Potent SARS-CoV-2 neutralizing antibodies with therapeutic effects in two animal models

Masaru Takeshita; Hidehiro Fukuyama; Katsuhiko Kamada; Takehisa Matsumoto; Chieko Makino-Okamura; Tomomi Uchikubo-Kamo; Yuri Tomabechi; Kazuharu Hanada; Saya Moriyama; Yoshimasa Takahashi; Hirohito Ishigaki; Misako Nakayama; Cong Thanh Nguyen; Yoshinori Kitagawa; Yasushi Itoh; Masaki Imai; Tadashi Maemura; Yuri Furusawa; Hiroshi Ueki; Kiyoko Iwatsuki-Horimoto; Mutsumi Ito; Seiya Yamayoshi; Yoshihiro Kawaoka; Mikako Shirouzu; Makoto Ishii; Hideyuki Saya; Yasushi Kondo; Yuko Kaneko; Katsuya Suzuki; Koichi Fukunaga; Tsutomu Takeuchi

doi:10.1016/j.isci.2022.105596

Potent SARS-CoV-2 neutralizing antibodies with therapeutic effects in two animal models

Masaru Takeshita, Hidehiro Fukuyama, Katsuhiko Kamada, Takehisa Matsumoto, Chieko Makino-Okamura, Tomomi Uchikubo-Kamo, Yuri Tomabechi, Kazuharu Hanada, Saya Moriyama, Yoshimasa Takahashi, Hirohito Ishigaki, Misako Nakayama, Cong Thanh Nguyen, Yoshinori Kitagawa, Yasushi Itoh, Masaki Imai, Tadashi Maemura, Yuri Furusawa, Hiroshi Ueki, Kiyoko Iwatsuki-HorimotoMutsumi Ito, Seiya Yamayoshi, Yoshihiro Kawaoka, Mikako Shirouzu, Makoto Ishii, Hideyuki Saya, Yasushi Kondo, Yuko Kaneko, Katsuya Suzuki, Koichi Fukunaga, Tsutomu Takeuchi

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

Abstract

The use of therapeutic neutralizing antibodies against SARS-CoV-2 infection has been highly effective. However, there remain few practical antibodies against viruses that are acquiring mutations. In this study, we created 494 monoclonal antibodies from patients with COVID-19-convalescent, and identified antibodies that exhibited the comparable neutralizing ability to clinically used antibodies in the neutralization assay using pseudovirus and authentic virus including variants of concerns. These antibodies have different profiles against various mutations, which were confirmed by cell-based assay and cryo-electron microscopy. To prevent antibody-dependent enhancement, N297A modification was introduced. Our antibodies showed a reduction of lung viral RNAs by therapeutic administration in a hamster model. In addition, an antibody cocktail consisting of three antibodies was also administered therapeutically to a macaque model, which resulted in reduced viral titers of swabs and lungs and reduced lung tissue damage scores. These results showed that our antibodies have sufficient antiviral activity as therapeutic candidates.

Original language	English
Article number	105596
Journal	iScience
Volume	25
Issue number	12
DOIs	https://doi.org/10.1016/j.isci.2022.105596
Publication status	Published - 2022 Dec 22

Keywords

Unology
immune response
virology

ASJC Scopus subject areas

General

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10.1016/j.isci.2022.105596

Cite this

Takeshita, M., Fukuyama, H., Kamada, K., Matsumoto, T., Makino-Okamura, C., Uchikubo-Kamo, T., Tomabechi, Y., Hanada, K., Moriyama, S., Takahashi, Y., Ishigaki, H., Nakayama, M., Nguyen, C. T., Kitagawa, Y., Itoh, Y., Imai, M., Maemura, T., Furusawa, Y., Ueki, H., ... Takeuchi, T. (2022). Potent SARS-CoV-2 neutralizing antibodies with therapeutic effects in two animal models. iScience, 25(12), Article 105596. https://doi.org/10.1016/j.isci.2022.105596

Takeshita, M, Fukuyama, H, Kamada, K, Matsumoto, T, Makino-Okamura, C, Uchikubo-Kamo, T, Tomabechi, Y, Hanada, K, Moriyama, S, Takahashi, Y, Ishigaki, H, Nakayama, M, Nguyen, CT, Kitagawa, Y, Itoh, Y, Imai, M, Maemura, T, Furusawa, Y, Ueki, H, Iwatsuki-Horimoto, K, Ito, M, Yamayoshi, S, Kawaoka, Y, Shirouzu, M, Ishii, M, Saya, H, Kondo, Y , Kaneko, Y, Suzuki, K, Fukunaga, K & Takeuchi, T 2022, 'Potent SARS-CoV-2 neutralizing antibodies with therapeutic effects in two animal models', iScience, vol. 25, no. 12, 105596. https://doi.org/10.1016/j.isci.2022.105596

