| Autor: |
Sylvia Rothenberger, Daniel L. Hurdiss, Marcel Walser, Francesca Malvezzi, Jennifer Mayor, Sarah Ryter, Hector Moreno, Nicole Liechti, Andreas Bosshart, Chloe Iss, Valérie Calabro, Andreas Cornelius, Tanja Hospodarsch, Alexandra Neculcea, Thamar Looser, Anja Schlegel, Simon Fontaine, Denis Villemagne, Maria Paladino, Yvonne Kaufmann, Doris Schaible, Iris Schlegel, Dieter Schiegg, Christof Zitt, Gabriel Sigrist, Marcel Straumann, Feyza Sacarcelik, Julia Wolter, Marco Comby, Julia M. Adler, Kathrin Eschke, Mariana Nascimento, Azza Abdelgawad, Achim D. Gruber, Judith Bushe, Olivia Kershaw, Heyrhyoung Lyoo, Chunyan Wang, Wentao Li, Ieva Drulyte, Wenjuan Du, H. Kaspar Binz, Rachel Herrup, Sabrina Lusvarghi, Sabari Nath Neerukonda, Russell Vassell, Wei Wang, Susanne Mangold, Christian Reichen, Filip Radom, Charles G. Knutson, Kamal K. Balavenkatraman, Krishnan Ramanathan, Seth Lewis, Randall Watson, Micha A. Haeuptle, Alexander Zürcher, Keith M. Dawson, Daniel Steiner, Carol D. Weiss, Patrick Amstutz, Frank J.M. van Kuppeveld, Michael T. Stumpp, Berend-Jan Bosch, Olivier Engler, Jakob Trimpert |
| Rok vydání: |
2021 |
| Předmět: |
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| DOI: |
10.1101/2021.02.03.429164 |
| Popis: |
The SARS-CoV-2 virus responsible for the COVID-19 pandemic has so far infected more than 160 million people globally, and continues to undergo genomic evolution. Emerging SARS-CoV-2 variants show increased infectivity and may lead to resistance against immune responses of previously immunized individuals or existing therapeutics, especially antibody-based therapies. Several monoclonal antibody therapeutics authorized for emergency use or in development have been shown to lose potency against some SARS-CoV-2 variants. Cocktails of two different monoclonal antibodies constitute a promising approach to protect against novel emerging variants as long as both antibodies are potent, but come with increased development complexity and therefore cost. As an alternative, we developed two multispecific DARPin® therapeutics, each combining three independent DARPin® domains binding the SARS-CoV-2 spike protein in one molecule, to potently neutralize the virus and overcome virus escape. Here, we show in a panel of in vitro studies that the multispecific DARPin® therapeutic design incorporated in our clinical candidate ensovibep (MP0420), achieved high neutralization potencies against the circulating SARS-CoV-2 variants B.1.1.7 (UK variant), B.1.351 (South African variant), P.1 (Brazilian variant), B.1.429 (South Californian variant), B.1.526 (New York variant), R.1 (Japanese variant), A.23.1 (Ugandan variant), and B.1.617 (Indian variant), and there is strong evidence that ensovibep also potently neutralizes the Indian variant B.1.618 based on the analysis of the key point mutations in the spike protein of this variant. Additionally, viral passaging experiments show potent protection by ensovibep and MP0423 against development of escape mutations. Finally, we demonstrate that the cooperative binding of the individual modules in a multispecific DARPin® antiviral is key for potent virus inhibition and protection from escape variants. These results, combined with the relatively small size and high production yields of DARPin® molecules, suggest that ensovibep is a highly valuable alternative to monoclonal antibody cocktails for global supply and demonstrate the strength of the DARPin® platform for achieving potent and lasting virus inhibition for SARS-CoV-2 and possibly other viruses. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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