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


  • S. Rothenberger
  • D.L. Hurdiss
  • M. Walser
  • F. Malvezzi
  • J. Mayor
  • S. Ryter
  • H. Moreno
  • N. Liechti
  • A. Bosshart
  • C. Iss
  • V. Calabro
  • A. Cornelius
  • T. Hospodarsch
  • A. Neculcea
  • T. Looser
  • A. Schlegel
  • S. Fontaine
  • D. Villemagne
  • M. Paladino
  • D. Schiegg
  • S. Mangold
  • C. Reichen
  • F. Radom
  • Y. Kaufmann
  • D. Schaible
  • I. Schlegel
  • C. Zitt
  • G. Sigrist
  • M. Straumann
  • J. Wolter
  • M. Comby
  • F. Sacarcelik
  • I. Drulyte
  • H. Lyoo
  • C. Wang
  • W. Li
  • W. Du
  • H.K. Binz
  • R. Herrup
  • S. Lusvarghi
  • S.N. Neerukonda
  • R. Vassell
  • W. Wang
  • J.M. Adler
  • K. Eschke
  • M. Nascimento
  • A. Abdelgawad
  • A.D. Gruber
  • J. Bushe
  • O. Kershaw
  • C.G. Knutson
  • K.K. Balavenkatraman
  • K. Ramanathan
  • E. Wyler
  • L.G. Teixeira Alves
  • S. Lewis
  • R. Watson
  • M.A. Haeuptle
  • A. Zürcher
  • K.M. Dawson
  • D. Steiner
  • C.D. Weiss
  • P. Amstutz
  • F.J.M. van Kuppeveld
  • M.T. Stumpp
  • B.J. Bosch
  • O. Engler
  • J. Trimpert


  • Nature Biotechnology


  • Nat Biotechnol 40 (12): 1845-1854


  • 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).