Abstract: bioRxiv preprint doi: https://doi.org/10.1101/2021.02.03.429164; this version posted December 17, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Ensovibep, a novel trispecific DARPin candidate that protects against 2 SARS-CoV-2 variants 3 Sylvia Rothenberger1,2,*, Daniel L. Hurdiss4,5,*, Marcel Walser3,*, Francesca Malvezzi3,*, Jennifer Mayor1,2, 4 Sarah Ryter1, Hector Moreno2, Nicole Liechti1, Andreas Bosshart3, Chloe Iss3, Valérie Calabro3, Andreas 5 Cornelius3, Tanja Hospodarsch3, Alexandra Neculcea3, Thamar Looser3, Anja Schlegel3, Simon Fontaine3, 6 Denis Villemagne3, Maria Paladino3, Yvonne Kaufmann3, Doris Schaible3, Iris Schlegel3, Dieter Schiegg3, 7 Christof Zitt3, Gabriel Sigrist3, Marcel Straumann3, Julia Wolter3, Marco Comby3, Julia M. Adler9, Kathrin 8 Eschke9, Mariana Nascimento9, Azza Abdelgawad9, Achim D. Gruber10, Judith Bushe10, Olivia Kershaw10, 9 Heyrhyoung Lyoo4, Chunyan Wang4, Wentao Li4, Ieva Drulyte6, Wenjuan Du4, H. Kaspar Binz7, Rachel 10 Herrup8, Sabrina Lusvarghi8, Sabari Nath Neerukonda8, Russell Vassell8, Wei Wang8, Susanne Mangold3, 11 Christian Reichen3, Filip Radom3, Charles G. Knutson11, Kamal K. Balavenkatraman12, Krishnan 12 Ramanathan13, Seth Lewis3, Randall Watson3, Micha A. Haeuptle3, Alexander Zürcher3, Keith M. 13 Dawson3, Daniel Steiner3, Carol D. Weiss8, Patrick Amstutz3, Frank J.M. van Kuppeveld4, Michael T. 14 Stumpp3,14,**, Berend-Jan Bosch4,**, Olivier Engler1,**, Jakob Trimpert9,** 15 16 * These first authors contributed equally to this work 17 ** These senior authors contributed equally to this work 18 1 19 2 20 1011 Lausanne, Switzerland 21 3 22 4 23 section, Faculty of Veterinary Medicine, Utrecht University, 3584 CL, Utrecht, The Netherlands. 24 5 25 Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands 26 6 27 7 28 8 29 Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA 30 9 31 10 32 Germany 33 11 34 12 Spiez Laboratory, Austrasse, 3700 Spiez, Switzerland Institute of Microbiology, University Hospital Center and University of Lausanne, Rue du Bugnon 48, Molecular Partners AG, Wagistrasse 14, 8952 Zurich-Schlieren, Switzerland Department Biomolecular Health Sciences, Division Infectious Diseases & Immunology - Virology Cryo-Electron Microscopy, Bijvoet Center for Biomolecular Research, Department of Chemistry, Materials and Structural Analysis, Thermo Fisher Scientific, Eindhoven, 5651 GG, The Netherlands. Binz Biotech Consulting, Lüssirainstrasse 52, 6300 Zug Laboratory of Immunoregulation, Division of Viral Products, Center for Biologics Evaluation and Freie Universität Berlin, Institut für Virologie, Robert-von Ostertag-Straße 7-13, 14163 Berlin, Germany Freie Universität Berlin, Institut für Tierpathologie, Robert-von Ostertag-Straße 15, 14163 Berlin, Novartis Institutes for BioMedical Research, PK Sciences, Cambridge, MA, USA Novartis Institutes for BioMedical Research, Preclinical Safety, Basel, Switzerland 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.02.03.429164; this version posted December 17, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the..