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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.

SUBMITTER: Takeshita M

PROVIDER: S-EPMC9664764 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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

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

iScience 20221115 12

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 ...[more]

PMID: 36406861

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Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle East respiratory syndrome coronavirus (MERS-CoV) are zoonotic betacoronaviruses that continue to have a significant impact on public health. Timely development and introduction of vaccines and antivirals against SARS-CoV-2 into the clinic have substantially mitigated the burden of COVID-19. However, a limited or lacking therapeutic arsenal for SARS-CoV-2 and MERS-CoV infections, respectively, calls for an expanded and diversified portfolio of antivirals against these coronavirus infections. In this report, we examined the efficacy of two potent 3CLpro inhibitors, 5d and 11d, in fatal animal models of SARS-CoV-2 and MERS-CoV to demonstrate their broad-spectrum activity against both viral infections. These compounds significantly increased the survival of mice in both models when treatment started 1 day post infection compared to no treatment which led to 100% fatality. Especially, the treatment with compound 11d resulted in 80% and 90% survival in SARS-CoV-2 and MERS-CoV-infected mice, respectively. Amelioration of lung viral load and histopathological changes in treated mice correlated well with improved survival in both infection models. Furthermore, compound 11d exhibited significant antiviral activities in K18-hACE2 mice infected with SARS-CoV-2 Omicron subvariant XBB.1.16. The results suggest that these are promising candidates for further development as broad-spectrum direct-acting antivirals against highly virulent human coronaviruses.IMPORTANCEHuman coronaviruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle East respiratory syndrome coronavirus (MERS-CoV) continue to have a significant impact on public health. A limited or lacking therapeutic arsenal for SARS-CoV-2 and MERS-CoV infections calls for an expanded and diversified portfolio of antivirals against these coronavirus infections. We have previously reported a series of small-molecule 3C-like protease (3CLpro) inhibitors against human coronaviruses. In this report, we demonstrated the in vivo efficacy of 3CLpro inhibitors for their broad-spectrum activity against both SARS-CoV-2 and MERS-CoV infections using the fatal animal models. The results suggest that these are promising candidates for further development as broad-spectrum direct-acting antivirals against highly virulent human coronaviruses.

Dataset Information

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

Publications

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

Similar Datasets

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