• Paul-Albert Koenig, Hrishikesh Das, Hejun Liu, Beate M Kümmerer, Florian N Gohr, Lea-Marie Jenster, Lisa D J Schiffelers, Yonas M Tesfamariam, Miki Uchima, Jennifer D Wuerth, Karl Gatterdam, Natalia Ruetalo, Maria H Christensen, Caroline I Fandrey, Sabine Normann, Jan M P Tödtmann, Steffen Pritzl, Leo Hanke, Jannik Boos, Meng Yuan, Xueyong Zhu, Jonathan L Schmid-Burgk, Hiroki Kato, Michael Schindler, Ian A Wilson, Matthias Geyer, Kerstin U Ludwig, B Martin Hällberg, Nicholas C Wu, and Florian I Schmidt.
• Core Facility Nanobodies, Medical Faculty, University of Bonn, 53127 Bonn, Germany. pakoenig@uni-bonn.de martin.hallberg@ki.se nicwu@illinois.edu fschmidt@uni-bonn.de.
• Science. 2021 Feb 12; 371 (6530).

AbstractThe pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread, with devastating consequences. For passive immunization efforts, nanobodies have size and cost advantages over conventional antibodies. In this study, we generated four neutralizing nanobodies that target the receptor binding domain of the SARS-CoV-2 spike protein. We used x-ray crystallography and cryo-electron microscopy to define two distinct binding epitopes. On the basis of these structures, we engineered multivalent nanobodies with more than 100 times the neutralizing activity of monovalent nanobodies. Biparatopic nanobody fusions suppressed the emergence of escape mutants. Several nanobody constructs neutralized through receptor binding competition, whereas other monovalent and biparatopic nanobodies triggered aberrant activation of the spike fusion machinery. These premature conformational changes in the spike protein forestalled productive fusion and rendered the virions noninfectious.Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

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