Nanobodies with cross-neutralizing activity provide prominent therapeutic efficacy in mild and severe COVID-19 rodent models

文献类型： 外文期刊

第一作者： Han, Qiuxue

作者： Han, Qiuxue;Xia, Xianzhu;Han, Qiuxue;Wang, Shen;Wang, Zhenshan;Zhang, Cheng;Wang, Xinyue;Feng, Na;Wang, Tiecheng;Zhao, Yongkun;Chi, Hang;Yan, Feihu;Xia, Xianzhu;Zhao, Yongkun;Yan, Feihu;Xia, Xianzhu

作者机构：

关键词： COVID-19; SARS-CoV-2; Nanobody; Broad-spectrum; Therapeutic; Rodent models

期刊名称：VIROLOGICA SINICA （ 影响因子：5.5； 五年影响因子：4.9 ）

ISSN： 1674-0769

年卷期： 2023 年 38 卷 5 期

页码：

收录情况： SCI

摘要： The weakened protective efficacy of COVID-19 vaccines and antibodies caused by SARS-CoV-2 variants presents a global health emergency, which underscores the urgent need for universal therapeutic antibody intervention for clinical patients. Here, we screened three alpacas-derived nanobodies (Nbs) with neutralizing activity from twenty RBD-specific Nbs. The three Nbs were fused with the Fc domain of human IgG, namely aVHH-11-Fc, aVHH-13-Fc and aVHH-14-Fc, which could specifically bind RBD protein and competitively inhibit the binding of ACE2 receptor to RBD. They effectively neutralized SARS-CoV-2 pseudoviruses D614G, Alpha, Beta, Gamma, Delta, and Omicron sub-lineages BA.1, BA.2, BA.4, and BA.5 and authentic SARS-CoV-2 prototype, Delta, and Omicron BA.1, BA.2 strains. In mice-adapted COVID-19 severe model, intranasal administration of aVHH-11-Fc, aVHH-13-Fc and aVHH-14-Fc effectively protected mice from lethal challenges and reduced viral loads in both the upper and lower respiratory tracts. In the COVID-19 mild model, aVHH-13-Fc, which represents the optimal neutralizing activity among the above three Nbs, effectively protected hamsters from the challenge of SARS-CoV-2 prototype, Delta, Omicron BA.1 and BA.2 by significantly reducing viral replication and pathological alterations in the lungs. In structural modeling of aVHH-13 and RBD, aVHH-13 binds to the receptor-binding motif region of RBD and interacts with some highly conserved epitopes. Taken together, our study illustrated that alpaca-derived Nbs offered a therapeutic countermeasure against SARS-CoV-2, including those Delta and Omicron variants which have evolved into global pandemic strains.

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