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

View ORCID ProfileMasaru 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, the Keio Donner Project
doi: https://doi.org/10.1101/2022.06.21.496751
Masaru Takeshita
aDivision of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
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  • ORCID record for Masaru Takeshita
  • For correspondence: takeshita@a5.keio.jp
Hidehiro Fukuyama
bRIKEN Center for Integrative Medical Sciences, Infectious Diseases Research unit, Kanagawa 230-0045, Japan
cRIKEN Center for Integrative Medical Sciences, Laboratory for Lymphocyte Differentiation, Kanagawa 230-0045, Japan
dCell Integrative Science Laboratory, Graduate School of Medical Life Science, Yokohama City University, Kanagawa 230-0045, Japan
eINSERM EST, Strasbour, 67037, France
fNear-InfraRed Photo-Immunotherapy Research Institute, Kansai Medical University, Hirakata, Osaka,573-1010, Japan
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Katsuhiko Kamada
gRIKEN Center for Biosystems Dynamics Research, Kanagawa 230-0045, Japan
hLaboratory for Glycometabolic Biochemistry Laboratory, RIKEN Cluster for Pioneering Research, Saitama 351-0198, Japan
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Takehisa Matsumoto
gRIKEN Center for Biosystems Dynamics Research, Kanagawa 230-0045, Japan
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Chieko Makino-Okamura
cRIKEN Center for Integrative Medical Sciences, Laboratory for Lymphocyte Differentiation, Kanagawa 230-0045, Japan
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Tomomi Uchikubo-Kamo
gRIKEN Center for Biosystems Dynamics Research, Kanagawa 230-0045, Japan
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Yuri Tomabechi
gRIKEN Center for Biosystems Dynamics Research, Kanagawa 230-0045, Japan
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Kazuharu Hanada
gRIKEN Center for Biosystems Dynamics Research, Kanagawa 230-0045, Japan
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Saya Moriyama
iResearch Center for Drug and Vaccine Development, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
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Yoshimasa Takahashi
iResearch Center for Drug and Vaccine Development, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
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Hirohito Ishigaki
jDepartment of Pathology, Shiga University of Medical Science, Shiga 520-2192, Japan
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Misako Nakayama
jDepartment of Pathology, Shiga University of Medical Science, Shiga 520-2192, Japan
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Cong Thanh Nguyen
jDepartment of Pathology, Shiga University of Medical Science, Shiga 520-2192, Japan
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Yoshinori Kitagawa
kDivision of Microbiology and Infectious Diseases, Department of Pathology, Shiga University of Medical Science, Shiga 520-2192, Japan
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Yasushi Itoh
jDepartment of Pathology, Shiga University of Medical Science, Shiga 520-2192, Japan
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Masaki Imai
lDivision of Virology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
mCenter for Global Viral Diseases, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
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Tadashi Maemura
nDepartment of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA
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Yuri Furusawa
lDivision of Virology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
mCenter for Global Viral Diseases, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
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Hiroshi Ueki
lDivision of Virology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
mCenter for Global Viral Diseases, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
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Kiyoko Iwatsuki-Horimoto
lDivision of Virology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
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Mutsumi Ito
lDivision of Virology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
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Seiya Yamayoshi
lDivision of Virology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
mCenter for Global Viral Diseases, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
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Yoshihiro Kawaoka
lDivision of Virology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
mCenter for Global Viral Diseases, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
nDepartment of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA
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Mikako Shirouzu
gRIKEN Center for Biosystems Dynamics Research, Kanagawa 230-0045, Japan
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Makoto Ishii
oDivision of Pulmonary Medicine, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
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Hideyuki Saya
pDivision of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 162-8640, Japan
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Yasushi Kondo
aDivision of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
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Yuko Kaneko
aDivision of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
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Katsuya Suzuki
aDivision of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
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Koichi Fukunaga
oDivision of Pulmonary Medicine, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
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Tsutomu Takeuchi
aDivision of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
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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 COVID-19-convalescent patients, and identified antibodies that exhibited 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, and 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.

Competing Interest Statement

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 manuscript (PCT/JP2021/35159). The remaining authors have no declarations of 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-NC 4.0 International license.
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Posted June 22, 2022.
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Fc-modified 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, the Keio Donner Project
bioRxiv 2022.06.21.496751; doi: https://doi.org/10.1101/2022.06.21.496751
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Fc-modified 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, the Keio Donner Project
bioRxiv 2022.06.21.496751; doi: https://doi.org/10.1101/2022.06.21.496751

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