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Nanobodies recognizing conserved hidden clefts of all SARS-CoV-2 spike variants

View ORCID ProfileRyota Maeda, View ORCID ProfileJunso Fujita, View ORCID ProfileYoshinobu Konishi, View ORCID ProfileYasuhiro Kazuma, View ORCID ProfileHiroyuki Yamazaki, View ORCID ProfileItsuki Anzai, View ORCID ProfileKeishi Yamaguchi, View ORCID ProfileKazuki Kasai, Kayoko Nagata, View ORCID ProfileYutaro Yamaoka, View ORCID ProfileKei Miyakawa, View ORCID ProfileAkihide Ryo, View ORCID ProfileKotaro Shirakawa, View ORCID ProfileFumiaki Makino, View ORCID ProfileYoshiharu Matsuura, View ORCID ProfileTsuyoshi Inoue, View ORCID ProfileAkihiro Imura, View ORCID ProfileKeiichi Namba, View ORCID ProfileAkifumi Takaori-Kondo
doi: https://doi.org/10.1101/2021.10.25.465714
Ryota Maeda
1Department of Haematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
2COGNANO Inc., Kyoto, 601-1255, Japan
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Junso Fujita
3Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan
4Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
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Yoshinobu Konishi
1Department of Haematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
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  • ORCID record for Yoshinobu Konishi
Yasuhiro Kazuma
1Department of Haematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
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Hiroyuki Yamazaki
2COGNANO Inc., Kyoto, 601-1255, Japan
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Itsuki Anzai
5Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
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Keishi Yamaguchi
4Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
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  • ORCID record for Keishi Yamaguchi
Kazuki Kasai
2COGNANO Inc., Kyoto, 601-1255, Japan
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  • ORCID record for Kazuki Kasai
Kayoko Nagata
1Department of Haematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
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Yutaro Yamaoka
6Department of Microbiology and Molecular Biodefense Research, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
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Kei Miyakawa
6Department of Microbiology and Molecular Biodefense Research, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
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Akihide Ryo
6Department of Microbiology and Molecular Biodefense Research, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
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Kotaro Shirakawa
1Department of Haematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
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Fumiaki Makino
3Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan
7JEOL Ltd, Tokyo 196-8558, Japan
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Yoshiharu Matsuura
8Centre for Infectious Disease Education and Research, Osaka University, Osaka 565-0871, Japan
9Laboratory of Virus Control, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
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Tsuyoshi Inoue
4Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
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  • ORCID record for Tsuyoshi Inoue
Akihiro Imura
2COGNANO Inc., Kyoto, 601-1255, Japan
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  • For correspondence: akihiroimura@cognano.co.jp keiichi@fbs.osaka-u.ac.jp atakaori@kuhp.kyoto-u.ac.jp
Keiichi Namba
3Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan
10JEOL YOKOGUSHI Research Alliance Laboratories, Osaka University, Osaka 565-0871, Japan
11RIKEN Centre for Biosystems Dynamics Research and SPring-8 Centre, Osaka 565-0871, Japan
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  • For correspondence: akihiroimura@cognano.co.jp keiichi@fbs.osaka-u.ac.jp atakaori@kuhp.kyoto-u.ac.jp
Akifumi Takaori-Kondo
1Department of Haematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
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  • ORCID record for Akifumi Takaori-Kondo
  • For correspondence: akihiroimura@cognano.co.jp keiichi@fbs.osaka-u.ac.jp atakaori@kuhp.kyoto-u.ac.jp
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Abstract

We are in the midst of the historic coronavirus infectious disease 2019 (COVID-19) pandemic caused by severe respiratory syndrome coronavirus 2 (SARS-CoV-2). Although countless efforts to control the pandemic have been attempted—most successfully, vaccination1–3—imbalances in accessibility to vaccines, medicines, and diagnostics among countries, regions, and populations have been problematic. Camelid variable regions of heavy chain-only antibodies (VHHs or nanobodies)4 have unique modalities: they are smaller, more stable, easier to customize, and, importantly, less expensive to produce than conventional antibodies5, 6. We present the sequences of nine alpaca nanobodies that detect the spike proteins of four SARS-CoV-2 variants of concern (VOCs)—namely, the alpha, beta, gamma, and delta variants. We show that they can quantify or detect spike variants via ELISA and lateral flow, kinetic, flow cytometric, microscopy, and Western blotting assays7. The panel of nanobodies broadly neutralized viral infection by pseudotyped SARS-CoV-2 VOCs. Structural analyses showed that a P86 clone targeted epitopes that were conserved yet unclassified on the receptor-binding domain (RBD) and located inside the N-terminal domain (NTD). Human antibodies have hardly accessed both regions; consequently, the clone buries hidden crevasses of SARS-CoV-2 spike proteins undetected by conventional antibodies and maintains activity against spike proteins carrying escape mutations.

Competing Interest Statement

The authors have declared no competing interest.

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 4.0 International license.
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Posted October 26, 2021.
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Nanobodies recognizing conserved hidden clefts of all SARS-CoV-2 spike variants
Ryota Maeda, Junso Fujita, Yoshinobu Konishi, Yasuhiro Kazuma, Hiroyuki Yamazaki, Itsuki Anzai, Keishi Yamaguchi, Kazuki Kasai, Kayoko Nagata, Yutaro Yamaoka, Kei Miyakawa, Akihide Ryo, Kotaro Shirakawa, Fumiaki Makino, Yoshiharu Matsuura, Tsuyoshi Inoue, Akihiro Imura, Keiichi Namba, Akifumi Takaori-Kondo
bioRxiv 2021.10.25.465714; doi: https://doi.org/10.1101/2021.10.25.465714
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Nanobodies recognizing conserved hidden clefts of all SARS-CoV-2 spike variants
Ryota Maeda, Junso Fujita, Yoshinobu Konishi, Yasuhiro Kazuma, Hiroyuki Yamazaki, Itsuki Anzai, Keishi Yamaguchi, Kazuki Kasai, Kayoko Nagata, Yutaro Yamaoka, Kei Miyakawa, Akihide Ryo, Kotaro Shirakawa, Fumiaki Makino, Yoshiharu Matsuura, Tsuyoshi Inoue, Akihiro Imura, Keiichi Namba, Akifumi Takaori-Kondo
bioRxiv 2021.10.25.465714; doi: https://doi.org/10.1101/2021.10.25.465714

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