Nature Biotechnology

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

Sylvia Rothenberger ^{1, 2}

Daniel L. Hurdiss ^{3, 4}

Marcel Walser ⁵

Francesca Malvezzi ⁵

Jennifer Mayor ^{1, 2}

Sarah Ryter ¹

Hector Moreno ²

Nicole Liechti ¹

Andreas Bosshart ⁵

Chloe Iss ⁵

Valérie Calabro ⁵

Andreas Cornelius ⁵

Tanja Hospodarsch ⁵

Alexandra Neculcea ⁵

Thamar Looser ⁵

Anja Schlegel ⁵

Simon Fontaine ⁵

Denis Villemagne ⁵

Maria Paladino ⁵

Schiegg Dieter ⁵

Susanne Mangold ⁵

Christian Reichen ⁵

Filip Radom ⁵

Yvonne Kaufmann ⁵

Doris Schaible ⁵

Iris Schlegel ⁵

Christof ZITT ⁵

Gabriel Sigrist ⁵

Marcel Straumann ⁵

Julia Wolter ⁵

Marco Comby ⁵

Feyza Sacarcelik ⁵

Ieva Drulyte ⁶

Heyrhyoung Lyoo ³

Chunyan Wang ³

Wentao Li ³

Wenjuan Du ³

H Kaspar Binz ⁷

Rachel Herrup ⁸

Sabrina Lusvarghi ⁸

Sabari Nath Neerukonda ⁸

Russell Vassell ⁸

Wei Wang ⁸

Julia M Adler ⁹

Kathrin Eschke ⁹

Mariana Nascimento ⁹

Azza Abdelgawad ⁹

Achim D. Gruber ¹⁰

Judith Bushe ¹⁰

Olivia Kershaw ¹⁰

Charles G. Knutson ¹¹

Kamal K Balavenkatraman ¹²

Krishnan Ramanathan ¹³

Emanuel Wyler ¹⁴

Luiz-Gustavo Teixeira Alves ¹⁴

Seth Lewis ⁵

Randall Watson ⁵

Micha A Haeuptle ⁵

Alexander Zürcher ⁵

Keith M Dawson ⁵

Daniel Steiner ⁵

Carol Weiss ⁸

Patrick Amstutz ⁵

Frank J. M. van Kuppeveld ³

Michael T. STUMPP ⁵

Berend-Jan Bosch ³

Olivier B Engler ¹

Jakob Trimpert ⁹

Hide authors affiliations Show authors affiliations: 14 affiliations

Spiez Laboratory, Austrasse, Spiez, Switzerland |

Institute of Microbiology, University Hospital Center and University of Lausanne, Lausanne, Switzerland |

Department Biomolecular Health Sciences, Division Infectious Diseases & Immunology - Virology section, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands |

⁴

Cryo-Electron Microscopy, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, Netherlands |

⁵

Molecular Partners Ag, Zurich-Schlieren, Switzerland |

⁶

Materials and Structural Analysis, Thermo Fisher Scientific, Eindhoven, Netherlands |

⁷

Binz Biotech Consulting, Zug, Switzerland |

⁸

Laboratory of Immunoregulation, Division of Viral Products, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, USA |

⁹

Freie Universität Berlin, Institut für Virologie, Berlin, Germany |

¹⁰

Freie Universität Berlin, Institut für Tierpathologie, Berlin, Germany |

¹¹

Novartis Institutes for BioMedical Research, PK Sciences, Cambridge, USA |

¹²

Novartis Institutes for BioMedical Research, Preclinical Safety, Basel, Switzerland |

¹³

Novartis Pharma Ag, Basel, Switzerland |

¹⁴

Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany |

Publication type: Journal Article

Publication date: 2022-07-21

Springer Nature

Journal: Nature Biotechnology

SJR: 18.117

CiteScore: 63.0

Impact factor: 33.1

ISSN: 10870156, 15461696

DOI: 10.1038/s41587-022-01382-3

Copy DOI

Molecular Medicine

Applied Microbiology and Biotechnology

Biotechnology

Bioengineering

Biomedical Engineering

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). Multiple variants of SARS-CoV-2 are inhibited by a trispecific DARPin.

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GOST Copy

Rothenberger S. et al. The trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants // Nature Biotechnology. 2022.

GOST all authors (up to 50) Copy

Rothenberger S. et al. The trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants // Nature Biotechnology. 2022.

