Anraku Yuki, Kita Shunsuke, Onodera Taishi, Sato Akihiko, Tadokoro Takashi, Ito Shiori, Adachi Yu, Kotaki Ryutaro, Suzuki Tateki, Sasaki Jiei, Shiwa-Sudo Nozomi, Iwata-Yoshikawa Naoko, Nagata Noriyo, Kobayashi Souta, Kazuki Yasuhiro, Oshimura Mitsuo, Nomura Takao, Sasaki Michihito, Orba Yasuko, Suzuki Tadaki, Sawa Hirofumi, Hashiguchi Takao, Fukuhara Hideo, Takahashi Yoshimasa, Maenaka Katsumi
Laboratory of Biomolecular Science, and Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, Tokyo, Japan.
Commun Biol. 2025 Mar 22;8(1):483. 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.
使用强效中和性严重急性呼吸综合征冠状病毒2（SARS-CoV-2）抗体的医学治疗在临床症状方面取得了显著改善，改变了新型冠状病毒肺炎（COVID-19）患者的重症状况。我们之前报道了一种具有强效中和活性的抗体NT-108。然而，NT-108中和活性的结构和功能基础尚未明确。在此，我们展示了NT-108在仓鼠模型中的治疗效果及其低剂量时的保护作用。此外，我们确定了NT-108与SARS-CoV-2刺突蛋白复合物的冷冻电镜结构。NT-108的单链Fv结构改善了冷冻电镜图谱，因为它防止了由Fab方向诱导的优先取向。NT-108的作用位点揭示了诸如E484K等逃逸突变如何在不减弱血管紧张素转换酶2（ACE2）亲和力的情况下逃避2类抗体的识别。NT-108强效中和活性的功能和结构基础为治疗性抗体的合理设计提供了见解。