@article{c5febd164c2a443dad03f1695465ee68,

title = "Potent SARS-CoV-2 neutralizing antibodies with therapeutic effects in two animal models",

abstract = "The use of therapeutic neutralizing antibodies against SARS-CoV-2 infection has been highly effective. However, there remain few practical antibodies against viruses that are acquiring mutations. In this study, we created 494 monoclonal antibodies from patients with COVID-19-convalescent, and identified antibodies that exhibited the comparable neutralizing ability to clinically used antibodies in the neutralization assay using pseudovirus and authentic virus including variants of concerns. These antibodies have different profiles against various mutations, which were confirmed by cell-based assay and cryo-electron microscopy. To prevent antibody-dependent enhancement, N297A modification was introduced. Our antibodies showed a reduction of lung viral RNAs by therapeutic administration in a hamster model. In addition, an antibody cocktail consisting of three antibodies was also administered therapeutically to a macaque model, which resulted in reduced viral titers of swabs and lungs and reduced lung tissue damage scores. These results showed that our antibodies have sufficient antiviral activity as therapeutic candidates.",

keywords = "Unology, immune response, virology",

author = "Masaru Takeshita and Hidehiro Fukuyama and Katsuhiko Kamada and Takehisa Matsumoto and Chieko Makino-Okamura and Tomomi Uchikubo-Kamo and Yuri Tomabechi and Kazuharu Hanada and Saya Moriyama and Yoshimasa Takahashi and Hirohito Ishigaki and Misako Nakayama and Nguyen, {Cong Thanh} and Yoshinori Kitagawa and Yasushi Itoh and Masaki Imai and Tadashi Maemura and Yuri Furusawa and Hiroshi Ueki and Kiyoko Iwatsuki-Horimoto and Mutsumi Ito and Seiya Yamayoshi and Yoshihiro Kawaoka and Mikako Shirouzu and Makoto Ishii and Hideyuki Saya and Yasushi Kondo and Yuko Kaneko and Katsuya Suzuki and Koichi Fukunaga and Tsutomu Takeuchi",

note = "Funding Information: We thank Yukari Kaneda, Mami Yamada, Mayumi Yonemochi, Mariko Ikeda, Mio Inoue, Naoko Kitagawa, and Hideaki Ishida for helping with the experiments, and Ikuo Kawamoto, Takahiro Nakagawa, Hideaki Tsuchiya, and Iori Itagaki for animal care. We also thank Dr. Takehiro Suzuki (Biomolecular Characterization Unit, RIKEN CSRS) for glycosylation analysis by mass spectrometry. The cryo-EM experiments were performed at the cryo-EM facility of the RIKEN Center for Biosystems Dynamics Research Yokohama. This study was supported by the Collaborative Research Resources , Keio University School of Medicine , and was funded by a research grant for COVID-19 in Keio University School of Medicine (Donner Research Project Grant); by AMED under Grant Numbers JP20fk0108283 , JP21ym0126022 , and JP21fk0108468 ; by the RIKEN President{\textquoteright}s discretionary funds; and by the Mitsubishi Foundation . Funding Information: We thank Yukari Kaneda, Mami Yamada, Mayumi Yonemochi, Mariko Ikeda, Mio Inoue, Naoko Kitagawa, and Hideaki Ishida for helping with the experiments, and Ikuo Kawamoto, Takahiro Nakagawa, Hideaki Tsuchiya, and Iori Itagaki for animal care. We also thank Dr. Takehiro Suzuki (Biomolecular Characterization Unit, RIKEN CSRS) for glycosylation analysis by mass spectrometry. The cryo-EM experiments were performed at the cryo-EM facility of the RIKEN Center for Biosystems Dynamics Research Yokohama. This study was supported by the Collaborative Research Resources, Keio University School of Medicine, and was funded by a research grant for COVID-19 in Keio University School of Medicine (Donner Research Project Grant); by AMED under Grant Numbers JP20fk0108283, JP21ym0126022, and JP21fk0108468; by the RIKEN President's discretionary funds; and by the Mitsubishi Foundation. M.T. H.S. Y.Kaneko, K.S. T.T. co-ordinated all of the research activities. M.T. wrote the initial draft of the article. Y.T. M.S. K.K. and Y.I. contributed to the editing of the article. H.S. M.Ishii, Y.Kondo, and K.F. contributed to the sample collection. M.T. performed cell-based Spike-ACE2 inhibition assay, cell sorting and antibody production, and biolayer interferometry. S.M. and Y.Takahashi performed the authentic virus neutralization assay. H.F. performed the fusion inhibition assay, pseudovirus/authentic virus neutralization assay, and viral uptake measurement by Fc receptors. C.M−O performed pseudovirus neutralization assay. M.S. K.K. and T.U. performed cryo-EM analysis. T.Matsumoto, Y.Tomabechi. K.H. prepared recombinant antibodies and spike trimer protein. M.Imai, T.Maemura, Y.F. H.U. K.I-H. M.I. S.Y. Y.Kawaoka, and M.T. performed the studies in Syrian hamsters. M.T. H.I. M.N. C.T.N. Y.Kitagawa, and Y.I. performed the infection study of cynomolgus macaques. M.T. K.S. H.S. T.T. Y.T. S.M. H.F. M.S. T.M. K.K. Y.I. H.I. M.N. Y.Kitagawa, and Y.Kawaoka declared that they are co-inventors on a patent application on neutralizing antibodies described in this article (PCT/JP2021/35159). The remaining authors have no declarations of interest. Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = dec,

