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

Autor: Rothenberger S; Spiez Laboratory, Austrasse, Spiez, Switzerland.; Institute of Microbiology, University Hospital Center and University of Lausanne, Lausanne, Switzerland., Hurdiss DL; Department Biomolecular Health Sciences, Division Infectious Diseases & Immunology - Virology section, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands.; Cryo-Electron Microscopy, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, Netherlands., Walser M; Molecular Partners AG, Zurich-Schlieren, Switzerland., Malvezzi F; Molecular Partners AG, Zurich-Schlieren, Switzerland., Mayor J; Spiez Laboratory, Austrasse, Spiez, Switzerland.; Institute of Microbiology, University Hospital Center and University of Lausanne, Lausanne, Switzerland., Ryter S; Spiez Laboratory, Austrasse, Spiez, Switzerland., Moreno H; Institute of Microbiology, University Hospital Center and University of Lausanne, Lausanne, Switzerland., Liechti N; Spiez Laboratory, Austrasse, Spiez, Switzerland., Bosshart A; Molecular Partners AG, Zurich-Schlieren, Switzerland., Iss C; Molecular Partners AG, Zurich-Schlieren, Switzerland., Calabro V; Molecular Partners AG, Zurich-Schlieren, Switzerland., Cornelius A; Molecular Partners AG, Zurich-Schlieren, Switzerland., Hospodarsch T; Molecular Partners AG, Zurich-Schlieren, Switzerland., Neculcea A; Molecular Partners AG, Zurich-Schlieren, Switzerland., Looser T; Molecular Partners AG, Zurich-Schlieren, Switzerland., Schlegel A; Molecular Partners AG, Zurich-Schlieren, Switzerland., Fontaine S; Molecular Partners AG, Zurich-Schlieren, Switzerland., Villemagne D; Molecular Partners AG, Zurich-Schlieren, Switzerland., Paladino M; Molecular Partners AG, Zurich-Schlieren, Switzerland., Schiegg D; Molecular Partners AG, Zurich-Schlieren, Switzerland., Mangold S; Molecular Partners AG, Zurich-Schlieren, Switzerland., Reichen C; Molecular Partners AG, Zurich-Schlieren, Switzerland., Radom F; Molecular Partners AG, Zurich-Schlieren, Switzerland., Kaufmann Y; Molecular Partners AG, Zurich-Schlieren, Switzerland., Schaible D; Molecular Partners AG, Zurich-Schlieren, Switzerland., Schlegel I; Molecular Partners AG, Zurich-Schlieren, Switzerland., Zitt C; Molecular Partners AG, Zurich-Schlieren, Switzerland., Sigrist G; Molecular Partners AG, Zurich-Schlieren, Switzerland., Straumann M; Molecular Partners AG, Zurich-Schlieren, Switzerland., Wolter J; Molecular Partners AG, Zurich-Schlieren, Switzerland., Comby M; Molecular Partners AG, Zurich-Schlieren, Switzerland., Sacarcelik F; Molecular Partners AG, Zurich-Schlieren, Switzerland., Drulyte I; Materials and Structural Analysis, Thermo Fisher Scientific, Eindhoven, Netherlands., Lyoo H; Department Biomolecular Health Sciences, Division Infectious Diseases & Immunology - Virology section, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands., Wang C; Department Biomolecular Health Sciences, Division Infectious Diseases & Immunology - Virology section, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands., Li W; Department Biomolecular Health Sciences, Division Infectious Diseases & Immunology - Virology section, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands., Du W; Department Biomolecular Health Sciences, Division Infectious Diseases & Immunology - Virology section, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands., Binz HK; Binz Biotech Consulting, Zug, Switzerland., Herrup R; Laboratory of Immunoregulation, Division of Viral Products, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA., Lusvarghi S; Laboratory of Immunoregulation, Division of Viral Products, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA., Neerukonda SN; Laboratory of Immunoregulation, Division of Viral Products, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA., Vassell R; Laboratory of Immunoregulation, Division of Viral Products, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA., Wang W; Laboratory of Immunoregulation, Division of Viral Products, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA., Adler JM; Freie Universität Berlin, Institut für Virologie, Berlin, Germany., Eschke K; Freie Universität Berlin, Institut für Virologie, Berlin, Germany., Nascimento M; Freie Universität Berlin, Institut für Virologie, Berlin, Germany., Abdelgawad A; Freie Universität Berlin, Institut für Virologie, Berlin, Germany., Gruber AD; Freie Universität Berlin, Institut für Tierpathologie, Berlin, Germany., Bushe J; Freie Universität Berlin, Institut für Tierpathologie, Berlin, Germany., Kershaw O; Freie Universität Berlin, Institut für Tierpathologie, Berlin, Germany., Knutson CG; Novartis Institutes for BioMedical Research, PK Sciences, Cambridge, MA, USA., Balavenkatraman KK; Novartis Institutes for BioMedical Research, Preclinical Safety, Basel, Switzerland., Ramanathan K; Novartis Pharma AG, Basel, Switzerland., Wyler E; Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany., Teixeira Alves LG; Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany., Lewis S; Molecular Partners AG, Zurich-Schlieren, Switzerland., Watson R; Molecular Partners AG, Zurich-Schlieren, Switzerland., Haeuptle MA; Molecular Partners AG, Zurich-Schlieren, Switzerland., Zürcher A; Molecular Partners AG, Zurich-Schlieren, Switzerland., Dawson KM; Molecular Partners AG, Zurich-Schlieren, Switzerland., Steiner D; Molecular Partners AG, Zurich-Schlieren, Switzerland., Weiss CD; Laboratory of Immunoregulation, Division of Viral Products, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA., Amstutz P; Molecular Partners AG, Zurich-Schlieren, Switzerland., van Kuppeveld FJM; Department Biomolecular Health Sciences, Division Infectious Diseases & Immunology - Virology section, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands., Stumpp MT; Molecular Partners AG, Zurich-Schlieren, Switzerland. info@molecularpartners.com., Bosch BJ; Department Biomolecular Health Sciences, Division Infectious Diseases & Immunology - Virology section, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands., Engler O; Spiez Laboratory, Austrasse, Spiez, Switzerland., Trimpert J; Freie Universität Berlin, Institut für Virologie, Berlin, Germany.
Jazyk: angličtina
Zdroj: Nature biotechnology [Nat Biotechnol] 2022 Dec; Vol. 40 (12), pp. 1845-1854. Date of Electronic Publication: 2022 Jul 21.
DOI: 10.1038/s41587-022-01382-3
Abstrakt: 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).
(© 2022. The Author(s).)
Databáze: MEDLINE
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