当前位置: X-MOL 学术Cell Res. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Rational development of a human antibody cocktail that deploys multiple functions to confer Pan-SARS-CoVs protection
Cell Research ( IF 44.1 ) Pub Date : 2020-12-01 , DOI: 10.1038/s41422-020-00444-y
Hangping Yao 1 , Yao Sun 2 , Yong-Qiang Deng 3 , Nan Wang 2 , Yongcong Tan 4 , Na-Na Zhang 3 , Xiao-Feng Li 3 , Chao Kong 4 , Yan-Peng Xu 3 , Qi Chen 3 , Tian-Shu Cao 3 , Hui Zhao 3 , Xintian Yan 4 , Lei Cao 2 , Zhe Lv 2 , Dandan Zhu 2 , Rui Feng 2 , Nanping Wu 1 , Wenhai Zhang 4 , Yuhao Hu 4 , Keda Chen 5 , Rong-Rong Zhang 3 , Qingyu Lv 3 , Shihui Sun 3 , Yunhua Zhou 4 , Run Yan 4 , Guan Yang 6 , Xinglu Sun 4 , Chanjuan Liu 4 , Xiangyun Lu 1 , Linfang Cheng 1 , Hongying Qiu 3 , Xing-Yao Huang 3 , Tianhao Weng 1 , Danrong Shi 1 , Weidong Jiang 7 , Junbin Shao 8 , Lei Wang 2 , Jie Zhang 8 , Tao Jiang 3 , Guojun Lang 4 , Cheng-Feng Qin 3 , Lanjuan Li 1 , Xiangxi Wang 2, 9
Affiliation  

Structural principles underlying the composition and synergistic mechanisms of protective monoclonal antibody cocktails are poorly defined. Here, we exploited antibody cooperativity to develop a therapeutic antibody cocktail against SARS-CoV-2. On the basis of our previously identified humanized cross-neutralizing antibody H014, we systematically analyzed a fully human naive antibody library and rationally identified a potent neutralizing antibody partner, P17, which confers effective protection in animal model. Cryo-EM studies dissected the nature of the P17 epitope, which is SARS-CoV-2 specific and distinctly different from that of H014. High-resolution structure of the SARS-CoV-2 spike in complex with H014 and P17, together with functional investigations revealed that in a two-antibody cocktail, synergistic neutralization was achieved by S1 shielding and conformational locking, thereby blocking receptor attachment and viral membrane fusion, conferring high potency as well as robustness against viral mutation escape. Furthermore, cluster analysis identified a hypothetical 3rd antibody partner for further reinforcing the cocktail as pan-SARS-CoVs therapeutics.



中文翻译:

合理开发具有多种功能以赋予 Pan-SARS-CoVs 保护的人类抗体混合物

保护性单克隆抗体混合物的组成和协同机制的结构原理尚不清楚。在这里,我们利用抗体协同性来开发针对 SARS-CoV-2 的治疗性抗体混合物。在我们之前鉴定的人源化交叉中和抗体H014的基础上,我们系统地分析了一个完全人类幼稚抗体库,并合理地鉴定了一个有效的中和抗体伙伴P17,它在动物模型中提供了有效的保护。Cryo-EM 研究剖析了 P17 表位的性质,它是 SARS-CoV-2 特异性的,与 H014 的表位明显不同。与 H014 和 P17 复合的 SARS-CoV-2 尖峰的高分辨率结构以及功能研究表明,在双抗体混合物中,通过 S1 屏蔽和构象锁定实现协同中和,从而阻断受体附着和病毒膜融合,赋予高效力和抗病毒突变逃逸的鲁棒性。此外,聚类分析确定了一种假设的第 3 种抗体伙伴,可进一步加强该鸡尾酒作为泛 SARS-CoV 疗法。

更新日期:2020-12-01
down
wechat
bug