day = "22",

doi = "10.1016/j.isci.2022.105596",

language = "English",

volume = "25",

journal = "iScience",

issn = "2589-0042",

publisher = "Elsevier Inc.",

number = "12",

}

TY - JOUR

T1 - Potent SARS-CoV-2 neutralizing antibodies with therapeutic effects in two animal models

AU - Takeshita, Masaru

AU - Fukuyama, Hidehiro

AU - Kamada, Katsuhiko

AU - Matsumoto, Takehisa

AU - Makino-Okamura, Chieko

AU - Uchikubo-Kamo, Tomomi

AU - Tomabechi, Yuri

AU - Hanada, Kazuharu

AU - Moriyama, Saya

AU - Takahashi, Yoshimasa

AU - Ishigaki, Hirohito

AU - Nakayama, Misako

AU - Nguyen, Cong Thanh

AU - Kitagawa, Yoshinori

AU - Itoh, Yasushi

AU - Imai, Masaki

AU - Maemura, Tadashi

AU - Furusawa, Yuri

AU - Ueki, Hiroshi

AU - Iwatsuki-Horimoto, Kiyoko

AU - Ito, Mutsumi

AU - Yamayoshi, Seiya

AU - Kawaoka, Yoshihiro

AU - Shirouzu, Mikako

AU - Ishii, Makoto

AU - Saya, Hideyuki

AU - Kondo, Yasushi

AU - Kaneko, Yuko

AU - Suzuki, Katsuya

AU - Fukunaga, Koichi

AU - Takeuchi, Tsutomu

N1 - Funding Information: We thank Yukari Kaneda, Mami Yamada, Mayumi Yonemochi, Mariko Ikeda, Mio Inoue, Naoko Kitagawa, and Hideaki Ishida for helping with the experiments, and Ikuo Kawamoto, Takahiro Nakagawa, Hideaki Tsuchiya, and Iori Itagaki for animal care. We also thank Dr. Takehiro Suzuki (Biomolecular Characterization Unit, RIKEN CSRS) for glycosylation analysis by mass spectrometry. The cryo-EM experiments were performed at the cryo-EM facility of the RIKEN Center for Biosystems Dynamics Research Yokohama. This study was supported by the Collaborative Research Resources , Keio University School of Medicine , and was funded by a research grant for COVID-19 in Keio University School of Medicine (Donner Research Project Grant); by AMED under Grant Numbers JP20fk0108283 , JP21ym0126022 , and JP21fk0108468 ; by the RIKEN President’s discretionary funds; and by the Mitsubishi Foundation . Funding Information: We thank Yukari Kaneda, Mami Yamada, Mayumi Yonemochi, Mariko Ikeda, Mio Inoue, Naoko Kitagawa, and Hideaki Ishida for helping with the experiments, and Ikuo Kawamoto, Takahiro Nakagawa, Hideaki Tsuchiya, and Iori Itagaki for animal care. We also thank Dr. Takehiro Suzuki (Biomolecular Characterization Unit, RIKEN CSRS) for glycosylation analysis by mass spectrometry. The cryo-EM experiments were performed at the cryo-EM facility of the RIKEN Center for Biosystems Dynamics Research Yokohama. This study was supported by the Collaborative Research Resources, Keio University School of Medicine, and was funded by a research grant for COVID-19 in Keio University School of Medicine (Donner Research Project Grant); by AMED under Grant Numbers JP20fk0108283, JP21ym0126022, and JP21fk0108468; by the RIKEN President's discretionary funds; and by the Mitsubishi Foundation. M.T. H.S. Y.Kaneko, K.S. T.T. co-ordinated all of the research activities. M.T. wrote the initial draft of the article. Y.T. M.S. K.K. and Y.I. contributed to the editing of the article. H.S. M.Ishii, Y.Kondo, and K.F. contributed to the sample collection. M.T. performed cell-based Spike-ACE2 inhibition assay, cell sorting and antibody production, and biolayer interferometry. S.M. and Y.Takahashi performed the authentic virus neutralization assay. H.F. performed the fusion inhibition assay, pseudovirus/authentic virus neutralization assay, and viral uptake measurement by Fc receptors. C.M−O performed pseudovirus neutralization assay. M.S. K.K. and T.U. performed