Tsugawa Yoji, Furukawa Kentaro, Ise Tomoko, Takayama Masahiro, Ota Takeshi, Kuroda Takayuki, Shano Shinya, Hashimoto Takashi, Konishi Haruyo, Ishihara Takeshi, Sato Masaaki, Kamada Haruhiko, Fukao Keita, Shishido Takao, Yoshikawa Mai, Takahashi Tatsuya, Nagata Satoshi
Shionogi Pharmaceutical Research Center, Osaka, Japan.
Laboratory of Antibody Design, Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan.
PLoS One. 2024 Dec 2;19(12):e0300297. doi: 10.1371/journal.pone.0300297. eCollection 2024.
The SARS-CoV-2 pandemic alerted the potential for significant harm due to future cross-species transmission of various animal coronaviruses to human. There is a significant need of antibody-based drugs to treat patients infected with previously unseen coronaviruses. In this study, we generated CV804, an antibody that binds to the S2 domain of SARS-CoV-2 spike protein, which is highly conserved across the coronavirus family and less susceptible to mutations. CV804 demonstrated broad cross-reactivities not only disease-associated human beta coronaviruses including SARS-CoV, MERS-CoV, HCoV-OC43, HCoV-HKU1 and with existing mutant strains of SARS-CoV-2 and but also with 20 representative animal-origin coronaviruses. CV804 exhibits strong antibody-dependent cellular cytotoxicity (ADCC) to SARS-CoV-2 spike protein expressed on cells in vitro, while completely lacks virus-neutralization activity. In animal models, CV804 suppressed disease progression caused by SARS-CoV-2 infection. Structural studies using HDX-MS combined with reactivity analysis with point mutants of recombinant spike proteins revealed that CV804 binds to a unique conformational epitope within the S2 domain of the spike proteins that is highly conserved among various coronaviruses. Overall, obtained data suggest that the non-neutralizing CV804 antibody recognizes the conformational structure of the spike protein displayed on the surface of infected cells and weakens the viral virulence by supporting the host immune cells' attack through ADCC activity in vivo. The CV804 epitope information revealed in this study is useful for designing pan-corona antibody therapeutics and universal coronavirus vaccines for preparing potential future pandemics.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）大流行警示了各种动物冠状病毒未来跨物种传播给人类可能造成重大危害。迫切需要基于抗体的药物来治疗感染新型冠状病毒的患者。在本研究中，我们制备了CV804，一种与SARS-CoV-2刺突蛋白S2结构域结合的抗体，该结构域在冠状病毒家族中高度保守且不易发生突变。CV804不仅对包括SARS-CoV、中东呼吸综合征冠状病毒（MERS-CoV）、人冠状病毒OC43（HCoV-OC43）、人冠状病毒HKU1（HCoV-HKU1）在内的与疾病相关的人类β冠状病毒以及SARS-CoV-2的现有突变株具有广泛的交叉反应性，而且还与20种具有代表性的动物源冠状病毒有交叉反应。CV804在体外对细胞上表达的SARS-CoV-2刺突蛋白表现出强大的抗体依赖性细胞毒性（ADCC），但完全缺乏病毒中和活性。在动物模型中，CV804抑制了SARS-CoV-2感染引起的疾病进展。使用氢氘交换质谱（HDX-MS）结合重组刺突蛋白点突变体的反应性分析进行的结构研究表明，CV804与刺突蛋白S2结构域内一个独特的构象表位结合，该表位在各种冠状病毒中高度保守。总体而言，所得数据表明，非中和性的CV804抗体识别感染细胞表面展示的刺突蛋白的构象结构，并通过在体内支持宿主免疫细胞通过ADCC活性进行攻击来减弱病毒毒力。本研究中揭示的CV804表位信息对于设计用于应对未来潜在大流行的泛冠状病毒抗体疗法和通用冠状病毒疫苗具有重要意义。
