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

• Published in: Communications biology Vol. 8; no. 1; pp. 483 - 12
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.03.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 631/326/596/4130; 631/535/1258/1259; 631/535/1266; 631/61/51/2318; 82/1; 82/103; ACE2; Angiotensin-Converting Enzyme 2; Animals; Antibodies; Antibodies, Neutralizing - chemistry; Antibodies, Neutralizing - immunology; Antibodies, Neutralizing - therapeutic use; Antibodies, Viral - chemistry; Antibodies, Viral - immunology; Antibodies, Viral - therapeutic use; Biomedical and Life Sciences; COVID-19; COVID-19 - immunology; COVID-19 - therapy; COVID-19 - virology; COVID-19 Drug Treatment; Cricetinae; Cryoelectron Microscopy; Humans; Life Sciences; Medical treatment; Mesocricetus; SARS-CoV-2 - genetics; SARS-CoV-2 - immunology; Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - chemistry; Spike Glycoprotein, Coronavirus - genetics; Spike Glycoprotein, Coronavirus - immunology; Structure-function relationships
• ISSN: 2399-3642; 2399-3642
• 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. A SARS-CoV-2 antibody, NT-108, exhibits potent therapeutic effects in vivo. Cryo-EM structure of the spike complexed with single-chain Fv of NT108 reveals its neutralizing mechanism, providing insight into antibody therapeutic design.