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Nanobodies to multiple spike variants and inhalation of nanobody-containing aerosols neutralize SARS-CoV-2 in cell culture and hamsters

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Aksu,  Metin
Department of Cellular Logistics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Güttler,  Thomas
Department of Cellular Logistics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Taxer,  Waltraud
Department of Cellular Logistics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Gregor,  Kathrin
Department of Cellular Logistics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Mußil,  Bianka
Department of Cellular Logistics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Rymarenko,  Oleh
Department of Cellular Logistics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Dobbelstein,  Matthias
Department of Cellular Logistics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Görlich,  Dirk
Department of Cellular Logistics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Citation

Aksu, M., Kumar, P., Güttler, T., Taxer, W., Gregor, K., Mußil, B., et al. (2024). Nanobodies to multiple spike variants and inhalation of nanobody-containing aerosols neutralize SARS-CoV-2 in cell culture and hamsters. Antiviral Research, 221: 105778. doi:10.1016/j.antiviral.2023.105778.


Cite as: https://hdl.handle.net/21.11116/0000-000E-2ABF-D
Abstract
The ongoing threat of COVID-19 has highlighted the need for effective prophylaxis and convenient therapies, especially for outpatient settings. We have previously developed highly potent single-domain (VHH) antibodies, also known as nanobodies, that target the Receptor Binding Domain (RBD) of the SARS-CoV-2 Spike protein and neutralize the Wuhan strain of the virus. In this study, we present a new generation of anti-RBD nanobodies with superior properties. The primary representative of this group, Re32D03, neutralizes Alpha to Delta as well as Omicron BA.2.75; other members neutralize, in addition, Omicron BA.1, BA.2, BA.4/5, and XBB.1. Crystal structures of RBD-nanobody complexes reveal how ACE2-binding is blocked and also explain the nanobodies’ tolerance to immune escape mutations. Through the cryo-EM structure of the Ma16B06-BA.1 Spike complex, we demonstrated how a single nanobody molecule can neutralize a trimeric spike. We also describe a method for large-scale production of these nanobodies in Pichia pastoris, and for formulating them into aerosols. Exposing hamsters to these aerosols, before or even 24 h after infection with SARS-CoV-2, significantly reduced virus load, weight loss and pathogenicity. These results show the potential of aerosolized nanobodies for prophylaxis and therapy of coronavirus infections.