Hurdiss Daniel L., Walser Marcel, Malvezzi Francesca, Mayor Jennifer, Ryter Sarah, Moreno Hector, Liechti NicoleORCID, Bosshart Andreas, Iss Chloé, Calabro Valérie, Cornelius Andreas, Hospodarsch Tanja, Neculcea Alexandra, Looser Thamar, Schlegel Anja, Fontaine Simon, Villemagne DenisORCID, 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 HeyrhyoungORCID, Wang Chunyan, Li Wentao, Du Wenjuan, Binz H. KasparORCID, Herrup Rachel, Lusvarghi SabrinaORCID, Neerukonda Sabari Nath, Vassell Russell, Wang Wei, Adler Julia M.ORCID, Eschke Kathrin, Nascimento Mariana, Abdelgawad Azza, Gruber Achim D., Bushe JudithORCID, Kershaw Olivia, Knutson Charles G., Balavenkatraman Kamal K., Ramanathan Krishnan, Wyler EmanuelORCID, Teixeira Alves Luiz Gustavo, Lewis Seth, Watson Randall, Haeuptle Micha A., Zürcher Alexander, Dawson Keith M.ORCID, Steiner Daniel, Weiss Carol D.ORCID, Amstutz Patrick, van Kuppeveld Frank J. M., Stumpp Michael T.ORCID, Bosch Berend-JanORCID, Engler OlivierORCID, Trimpert JakobORCID
Abstract
AbstractThe 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).
Publisher
Springer Science and Business Media LLC
Subject
Biomedical Engineering,Molecular Medicine,Applied Microbiology and Biotechnology,Bioengineering,Biotechnology
Reference74 articles.
1. Baum, A. et al. Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies. Science 369, 1014–1018 (2020). 2. Copin, R. et al. The monoclonal antibody combination REGEN-COV protects against SARS-CoV-2 mutational escape in preclinical and human studies. Cell 184, 3949–3961 (2021). 3. Ku, Z. et al. Molecular determinants and mechanism for antibody cocktail preventing SARS-CoV-2 escape. Nat. Commun. 12, 469 (2021). 4. Binz, H. K. et al. Design and characterization of MP0250, a tri-specific anti-HGF/anti-VEGF DARPin® drug candidate. MAbs 9, 1262–1269 (2017). 5. Fiedler, U. et al. MP0250, a VEGF and HGF neutralizing DARPin® molecule shows high anti-tumor efficacy in mouse xenograft and patient-derived tumor models. Oncotarget 8, 98371–98383 (2017).
Cited by
25 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|