Molecular Imaging Center, Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-sen Universitygrid.12981.33, Zhuhai, China.
Zhuhai Trinomab Biotechnology Co., Ltd., Zhuhai, China.
Microbiol Spectr. 2021 Oct 31;9(2):e0135221. doi: 10.1128/Spectrum.01352-21. Epub 2021 Oct 13.
The emerging new lineages of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have marked a new phase of coronavirus disease 2019 (COVID-19). Understanding the recognition mechanisms of potent neutralizing monoclonal antibodies (NAbs) against the spike protein is pivotal for developing new vaccines and antibody drugs. Here, we isolated several monoclonal antibodies (MAbs) against the SARS-CoV-2 spike protein receptor-binding domain (S-RBD) from the B cell receptor repertoires of a SARS-CoV-2 convalescent. Among these MAbs, the antibody nCoV617 demonstrates the most potent neutralizing activity against authentic SARS-CoV-2 infection, as well as prophylactic and therapeutic efficacies against the human angiotensin-converting enzyme 2 (ACE2) transgenic mouse model . The crystal structure of S-RBD in complex with nCoV617 reveals that nCoV617 mainly binds to the back of the "ridge" of RBD and shares limited binding residues with ACE2. Under the background of the S-trimer model, it potentially binds to both "up" and "down" conformations of S-RBD. mutagenesis assays show that mutant residues found in the emerging new lineage B.1.1.7 of SARS-CoV-2 do not affect nCoV617 binding to the S-RBD. These results provide a new human-sourced neutralizing antibody against the S-RBD and assist vaccine development. COVID-19 is a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The COVID-19 pandemic has posed a serious threat to global health and the economy, so it is necessary to find safe and effective antibody drugs and treatments. The receptor-binding domain (RBD) in the SARS-CoV-2 spike protein is responsible for binding to the angiotensin-converting enzyme 2 (ACE2) receptor. It contains a variety of dominant neutralizing epitopes and is an important antigen for the development of new coronavirus antibodies. The significance of our research lies in the determination of new epitopes, the discovery of antibodies against RBD, and the evaluation of the antibodies' neutralizing effect. The identified antibodies here may be drug candidates for the development of clinical interventions for SARS-CoV-2.
新型严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）的新兴谱系标志着 2019 年冠状病毒病（COVID-19）的新阶段。了解针对刺突蛋白的有效中和单克隆抗体（NAb）的识别机制对于开发新的疫苗和抗体药物至关重要。在这里，我们从 SARS-CoV-2 恢复期的 B 细胞受体库中分离出几种针对 SARS-CoV-2 刺突蛋白受体结合域（S-RBD）的单克隆抗体（MAb）。在这些 MAb 中，抗体 nCoV617 对真实 SARS-CoV-2 感染表现出最强的中和活性，以及对人血管紧张素转化酶 2（ACE2）转基因小鼠模型的预防和治疗功效。S-RBD 与 nCoV617 复合物的晶体结构表明，nCoV617 主要结合 RBD 的“脊”的背面，与 ACE2 共享有限的结合残基。在 S-三聚体模型的背景下，它可能与 S-RBD 的“向上”和“向下”构象都结合。突变分析表明，在 SARS-CoV-2 的新兴新谱系 B.1.1.7 中发现的突变残基不影响 nCoV617 与 S-RBD 的结合。这些结果提供了一种针对 S-RBD 的新型人源中和抗体，并有助于疫苗开发。COVID-19 是一种由严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）引起的呼吸道疾病。COVID-19 大流行对全球健康和经济构成了严重威胁，因此有必要寻找安全有效的抗体药物和治疗方法。SARS-CoV-2 刺突蛋白中的受体结合域（RBD）负责与血管紧张素转化酶 2（ACE2）受体结合。它包含多种主要的中和表位，是开发新型冠状病毒抗体的重要抗原。我们研究的意义在于确定新的表位，发现针对 RBD 的抗体，并评估抗体的中和效果。这里鉴定的抗体可能是开发针对 SARS-CoV-2 的临床干预措施的候选药物。
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