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

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) clini...

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Autores principales: Rothenberger, Sylvia, Hurdiss, Daniel L., Walser, Marcel, Malvezzi, Francesca, Mayor, Jennifer, Ryter, Sarah, Moreno, Hector, Liechti, Nicole, Bosshart, Andreas, Iss, Chloé, Calabro, Valérie, Cornelius, Andreas, Hospodarsch, Tanja, Neculcea, Alexandra, Looser, Thamar, Schlegel, Anja, Fontaine, Simon, Villemagne, Denis, 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, Heyrhyoung, Wang, Chunyan, Li, Wentao, Du, Wenjuan, Binz, H. Kaspar, Herrup, Rachel, Lusvarghi, Sabrina, Neerukonda, Sabari Nath, Vassell, Russell, Wang, Wei, Adler, Julia M., Eschke, Kathrin, Nascimento, Mariana, Abdelgawad, Azza, Gruber, Achim D., Bushe, Judith, Kershaw, Olivia, Knutson, Charles G., Balavenkatraman, Kamal K., Ramanathan, Krishnan, Wyler, Emanuel, Teixeira Alves, Luiz Gustavo, Lewis, Seth, Watson, Randall, Haeuptle, Micha A., Zürcher, Alexander, Dawson, Keith M., Steiner, Daniel, Weiss, Carol D., Amstutz, Patrick, van Kuppeveld, Frank J. M., Stumpp, Michael T., Bosch, Berend-Jan, Engler, Olivier, Trimpert, Jakob
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group US 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9750863/
https://www.ncbi.nlm.nih.gov/pubmed/35864170
http://dx.doi.org/10.1038/s41587-022-01382-3
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author Rothenberger, Sylvia
Hurdiss, Daniel L.
Walser, Marcel
Malvezzi, Francesca
Mayor, Jennifer
Ryter, Sarah
Moreno, Hector
Liechti, Nicole
Bosshart, Andreas
Iss, Chloé
Calabro, Valérie
Cornelius, Andreas
Hospodarsch, Tanja
Neculcea, Alexandra
Looser, Thamar
Schlegel, Anja
Fontaine, Simon
Villemagne, Denis
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, Heyrhyoung
Wang, Chunyan
Li, Wentao
Du, Wenjuan
Binz, H. Kaspar
Herrup, Rachel
Lusvarghi, Sabrina
Neerukonda, Sabari Nath
Vassell, Russell
Wang, Wei
Adler, Julia M.
Eschke, Kathrin
Nascimento, Mariana
Abdelgawad, Azza
Gruber, Achim D.
Bushe, Judith
Kershaw, Olivia
Knutson, Charles G.
Balavenkatraman, Kamal K.
Ramanathan, Krishnan
Wyler, Emanuel
Teixeira Alves, Luiz Gustavo
Lewis, Seth
Watson, Randall
Haeuptle, Micha A.
Zürcher, Alexander
Dawson, Keith M.
Steiner, Daniel
Weiss, Carol D.
Amstutz, Patrick
van Kuppeveld, Frank J. M.
Stumpp, Michael T.
Bosch, Berend-Jan
Engler, Olivier
Trimpert, Jakob
author_facet Rothenberger, Sylvia
Hurdiss, Daniel L.
Walser, Marcel
Malvezzi, Francesca
Mayor, Jennifer
Ryter, Sarah
Moreno, Hector
Liechti, Nicole
Bosshart, Andreas
Iss, Chloé
Calabro, Valérie
Cornelius, Andreas
Hospodarsch, Tanja
Neculcea, Alexandra
Looser, Thamar
Schlegel, Anja
Fontaine, Simon
Villemagne, Denis
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, Heyrhyoung
Wang, Chunyan
Li, Wentao
Du, Wenjuan
Binz, H. Kaspar
Herrup, Rachel
Lusvarghi, Sabrina
Neerukonda, Sabari Nath
Vassell, Russell
Wang, Wei
Adler, Julia M.
Eschke, Kathrin
Nascimento, Mariana
Abdelgawad, Azza
Gruber, Achim D.
Bushe, Judith
Kershaw, Olivia
Knutson, Charles G.
