SARS-CoV-2刺突蛋白NTD和RBD结构域的人抗体识别和中和模式,Scientific Reports

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SARS-CoV-2刺突蛋白NTD和RBD结构域的人抗体识别和中和模式
Scientific Reports ( IF 3.8 ) Pub Date : 2022-11-22 , DOI: 10.1038/s41598-022-24730-4
Ryota Otsubo ₁ , Takeharu Minamitani _{1,

2} , Kouji Kobiyama _{3,

4} , Junso Fujita _{5,

6} , Toshihiro Ito _{7,

8} , Shiori Ueno ₉ , Itsuki Anzai ₁₀ , Hiroki Tanino ₆ , Hiroshi Aoyama ₆ , Yoshiharu Matsuura _{11,

12} , Keiichi Namba _{5,

13,

14} , Ken-Ichi Imadome ₁₅ , Ken J Ishii _{3,

4} , Kouhei Tsumoto _{16,

17,

18} , Wataru Kamitani ₉ , Teruhito Yasui ₁

Affiliation

Laboratory of Infectious Diseases and Immunity, Center for Vaccine and Adjuvant Research (CVAR), National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan.
Toyama Prefectural Institute for Pharmaceutical Research, 17-1 Nakataikoyama, Imizu, Toyama, 939-0363, Japan.
Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
Laboratory of Adjuvant Innovation, CVAR, NIBIOHN, 7-6-8 Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan.
Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Laboratory of Proteome Research, NIBIOHN, 7-6-8 Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan.
Laboratory of Experimental Immunology, Department of Regeneration Science and Engineering, Institute for Life and Medical Sciences, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.
Department of Infectious Diseases and Host Defense, Graduate School of Medicine, Gunma University, 3-39-22 Syowa-cho, Maebashi, Gunma, 371-8511, Japan.
Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Centre for Infectious Disease Education and Research, Osaka University, 2-8 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Laboratory of Virus Control, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
JEOL YOKOGUSHI Research Alliance Laboratories, Osaka University, 1-3 Yamadaoka, Suita, Osaka, 565-0871, Japan.
RIKEN SPring-8 Center, 1-3 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Department of Advanced Medicine for Infections, National Center for Child Health and Development (NCCHD), 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan.
Center for Drug Discovery Research (CDDR), National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan.
Department of Bioengineering, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.
Medical Proteomics Laboratory, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.

严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 会导致 2019 年冠状病毒病 (COVID-19)。Delta 和 Omicron 等令人担忧的变体 (VOC) 已经出现，它们继续传播大流行病。据报道，这些 VOC 会降低疫苗效力并逃避许多靶向糖基化刺突 (S) 蛋白受体结合域 (RBD) 的中和单克隆抗体 (mAb)，该蛋白由 S1 和 S2 亚基组成。因此，需要确定最佳目标区域以获得可以对抗 VOC 的中和抗体。迄今为止尚未确定此类区域。我们使用从 COVID-19 康复的志愿者中提取的外周血单核细胞获得了 2 个单克隆抗体，NIBIC-71 和 7G7。两种 mAb 都对野生型 SARS-CoV-2 和 Delta 具有中和活性，但对 Omicron 没有。NIBIC-71 与 RBD 结合，而 7G7 识别 S1 的 N 末端结构域。特别是，7G7 抑制 S1/S2 切割，但不抑制 S 蛋白与血管紧张素转换酶 2 之间的相互作用；它抑制了病毒进入。因此，证明了靶向抑制 S1/2 裂解的中和 mAb 的功效。这些结果表明，靶向阻断 S1/S2 裂解的中和 mAb 可能与各种 VOC 发生交叉反应。

"点击查看英文标题和摘要"

Human antibody recognition and neutralization mode on the NTD and RBD domains of SARS-CoV-2 spike protein

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). Variants of concern (VOCs) such as Delta and Omicron have developed, which continue to spread the pandemic. It has been reported that these VOCs reduce vaccine efficacy and evade many neutralizing monoclonal antibodies (mAbs) that target the receptor binding domain (RBD) of the glycosylated spike (S) protein, which consists of the S1 and S2 subunits. Therefore, identification of optimal target regions is required to obtain neutralizing antibodies that can counter VOCs. Such regions have not been identified to date. We obtained 2 mAbs, NIBIC-71 and 7G7, using peripheral blood mononuclear cells derived from volunteers who recovered from COVID-19. Both mAbs had neutralizing activity against wild-type SARS-CoV-2 and Delta, but not Omicron. NIBIC-71 binds to the RBD, whereas 7G7 recognizes the N-terminal domain of the S1. In particular, 7G7 inhibited S1/S2 cleavage but not the interaction between the S protein and angiotensin-converting enzyme 2; it suppressed viral entry. Thus, the efficacy of a neutralizing mAb targeting inhibition of S1/2 cleavage was demonstrated. These results suggest that neutralizing mAbs targeting blockade of S1/S2 cleavage are likely to be cross-reactive against various VOCs.

更新日期：2022-11-26

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