Broad neutralization of SARS-CoV-2 variants by an inhalable bispecific single-domain antibody.
Broad neutralization of SARS-CoV-2 variants by an inhalable bispecific single-domain antibody.
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可吸入双特异性单域抗体广泛中和 SARS-CoV-2 变体
DOI：
10.1016/j.cell.2022.03.009
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发表时间：
2022-04-14
期刊：
影响因子：
64.5
通讯作者：
Ying T
中科院分区：
文献类型：
--
作者：
Li C;Zhan W;Yang Z;Tu C;Hu G;Zhang X;Song W;Du S;Zhu Y;Huang K;Kong Y;Zhang M;Mao Q;Gu X;Zhang Y;Xie Y;Deng Q;Song Y;Chen Z;Lu L;Jiang S;Wu Y;Sun L;Ying T
SARS-CoV-2疫苗和治疗性抗体的有效性受到病毒变异体的不断出现以及抗体从循环到呼吸道病毒感染部位的扩散受限的限制。在这里，我们报告了两个高度保守的区域上的Omicron变体受体结合域的广泛中和抗体的识别。此外，我们产生了一种双特异性单结构域抗体，其能够同时和协同地结合单个Omicron变体受体结合结构域上的这两个区域，如通过冷冻EM结构所揭示的。我们证明了这种双特异性抗体可以通过吸入给药有效地递送到肺部，并且在SARS-CoV-2感染的小鼠模型中表现出精致的中和宽度和治疗功效。重要的是，这项研究还破译了刺突三聚体界面内一种不常见且高度保守的隐藏表位，这可能对广泛保护性SARS-CoV-2疫苗和治疗方法的设计具有影响。在小鼠吸入一种工程化的双特异性单域抗体后，可以观察到对SARS-CoV-2感染的治疗效果，该抗体同时靶向刺突蛋白受体结合域上的两个点。
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. Therapeutic effects against SARS-CoV-2 infection are seen in mice after inhalation of an engineered, bispecific, single-domain antibody that simultaneously targets two points on the spike protein receptor-binding domain.
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