cryo-EM analysis. T.Matsumoto, Y.Tomabechi. K.H. prepared recombinant antibodies and spike trimer protein. M.Imai, T.Maemura, Y.F. H.U. K.I-H. M.I. S.Y. Y.Kawaoka, and M.T. performed the studies in Syrian hamsters. M.T. H.I. M.N. C.T.N. Y.Kitagawa, and Y.I. performed the infection study of cynomolgus macaques. M.T. K.S. H.S. T.T. Y.T. S.M. H.F. M.S. T.M. K.K. Y.I. H.I. M.N. Y.Kitagawa, and Y.Kawaoka declared that they are co-inventors on a patent application on neutralizing antibodies described in this article (PCT/JP2021/35159). The remaining authors have no declarations of interest. Publisher Copyright: © 2022 The Author(s)

PY - 2022/12/22

Y1 - 2022/12/22

N2 - The use of therapeutic neutralizing antibodies against SARS-CoV-2 infection has been highly effective. However, there remain few practical antibodies against viruses that are acquiring mutations. In this study, we created 494 monoclonal antibodies from patients with COVID-19-convalescent, and identified antibodies that exhibited the comparable neutralizing ability to clinically used antibodies in the neutralization assay using pseudovirus and authentic virus including variants of concerns. These antibodies have different profiles against various mutations, which were confirmed by cell-based assay and cryo-electron microscopy. To prevent antibody-dependent enhancement, N297A modification was introduced. Our antibodies showed a reduction of lung viral RNAs by therapeutic administration in a hamster model. In addition, an antibody cocktail consisting of three antibodies was also administered therapeutically to a macaque model, which resulted in reduced viral titers of swabs and lungs and reduced lung tissue damage scores. These results showed that our antibodies have sufficient antiviral activity as therapeutic candidates.

AB - The use of therapeutic neutralizing antibodies against SARS-CoV-2 infection has been highly effective. However, there remain few practical antibodies against viruses that are acquiring mutations. In this study, we created 494 monoclonal antibodies from patients with COVID-19-convalescent, and identified antibodies that exhibited the comparable neutralizing ability to clinically used antibodies in the neutralization assay using pseudovirus and authentic virus including variants of concerns. These antibodies have different profiles against various mutations, which were confirmed by cell-based assay and cryo-electron microscopy. To prevent antibody-dependent enhancement, N297A modification was introduced. Our antibodies showed a reduction of lung viral RNAs by therapeutic administration in a hamster model. In addition, an antibody cocktail consisting of three antibodies was also administered therapeutically to a macaque model, which resulted in reduced viral titers of swabs and lungs and reduced lung tissue damage scores. These results showed that our antibodies have sufficient antiviral activity as therapeutic candidates.

KW - Unology

KW - immune response

KW - virology

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UR - http://www.scopus.com/inward/citedby.url?scp=85145599511&partnerID=8YFLogxK

U2 - 10.1016/j.isci.2022.105596

DO - 10.1016/j.isci.2022.105596

M3 - Article

AN - SCOPUS:85145599511

SN - 2589-0042

VL - 25

JO - iScience

JF - iScience

IS - 12

M1 - 105596

ER -

Potent SARS-CoV-2 neutralizing antibodies with therapeutic effects in two animal models

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