RIS |

Cite this

RIS Copy

TY - JOUR

DO - 10.1038/s41587-022-01382-3

UR - https://doi.org/10.1038/s41587-022-01382-3

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

T2 - Nature Biotechnology

AU - Rothenberger, Sylvia

AU - Hurdiss, Daniel L.

AU - Walser, Marcel

AU - Malvezzi, Francesca

AU - Mayor, Jennifer

AU - Ryter, Sarah

AU - Moreno, Hector

AU - Liechti, Nicole

AU - Bosshart, Andreas

AU - Iss, Chloe

AU - Calabro, Valérie

AU - Cornelius, Andreas

AU - Hospodarsch, Tanja

AU - Neculcea, Alexandra

AU - Looser, Thamar

AU - Schlegel, Anja

AU - Fontaine, Simon

AU - Villemagne, Denis

AU - Paladino, Maria

AU - Dieter, Schiegg

AU - Mangold, Susanne

AU - Reichen, Christian

AU - Radom, Filip

AU - Kaufmann, Yvonne

AU - Schaible, Doris

AU - Schlegel, Iris

AU - ZITT, Christof

AU - Sigrist, Gabriel

AU - Straumann, Marcel

AU - Wolter, Julia

AU - Comby, Marco

AU - Sacarcelik, Feyza

AU - Drulyte, Ieva

AU - Lyoo, Heyrhyoung

AU - Wang, Chunyan

AU - Li, Wentao

AU - Du, Wenjuan

AU - Binz, H Kaspar

AU - Herrup, Rachel

AU - Lusvarghi, Sabrina

AU - Neerukonda, Sabari Nath

AU - Vassell, Russell

AU - Wang, Wei

AU - Adler, Julia M

AU - Eschke, Kathrin

AU - Nascimento, Mariana

AU - Abdelgawad, Azza

AU - Gruber, Achim D.

AU - Bushe, Judith

AU - Kershaw, Olivia

AU - Knutson, Charles G.

AU - Balavenkatraman, Kamal K

AU - Ramanathan, Krishnan

AU - Wyler, Emanuel

AU - Teixeira Alves, Luiz-Gustavo

AU - Lewis, Seth

AU - Watson, Randall

AU - Haeuptle, Micha A

AU - Zürcher, Alexander

AU - Dawson, Keith M

AU - Steiner, Daniel

AU - Weiss, Carol

AU - Amstutz, Patrick

AU - van Kuppeveld, Frank J. M.

AU - STUMPP, Michael T.

AU - Bosch, Berend-Jan

AU - Engler, Olivier B

AU - Trimpert, Jakob

PY - 2022

DA - 2022/07/21

PB - Springer Nature

SN - 1087-0156

SN - 1546-1696

ER -

BibTex

Cite this

BibTex (up to 50 authors) Copy

@article{2022_Rothenberger,

author = {Sylvia Rothenberger and Daniel L. Hurdiss and Marcel Walser and Francesca Malvezzi and Jennifer Mayor and Sarah Ryter and Hector Moreno and Nicole Liechti and Andreas Bosshart and Chloe Iss and Valérie Calabro and Andreas Cornelius and Tanja Hospodarsch and Alexandra Neculcea and Thamar Looser and Anja Schlegel and Simon Fontaine and Denis Villemagne and Maria Paladino and Schiegg Dieter and Susanne Mangold and Christian Reichen and Filip Radom and Yvonne Kaufmann and Doris Schaible and Iris Schlegel and Christof ZITT and Gabriel Sigrist and Marcel Straumann and Julia Wolter and Marco Comby and Feyza Sacarcelik and Ieva Drulyte and Heyrhyoung Lyoo and Chunyan Wang and Wentao Li and Wenjuan Du and H Kaspar Binz and Rachel Herrup and Sabrina Lusvarghi and Sabari Nath Neerukonda and Russell Vassell and Wei Wang and Julia M Adler and Kathrin Eschke and Mariana Nascimento and Azza Abdelgawad and Achim D. Gruber and Judith Bushe and Olivia Kershaw and others},

title = {The trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants},

journal = {Nature Biotechnology},

year = {2022},

publisher = {Springer Nature},

month = {jul},

url = {https://doi.org/10.1038/s41587-022-01382-3},

doi = {10.1038/s41587-022-01382-3}

}

Found error?

Publisher

Springer Nature

Journal

Nature Biotechnology

SJR

18.117

CiteScore

63.0

Impact factor

33.1

ISSN

10870156 (Print)

15461696 (Electronic)