tetano
Editor, Senior Moderator
Nat Biotechnol
. 2022 Jul 21.
doi: 10.1038/s41587-022-01382-3. Online ahead of print.
The trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants
Sylvia Rothenberger[SUP] #[/SUP][SUP] 1 2 [/SUP], Daniel L Hurdiss[SUP] #[/SUP][SUP] 3 4 [/SUP], Marcel Walser[SUP] #[/SUP][SUP] 5 [/SUP], Francesca Malvezzi[SUP] #[/SUP][SUP] 5 [/SUP], Jennifer Mayor[SUP] 1 2 [/SUP], Sarah Ryter[SUP] 1 [/SUP], Hector Moreno[SUP] 2 [/SUP], Nicole Liechti[SUP] 1 [/SUP], Andreas Bosshart[SUP] 5 [/SUP], Chloé Iss[SUP] 5 [/SUP], Valérie Calabro[SUP] 5 [/SUP], Andreas Cornelius[SUP] 5 [/SUP], Tanja Hospodarsch[SUP] 5 [/SUP], Alexandra Neculcea[SUP] 5 [/SUP], Thamar Looser[SUP] 5 [/SUP], Anja Schlegel[SUP] 5 [/SUP], Simon Fontaine[SUP] 5 [/SUP], Denis Villemagne[SUP] 5 [/SUP], Maria Paladino[SUP] 5 [/SUP], Dieter Schiegg[SUP] 5 [/SUP], Susanne Mangold[SUP] 5 [/SUP], Christian Reichen[SUP] 5 [/SUP], Filip Radom[SUP] 5 [/SUP], Yvonne Kaufmann[SUP] 5 [/SUP], Doris Schaible[SUP] 5 [/SUP], Iris Schlegel[SUP] 5 [/SUP], Christof Zitt[SUP] 5 [/SUP], Gabriel Sigrist[SUP] 5 [/SUP], Marcel Straumann[SUP] 5 [/SUP], Julia Wolter[SUP] 5 [/SUP], Marco Comby[SUP] 5 [/SUP], Feyza Sacarcelik[SUP] 5 [/SUP], Ieva Drulyte[SUP] 6 [/SUP], Heyrhyoung Lyoo[SUP] 3 [/SUP], Chunyan Wang[SUP] 3 [/SUP], Wentao Li[SUP] 3 [/SUP], Wenjuan Du[SUP] 3 [/SUP], H Kaspar Binz[SUP] 7 [/SUP], Rachel Herrup[SUP] 8 [/SUP], Sabrina Lusvarghi[SUP] 8 [/SUP], Sabari Nath Neerukonda[SUP] 8 [/SUP], Russell Vassell[SUP] 8 [/SUP], Wei Wang[SUP] 8 [/SUP], Julia M Adler[SUP] 9 [/SUP], Kathrin Eschke[SUP] 9 [/SUP], Mariana Nascimento[SUP] 9 [/SUP], Azza Abdelgawad[SUP] 9 [/SUP], Achim D Gruber[SUP] 10 [/SUP], Judith Bushe[SUP] 10 [/SUP], Olivia Kershaw[SUP] 10 [/SUP], Charles G Knutson[SUP] 11 [/SUP], Kamal K Balavenkatraman[SUP] 12 [/SUP], Krishnan Ramanathan[SUP] 13 [/SUP], Emanuel Wyler[SUP] 14 [/SUP], Luiz Gustavo Teixeira Alves[SUP] 14 [/SUP], Seth Lewis[SUP] 5 [/SUP], Randall Watson[SUP] 5 [/SUP], Micha A Haeuptle[SUP] 5 [/SUP], Alexander Zürcher[SUP] 5 [/SUP], Keith M Dawson[SUP] 5 [/SUP], Daniel Steiner[SUP] 5 [/SUP], Carol D Weiss[SUP] 8 [/SUP], Patrick Amstutz[SUP] 5 [/SUP], Frank J M van Kuppeveld[SUP] 3 [/SUP], Michael T Stumpp[SUP] 15 [/SUP], Berend-Jan Bosch[SUP] 3 [/SUP], Olivier Engler[SUP] 1 [/SUP], Jakob Trimpert[SUP] 9 [/SUP]
Affiliations
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).
