Structural and virological identification of neutralizing antibody footprint provides insights into therapeutic antibody design against SARS-CoV-2 variants
Medical treatments using potent neutralizing SARS-CoV-2 antibodies have achieved remarkable improvements in clinical symptoms, changing the situation for the severity of COVID-19 patients. We previously reported an antibody, NT-108 with potent neutralizing activity. However, the structural and functional basis for the neutralizing activity of NT-108 has not yet been understood. Here, we demonstrated the therapeutic effects of NT-108 in a hamster model and its protective effects at low doses. Furthermore, we determined the cryo-EM structure of NT-108 in complex with SARS-CoV-2 spike. The single-chain Fv construction of NT-108 improved the cryo-EM maps because of the prevention of preferred orientations induced by Fab orientation. The footprints of NT-108 illuminated how escape mutations such as E484K evade from class 2 antibody recognition without ACE2 affinity attenuation. The functional and structural basis for the potent neutralizing activity of NT-108 provides insights into the rational design of therapeutic antibodies.
Authors
- Yasuhiro Kazuki (ORCID: https://orcid.org/0000-0003-4818-4710)
- Taishi Onodera (ORCID: https://orcid.org/0000-0002-7079-3339)
- Yoshimasa Takahashi (ORCID: https://orcid.org/0000-0001-6342-4087)
- Noriyo Nagata
- Tadaki Suzuki (ORCID: https://orcid.org/0000-0002-3820-9542)
- Naoko Iwata‐Yoshikawa (ORCID: https://orcid.org/0000-0001-7818-686X)
- Yasuko Orba
- Hirofumi Sawa (ORCID: https://orcid.org/0000-0003-2569-2755)
- Yuki Anraku (ORCID: https://orcid.org/0000-0002-5731-0902)
- Akihiko Sato (ORCID: https://orcid.org/0000-0001-6625-1679)
- Katsumi Maenaka (ORCID: https://orcid.org/0000-0002-5459-521X)
- Yu Adachi (ORCID: https://orcid.org/0000-0002-8573-987X)
- Takashi Tadokoro (ORCID: https://orcid.org/0000-0002-3390-4861)
- Jiei Sasaki (ORCID: https://orcid.org/0000-0002-5129-2336)
- Tateki Suzuki (ORCID: https://orcid.org/0000-0002-6946-3850)
- Nozomi Shiwa-Sudo
- Michihito Sasaki (ORCID: https://orcid.org/0000-0003-1607-2175)
- Takao Hashiguchi (ORCID: https://orcid.org/0000-0001-7578-7571)
- Shiori Ito (ORCID: https://orcid.org/0000-0002-3562-9322)
- Shunsuke Kita (ORCID: https://orcid.org/0000-0003-3969-302X)
- Hideo Fukuhara (ORCID: https://orcid.org/0000-0002-7035-8206)
- Ryutaro Kotaki (ORCID: https://orcid.org/0000-0001-7965-1671)
- Mitsuo Oshimura
- Takao Nomura
- Shôichi Kobayashi (ORCID: https://orcid.org/0009-0001-1242-2097)
Institutions
- Hokkaido University of Science (JP)
- Kyushu University (JP)
- Sapporo University (JP)
- Hokkaido University (JP)
- Hokkaido Pharmaceutical University (JP)
- Kyoto University (JP)
- Global Virus Network (US)
- National Institute of Infectious Diseases (JP)
- Japan Science and Technology Agency (JP)
- Shionogi (Japan) (JP)
- Tottori University (JP)
- Futaba (Japan) (JP)
- Hokkai Gakuen University (JP)
Publication Details
- Journal
- Communications Biology
- Published
- 2025-03-22
- DOI
- https://doi.org/10.1038/s42003-025-07827-0
- Citations
- 1
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 1.40
Funders
- Takeda Science Foundation
- Japan Science and Technology Agency