ACE2-targeting monoclonal antibody as potent and broad-spectrum coronavirus blocker,Signal Transduction and Targeted Therapy

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ACE2-targeting monoclonal antibody as potent and broad-spectrum coronavirus blocker
Signal Transduction and Targeted Therapy ( IF 39.3 ) Pub Date : 2021-08-25 , DOI: 10.1038/s41392-021-00740-y
Yuning Chen _{1,

2} , Ya-Nan Zhang _{2,

3} , Renhong Yan ₄ , Guifeng Wang ₁ , Yuanyuan Zhang ₄ , Zhe-Rui Zhang _{2,

3} , Yaning Li ₅ , Jianxia Ou ₆ , Wendi Chu _{1,

2} , Zhijuan Liang _{1,

2} , Yongmei Wang _{1,

2} , Yi-Li Chen _{7,

8} , Ganjun Chen ₇ , Qi Wang ₁ , Qiang Zhou ₄ , Bo Zhang _{3,

9} , Chunhe Wang _{1,

2,

6,

7,

8}

Affiliation

Biotherapeutics Discovery Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
University of Chinese Academy of Sciences, Beijing, China.
Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-ScienceChinese Academy of Sciences, Wuhan, Hubei, China.
Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, and Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China.
Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
Dartsbio Pharmaceuticals, Zhongshan, Guangdong, China.
Fudan University, School of Pharmacy, Shanghai, China.
Drug Discovery Center for Infectious Disease, Nankai University, Tianjin, China.

The evolution of coronaviruses, such as SARS-CoV-2, makes broad-spectrum coronavirus preventional or therapeutical strategies highly sought after. Here we report a human angiotensin-converting enzyme 2 (ACE2)-targeting monoclonal antibody, 3E8, blocked the S1-subunits and pseudo-typed virus constructs from multiple coronaviruses including SARS-CoV-2, SARS-CoV-2 mutant variants (SARS-CoV-2-D614G, B.1.1.7, B.1.351, B.1.617.1, and P.1), SARS-CoV and HCoV-NL63, without markedly affecting the physiological activities of ACE2 or causing severe toxicity in ACE2 “knock-in” mice. 3E8 also blocked live SARS-CoV-2 infection in vitro and in a prophylactic mouse model of COVID-19. Cryo-EM and “alanine walk” studies revealed the key binding residues on ACE2 interacting with the CDR3 domain of 3E8 heavy chain. Although full evaluation of safety in non-human primates is necessary before clinical development of 3E8, we provided a potentially potent and “broad-spectrum” management strategy against all coronaviruses that utilize ACE2 as entry receptors and disclosed an anti-coronavirus epitope on human ACE2.

中文翻译：

ACE2 靶向单克隆抗体作为有效的广谱冠状病毒阻断剂

冠状病毒的进化，例如 SARS-CoV-2，使得广谱冠状病毒的预防或治疗策略备受追捧。在这里，我们报告了一种靶向人血管紧张素转换酶 2 (ACE2) 的单克隆抗体 3E8，它阻断了多种冠状病毒的 S1 亚基和假型病毒构建体，包括 SARS-CoV-2、SARS-CoV-2 突变变体（SARS -CoV-2-D614G、B.1.1.7、B.1.351、B.1.617.1 和 P.1)、SARS-CoV 和 HCoV-NL63，对 ACE2 的生理活性没有显着影响或在ACE2“敲入”老鼠。3E8 还在体外和 COVID-19 的预防性小鼠模型中阻断了活的 SARS-CoV-2 感染。冷冻电镜和“丙氨酸步行”研究揭示了 ACE2 上与 3E8 重链的 CDR3 结构域相互作用的关键结合残基。尽管在 3E8 临床开发之前对非人类灵长类动物的安全性进行全面评估是必要的，但我们提供了针对所有利用 ACE2 作为进入受体的冠状病毒的潜在有效和“广谱”管理策略，并公开了人类 ACE2 上的抗冠状病毒表位.

更新日期：2021-08-25

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