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Multispecific DARPin® therapeutics demonstrate very high potency against SARS-CoV-2 variants in vitro

Sylvia Rothenberger, Marcel Walser, Francesca Malvezzi, Jennifer Mayor, Sarah Ryter, Hector Moreno, Nicole Liechti, Silvan Hälg, Andreas Bosshart, Chloe Iss, Valérie Calabro, Andreas Cornelius, Tanja Hospodarsch, Alexandra Neculcea, Thamar Looser, Rachel Herrup, Sabrina Lusvarghi, Sabari Nath Neerukonda, Russell Vassell, Wei Wang, Susanne Mangold, Christian Reichen, Filip Radom, Keith M. Dawson, Seth Lewis, Daniel Steiner, Carol D. Weiss, Patrick Amstutz, Olivier Engler, View ORCID ProfileMichael T. Stumpp
doi: https://doi.org/10.1101/2021.02.03.429164
Sylvia Rothenberger
1Spiez Laboratory, Austrasse, 3700 Spiez, Switzerland
2Institute of Microbiology, University Hospital Center and University of Lausanne, Rue du Bugnon 48, 1011 Lausanne, Switzerland
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Marcel Walser
3Molecular Partners AG, Wagistrasse 14, 8952 Zurich-Schlieren, Switzerland
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Francesca Malvezzi
3Molecular Partners AG, Wagistrasse 14, 8952 Zurich-Schlieren, Switzerland
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Jennifer Mayor
1Spiez Laboratory, Austrasse, 3700 Spiez, Switzerland
2Institute of Microbiology, University Hospital Center and University of Lausanne, Rue du Bugnon 48, 1011 Lausanne, Switzerland
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Sarah Ryter
1Spiez Laboratory, Austrasse, 3700 Spiez, Switzerland
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Hector Moreno
2Institute of Microbiology, University Hospital Center and University of Lausanne, Rue du Bugnon 48, 1011 Lausanne, Switzerland
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Nicole Liechti
1Spiez Laboratory, Austrasse, 3700 Spiez, Switzerland
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Silvan Hälg
4Swiss Tropical and Public Health Institute, Department Epidemiology and Public Health, Basel, Switzerland. University of Basel, Basel, Switzerland
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Andreas Bosshart
3Molecular Partners AG, Wagistrasse 14, 8952 Zurich-Schlieren, Switzerland
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Chloe Iss
3Molecular Partners AG, Wagistrasse 14, 8952 Zurich-Schlieren, Switzerland
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Valérie Calabro
3Molecular Partners AG, Wagistrasse 14, 8952 Zurich-Schlieren, Switzerland
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Andreas Cornelius
3Molecular Partners AG, Wagistrasse 14, 8952 Zurich-Schlieren, Switzerland
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Tanja Hospodarsch
3Molecular Partners AG, Wagistrasse 14, 8952 Zurich-Schlieren, Switzerland
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Alexandra Neculcea
3Molecular Partners AG, Wagistrasse 14, 8952 Zurich-Schlieren, Switzerland
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Thamar Looser
3Molecular Partners AG, Wagistrasse 14, 8952 Zurich-Schlieren, Switzerland
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Rachel Herrup
5Laboratory of Immunoregulation, Division of Viral Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
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Sabrina Lusvarghi
5Laboratory of Immunoregulation, Division of Viral Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
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Sabari Nath Neerukonda
5Laboratory of Immunoregulation, Division of Viral Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
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Russell Vassell
5Laboratory of Immunoregulation, Division of Viral Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
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Wei Wang
5Laboratory of Immunoregulation, Division of Viral Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
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Susanne Mangold
3Molecular Partners AG, Wagistrasse 14, 8952 Zurich-Schlieren, Switzerland
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Christian Reichen
3Molecular Partners AG, Wagistrasse 14, 8952 Zurich-Schlieren, Switzerland
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Filip Radom
3Molecular Partners AG, Wagistrasse 14, 8952 Zurich-Schlieren, Switzerland
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Keith M. Dawson
3Molecular Partners AG, Wagistrasse 14, 8952 Zurich-Schlieren, Switzerland
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Seth Lewis
3Molecular Partners AG, Wagistrasse 14, 8952 Zurich-Schlieren, Switzerland
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Daniel Steiner
3Molecular Partners AG, Wagistrasse 14, 8952 Zurich-Schlieren, Switzerland
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Carol D. Weiss
5Laboratory of Immunoregulation, Division of Viral Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
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Patrick Amstutz
3Molecular Partners AG, Wagistrasse 14, 8952 Zurich-Schlieren, Switzerland
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Olivier Engler
1Spiez Laboratory, Austrasse, 3700 Spiez, Switzerland
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Michael T. Stumpp
3Molecular Partners AG, Wagistrasse 14, 8952 Zurich-Schlieren, Switzerland
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  • ORCID record for Michael T. Stumpp
  • For correspondence: info@molecularpartners.com
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Abstract

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.

Competing Interest Statement

Molecular Partners authors own performance share units and/or stock of the company.

Footnotes

  • DARPin® is a registered trademark owned by Molecular Partners AG

  • The revision includes additional data, highly relevant for the COVID-19 pandemic, incl. data from the viral strains first described in India (B.1.617 & .618).

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 26, 2021.
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Multispecific DARPin® therapeutics demonstrate very high potency against SARS-CoV-2 variants in vitro
Sylvia Rothenberger, Marcel Walser, Francesca Malvezzi, Jennifer Mayor, Sarah Ryter, Hector Moreno, Nicole Liechti, Silvan Hälg, Andreas Bosshart, Chloe Iss, Valérie Calabro, Andreas Cornelius, Tanja Hospodarsch, Alexandra Neculcea, Thamar Looser, Rachel Herrup, Sabrina Lusvarghi, Sabari Nath Neerukonda, Russell Vassell, Wei Wang, Susanne Mangold, Christian Reichen, Filip Radom, Keith M. Dawson, Seth Lewis, Daniel Steiner, Carol D. Weiss, Patrick Amstutz, Olivier Engler, Michael T. Stumpp
bioRxiv 2021.02.03.429164; doi: https://doi.org/10.1101/2021.02.03.429164
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Multispecific DARPin® therapeutics demonstrate very high potency against SARS-CoV-2 variants in vitro
Sylvia Rothenberger, Marcel Walser, Francesca Malvezzi, Jennifer Mayor, Sarah Ryter, Hector Moreno, Nicole Liechti, Silvan Hälg, Andreas Bosshart, Chloe Iss, Valérie Calabro, Andreas Cornelius, Tanja Hospodarsch, Alexandra Neculcea, Thamar Looser, Rachel Herrup, Sabrina Lusvarghi, Sabari Nath Neerukonda, Russell Vassell, Wei Wang, Susanne Mangold, Christian Reichen, Filip Radom, Keith M. Dawson, Seth Lewis, Daniel Steiner, Carol D. Weiss, Patrick Amstutz, Olivier Engler, Michael T. Stumpp
bioRxiv 2021.02.03.429164; doi: https://doi.org/10.1101/2021.02.03.429164

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