A Heterodimeric Antibody Fragment for Passive Immunotherapy Against Norovirus Infection
A Heterodimeric Antibody Fragment for Passive Immunotherapy Against Norovirus Infection
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DOI：
10.1093/infdis/jiaa115
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发表时间：
2020-08-01
影响因子：
6.4
通讯作者：
Kiyono, Hiroshi
中科院分区：
文献类型：
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作者：
Yuki, Yoshikazu;Kurokawa, Shiho;Kiyono, Hiroshi
据估计，全世界每年有6.85亿人感染诺如病毒，20万人死亡。虽然针对诺如病毒1 .4和1基因型的疫苗正在开发中，但没有关于针对其他诺如病毒基因型的疫苗或单克隆抗体的信息。本研究构建了2个可变结构域羊驼重链抗体片段（VHHs）克隆7C6和1E4，分别用于抗GII.4和GII.17人诺如病毒。虽然7C6与GII.17、GII.6、GII.3和GII.4的病毒样颗粒（VLPs）发生交叉反应，但它只中和GII.4诺如病毒。相比之下，1E4只与GII.17 VLPs反应并中和。这两种vhs都阻断了VLP与人诱导多能干细胞来源的肠上皮细胞和碳水化合物附着因子的结合。利用这两个VHH，我们产生了一个异二聚体VHH片段，可以中和GII.4和GII.17诺如病毒。由于VHH片段是热稳定和酸稳定的重组单克隆抗体，因此异源二聚体可能用于口服免疫治疗和预防年轻人、老年人或免疫功能低下者的GII.4和GII.17诺如病毒。
Human noroviruses cause an estimated 685 million infections and 200 000 deaths annually worldwide. Although vaccines against GII.4 and GI.1 genotypes are under development, no information is available regarding vaccines or monoclonal antibodies to other noroviral genotypes. Here, we developed 2 variable-domain llama heavy-chain antibody fragment (VHHs) clones, 7C6 and 1E4, against GII.4 and GII.17 human noroviruses, respectively. Although 7C6 cross-reacted with virus-like particles (VLPs) of GII.17, GII.6, GII.3, and GII.4, it neutralized only GII.4 norovirus. In contrast, 1E4 reacted with and neutralized only GII.17 VLPs. Both VHHs blocked VLP binding to human induced pluripotent stem cell-derived intestinal epithelial cells and carbohydrate attachment factors. Using these 2 VHHs, we produced a heterodimeric VHH fragment that neutralized both GII.4 and GII.17 noroviruses. Because VHH fragments are heat- and acid-stable recombinant monoclonal antibodies, the heterodimer likely will be useful for oral immunotherapy and prophylaxis against GII.4 and GII.17 noroviruses in young, elderly, or immunocompromised persons.