MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Disease and Biosecurity, The Fifth People's Hospital of Shanghai, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Shanghai Key Laboratory of Lung Inflammation and Injury, Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Engineering Research Center for Synthetic Immunology, Shanghai 200032, China.
Cell. 2022 Apr 14;185(8):1389-1401.e18. doi: 10.1016/j.cell.2022.03.009. Epub 2022 Mar 10.
The effectiveness of SARS-CoV-2 vaccines and therapeutic antibodies have been limited by the continuous emergence of viral variants and by the restricted diffusion of antibodies from circulation into the sites of respiratory virus infection. Here, we report the identification of two highly conserved regions on the Omicron variant receptor-binding domain recognized by broadly neutralizing antibodies. Furthermore, we generated a bispecific single-domain antibody that was able to simultaneously and synergistically bind these two regions on a single Omicron variant receptor-binding domain as revealed by cryo-EM structures. We demonstrated that this bispecific antibody can be effectively delivered to lung via inhalation administration and exhibits exquisite neutralization breadth and therapeutic efficacy in mouse models of SARS-CoV-2 infections. Importantly, this study also deciphered an uncommon and highly conserved cryptic epitope within the spike trimeric interface that may have implications for the design of broadly protective SARS-CoV-2 vaccines and therapeutics.
SARS-CoV-2 疫苗和治疗性抗体的有效性受到病毒变异的不断出现以及抗体从循环系统扩散到呼吸道病毒感染部位的限制。在这里，我们报告了两种在 Omicron 变异受体结合域上高度保守的区域的鉴定，这些区域被广泛中和抗体所识别。此外，我们生成了一种双特异性单域抗体，该抗体能够在冷冻电镜结构中同时协同结合单个 Omicron 变异受体结合域上的这两个区域。我们证明，这种双特异性抗体可以通过吸入给药有效地递送到肺部，并在 SARS-CoV-2 感染的小鼠模型中表现出出色的中和广度和治疗效果。重要的是，这项研究还揭示了刺突三聚体界面内一个罕见且高度保守的隐藏表位，这可能对设计广泛保护的 SARS-CoV-2 疫苗和治疗方法具有重要意义。
