1区 · 综合性期刊
ArticleOA
作者: Chai, Benjie ; Yang, Kai ; Xiang, Ye ; Zhuang, Xinyu ; Li, Ruofan ; Tian, Mingyao ; Le, Ting ; Liu, Zhida ; Qi, Shaolong ; Liu, Yubin ; Yu, Guocan ; Tian, Chongyu ; Chen, Yunfeng ; Lei, Jiaqi ; Wang, Jinyong ; Ma, Enhao ; Cheng, Gong ; Shi, Huicheng ; Wang, Weixiao ; Tai, Wanbo ; Feng, Shengyong
Abstract:The respiratory system, especially the lung, is the key site of pathological injury induced by SARS-CoV-2 infection. Given the low feasibility of targeted delivery of antibodies into the lungs by intravenous administration and the short half-life period of antibodies in the lungs by intranasal or aerosolized immunization, mRNA encoding broadly neutralizing antibodies with lung-targeting capability can perfectly provide high-titer antibodies in lungs to prevent the SARS-CoV-2 infection. Here, we firstly identify a human monoclonal antibody, 8-9D, with broad neutralizing potency against SARS-CoV-2 variants. The neutralization mechanism of this antibody is explained by the structural characteristics of 8-9D Fabs in complex with the Omicron BA.5 spike. In addition, we evaluate the efficacy of 8-9D using a safe and robust mRNA delivery platform and compare the performance of 8-9D when its mRNA is and is not selectively delivered to the lungs. The lung-selective delivery of the 8-9D mRNA enables the expression of neutralizing antibodies in the lungs which blocks the invasion of the virus, thus effectively protecting female K18-hACE2 transgenic mice from challenge with the Beta or Omicron BA.1 variant. Our work underscores the potential application of lung-selective mRNA antibodies in the prevention and treatment of infections caused by circulating SARS-CoV-2 variants.