. 2022 Jul 21.
doi: 10.1038/s41587-022-01382-3. Online ahead of print.
The trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants
Sylvia Rothenberger[SUP] #[/SUP][SUP] 1 2 [/SUP], Daniel L Hurdiss[SUP] #[/SUP][SUP] 3 4 [/SUP], Marcel Walser[SUP] #[/SUP][SUP] 5 [/SUP], Francesca Malvezzi[SUP] #[/SUP][SUP] 5 [/SUP], Jennifer Mayor[SUP] 1 2 [/SUP], Sarah Ryter[SUP] 1 [/SUP], Hector Moreno[SUP] 2 [/SUP], Nicole Liechti[SUP] 1 [/SUP], Andreas Bosshart[SUP] 5 [/SUP], Chloé Iss[SUP] 5 [/SUP], Valérie Calabro[SUP] 5 [/SUP], Andreas Cornelius[SUP] 5 [/SUP], Tanja Hospodarsch[SUP] 5 [/SUP], Alexandra Neculcea[SUP] 5 [/SUP], Thamar Looser[SUP] 5 [/SUP], Anja Schlegel[SUP] 5 [/SUP], Simon Fontaine[SUP] 5 [/SUP], Denis Villemagne[SUP] 5 [/SUP], Maria Paladino[SUP] 5 [/SUP], Dieter Schiegg[SUP] 5 [/SUP], Susanne Mangold[SUP] 5 [/SUP], Christian Reichen[SUP] 5 [/SUP], Filip Radom[SUP] 5 [/SUP], Yvonne Kaufmann[SUP] 5 [/SUP], Doris Schaible[SUP] 5 [/SUP], Iris Schlegel[SUP] 5 [/SUP], Christof Zitt[SUP] 5 [/SUP], Gabriel Sigrist[SUP] 5 [/SUP], Marcel Straumann[SUP] 5 [/SUP], Julia Wolter[SUP] 5 [/SUP], Marco Comby[SUP] 5 [/SUP], Feyza Sacarcelik[SUP] 5 [/SUP], Ieva Drulyte[SUP] 6 [/SUP], Heyrhyoung Lyoo[SUP] 3 [/SUP], Chunyan Wang[SUP] 3 [/SUP], Wentao Li[SUP] 3 [/SUP], Wenjuan Du[SUP] 3 [/SUP], H Kaspar Binz[SUP] 7 [/SUP], Rachel Herrup[SUP] 8 [/SUP], Sabrina Lusvarghi[SUP] 8 [/SUP], Sabari Nath Neerukonda[SUP] 8 [/SUP], Russell Vassell[SUP] 8 [/SUP], Wei Wang[SUP] 8 [/SUP], Julia M Adler[SUP] 9 [/SUP], Kathrin Eschke[SUP] 9 [/SUP], Mariana Nascimento[SUP] 9 [/SUP], Azza Abdelgawad[SUP] 9 [/SUP], Achim D Gruber[SUP] 10 [/SUP], Judith Bushe[SUP] 10 [/SUP], Olivia Kershaw[SUP] 10 [/SUP], Charles G Knutson[SUP] 11 [/SUP], Kamal K Balavenkatraman[SUP] 12 [/SUP], Krishnan Ramanathan[SUP] 13 [/SUP], Emanuel Wyler[SUP] 14 [/SUP], Luiz Gustavo Teixeira Alves[SUP] 14 [/SUP], Seth Lewis[SUP] 5 [/SUP], Randall Watson[SUP] 5 [/SUP], Micha A Haeuptle[SUP] 5 [/SUP], Alexander Zürcher[SUP] 5 [/SUP], Keith M Dawson[SUP] 5 [/SUP], Daniel Steiner[SUP] 5 [/SUP], Carol D Weiss[SUP] 8 [/SUP], Patrick Amstutz[SUP] 5 [/SUP], Frank J M van Kuppeveld[SUP] 3 [/SUP], Michael T Stumpp[SUP] 15 [/SUP], Berend-Jan Bosch[SUP] 3 [/SUP], Olivier Engler[SUP] 1 [/SUP], Jakob Trimpert[SUP] 9 [/SUP]
Affiliations
- PMID: 35864170
- DOI: 10.1038/s41587-022-01382-3
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).