tetano
Editor, Senior Moderator
Commun Biol
. 2025 Mar 22;8(1):483.
doi: 10.1038/s42003-025-07827-0. Structural and virological identification of neutralizing antibody footprint provides insights into therapeutic antibody design against SARS-CoV-2 variants
Yuki Anraku[SUP] 1 [/SUP], Shunsuke Kita[SUP] 2 [/SUP], Taishi Onodera[SUP] 3 [/SUP], Akihiko Sato[SUP] 4 5 6 [/SUP], Takashi Tadokoro[SUP] 1 [/SUP], Shiori Ito[SUP] 1 [/SUP], Yu Adachi[SUP] 3 [/SUP], Ryutaro Kotaki[SUP] 3 [/SUP], Tateki Suzuki[SUP] 7 [/SUP], Jiei Sasaki[SUP] 7 [/SUP], Nozomi Shiwa-Sudo[SUP] 8 [/SUP], Naoko Iwata-Yoshikawa[SUP] 8 [/SUP], Noriyo Nagata[SUP] 8 [/SUP], Souta Kobayashi[SUP] 1 [/SUP], Yasuhiro Kazuki[SUP] 9 10 [/SUP], Mitsuo Oshimura[SUP] 11 [/SUP], Takao Nomura[SUP] 1 [/SUP], Michihito Sasaki[SUP] 5 6 [/SUP], Yasuko Orba[SUP] 5 6 12 13 [/SUP], Tadaki Suzuki[SUP] 8 [/SUP], Hirofumi Sawa[SUP] 6 12 13 14 [/SUP], Takao Hashiguchi[SUP] 7 15 16 [/SUP], Hideo Fukuhara[SUP] 1 17 [/SUP], Yoshimasa Takahashi[SUP] 18 19 [/SUP], Katsumi Maenaka[SUP] 20 21 22 23 24 25 [/SUP]
Affiliations
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.
. 2025 Mar 22;8(1):483.
doi: 10.1038/s42003-025-07827-0. Structural and virological identification of neutralizing antibody footprint provides insights into therapeutic antibody design against SARS-CoV-2 variants
Yuki Anraku[SUP] 1 [/SUP], Shunsuke Kita[SUP] 2 [/SUP], Taishi Onodera[SUP] 3 [/SUP], Akihiko Sato[SUP] 4 5 6 [/SUP], Takashi Tadokoro[SUP] 1 [/SUP], Shiori Ito[SUP] 1 [/SUP], Yu Adachi[SUP] 3 [/SUP], Ryutaro Kotaki[SUP] 3 [/SUP], Tateki Suzuki[SUP] 7 [/SUP], Jiei Sasaki[SUP] 7 [/SUP], Nozomi Shiwa-Sudo[SUP] 8 [/SUP], Naoko Iwata-Yoshikawa[SUP] 8 [/SUP], Noriyo Nagata[SUP] 8 [/SUP], Souta Kobayashi[SUP] 1 [/SUP], Yasuhiro Kazuki[SUP] 9 10 [/SUP], Mitsuo Oshimura[SUP] 11 [/SUP], Takao Nomura[SUP] 1 [/SUP], Michihito Sasaki[SUP] 5 6 [/SUP], Yasuko Orba[SUP] 5 6 12 13 [/SUP], Tadaki Suzuki[SUP] 8 [/SUP], Hirofumi Sawa[SUP] 6 12 13 14 [/SUP], Takao Hashiguchi[SUP] 7 15 16 [/SUP], Hideo Fukuhara[SUP] 1 17 [/SUP], Yoshimasa Takahashi[SUP] 18 19 [/SUP], Katsumi Maenaka[SUP] 20 21 22 23 24 25 [/SUP]
Affiliations
- PMID: 40121330
- PMCID: PMC11929858
- DOI: 10.1038/s42003-025-07827-0
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.