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<p>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.</p>

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Structural and virological identification of neutralizing antibody footprint provides insights into therapeutic antibody design against SARS-CoV-2 variants

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月22日

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  • Yuki Anraku,
  • Shunsuke Kita,
  • Taishi Onodera,
  • Akihiko Sato,
  • Takashi Tadokoro,
  • Shiori Ito,
  • Yu Adachi,
  • Ryutaro Kotaki,
  • Tateki Suzuki,
  • Jiei Sasaki,
  • Nozomi Shiwa-Sudo,
  • Naoko Iwata-Yoshikawa,
  • Noriyo Nagata,
  • Souta Kobayashi,
  • Yasuhiro Kazuki,
  • Mitsuo Oshimura,
  • Takao Nomura,
  • Michihito Sasaki,
  • Yasuko Orba,
  • Tadaki Suzuki,
  • Hirofumi Sawa,
  • Takao Hashiguchi,
  • Hideo Fukuhara,
  • Yoshimasa Takahashi,
  • Katsumi Maenaka

摘要

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.