Balavenkatraman, Kamal K.
Ramanathan, Krishnan
Wyler, Emanuel
Teixeira Alves, Luiz Gustavo
Lewis, Seth
Watson, Randall
Haeuptle, Micha A.
Zürcher, Alexander
Dawson, Keith M.
Steiner, Daniel
Weiss, Carol D.
Amstutz, Patrick
van Kuppeveld, Frank J. M.
Stumpp, Michael T.
Bosch, Berend-Jan
Engler, Olivier
Trimpert, Jakob
author_sort Rothenberger, Sylvia
collection PubMed
description 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).
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spelling pubmed-97508632022-12-16 The trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants Rothenberger, Sylvia Hurdiss, Daniel L. Walser, Marcel Malvezzi, Francesca Mayor, Jennifer Ryter, Sarah Moreno, Hector Liechti, Nicole Bosshart, Andreas Iss, Chloé Calabro, Valérie Cornelius, Andreas Hospodarsch, Tanja Neculcea, Alexandra Looser, Thamar Schlegel, Anja Fontaine, Simon Villemagne, Denis 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, Heyrhyoung Wang, Chunyan Li, Wentao Du, Wenjuan Binz, H. Kaspar Herrup, Rachel Lusvarghi, Sabrina Neerukonda, Sabari Nath Vassell, Russell Wang, Wei Adler, Julia M. Eschke, Kathrin Nascimento, Mariana Abdelgawad, Azza Gruber, Achim D. Bushe, Judith Kershaw, Olivia Knutson, Charles G. Balavenkatraman, Kamal K. Ramanathan, Krishnan Wyler, Emanuel Teixeira Alves, Luiz Gustavo Lewis, Seth Watson, Randall Haeuptle, Micha A. Zürcher, Alexander Dawson, Keith M. Steiner, Daniel Weiss, Carol D. Amstutz, Patrick van Kuppeveld, Frank J. M. Stumpp, Michael T. Bosch, Berend-Jan Engler, Olivier Trimpert, Jakob Nat Biotechnol Article 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). Nature Publishing Group US 2022-07-21 2022 /pmc/articles/PMC9750863/ /pubmed/35864170 http://dx.doi.org/10.1038/s41587-022-01382-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Rothenberger, Sylvia
Hurdiss, Daniel L.
Walser, Marcel
Malvezzi, Francesca
Mayor, Jennifer
Ryter, Sarah
Moreno, Hector
Liechti, Nicole
Bosshart, Andreas
Iss, Chloé
Calabro, Valérie
Cornelius, Andreas
Hospodarsch, Tanja
Neculcea, Alexandra
Looser, Thamar
Schlegel, Anja
Fontaine, Simon
Villemagne, Denis
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, Heyrhyoung
Wang, Chunyan
Li, Wentao
Du, Wenjuan
Binz, H. Kaspar
Herrup, Rachel
Lusvarghi, Sabrina
Neerukonda, Sabari Nath
Vassell, Russell
Wang, Wei
Adler, Julia M.
Eschke, Kathrin
Nascimento, Mariana
Abdelgawad, Azza
Gruber, Achim D.
Bushe, Judith
Kershaw, Olivia
Knutson, Charles G.
Balavenkatraman, Kamal K.
Ramanathan, Krishnan
Wyler, Emanuel
Teixeira Alves, Luiz Gustavo
Lewis, Seth
Watson, Randall
Haeuptle, Micha A.
Zürcher, Alexander
Dawson, Keith M.
Steiner, Daniel
Weiss, Carol D.
Amstutz, Patrick
van Kuppeveld, Frank J. M.
Stumpp, Michael T.
Bosch, Berend-Jan
Engler, Olivier
Trimpert, Jakob
The trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants
title The trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants
title_full The trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants
title_fullStr The trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants
title_full_unstemmed The trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants
title_short The trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants
title_sort trispecific darpin ensovibep inhibits diverse sars-cov-2 variants
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9750863/
https://www.ncbi.nlm.nih.gov/pubmed/35864170
http://dx.doi.org/10.1038/s41587-022-01382-3
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