Antiviral Activity of a Llama-Derived Single-Domain Antibody against Enterovirus A71

Peng-Nien Huang, Hsiang-Ching Wang, Hui-Chen Hung, Sung-Nien Tseng, Teng-Yuan Chang, Min-Yuan Chou, Yu-Jen Chen, Yun-Ming Wang, Shin-Ru Shih, John Tsu-An Hsu*

*此作品的通信作者

研究成果: Article同行評審

5 引文 斯高帕斯(Scopus)

摘要

In the past few decades, enterovirus A71 (EVA71) has caused devastating outbreaks in the Asia-Pacific region, resulting in serious sequelae in infected young children. No preventive or therapeutic interventions are currently available for curing EVA71 infection, highlighting a great unmet medical need for this disease. Here, we showed that one novel single-domain antibody (sdAb), F1, isolated from an immunized llama, could alleviate EVA71 infection both in vitro and in vivo. We also confirmed that the sdAb clone F1 recognizes EVA71 through a novel conformational epitope comprising the highly conserved region of VP3 capsid protein by using competitive-binding and overlapping-peptide enzyme-linked immunosorbent assays (ELISAs). Because of the virion's icosahedral structure, we reasoned that adjacent epitopes must be clustered within molecular ranges that may be simultaneously bound by an engineered antibody with multiple valency. Therefore, two singledomain binding modules (F1) were fused to generate an sdAb-in-tandem design so that the capture of viral antigens could be further increased by valency effects. We showed that the tetravalent construct F1xF1-hFc, containing two sdAb-intandem on a fragment crystallizable (Fc) scaffold, exhibits more potent neutralization activity against EVA71 than does the bivalent sdAb F1-hFc by at least 5.8-fold. We also demonstrated that, using a human scavenger receptor class B member 2 (hSCARB2) transgenic mouse model, a half dose of the F1xF1-hFc provided better protection against EVA71 infection than did the F1-hFc. Thus, our study furnishes important insights into multivalent sdAb engineering against viral infection and provides a novel strategic deployment approach for preparedness of emerging infectious diseases such as EVA71.

原文English
文章編號ARTN e01922-19
頁數17
期刊Antimicrobial Agents and Chemotherapy
64
發行號5
DOIs
出版狀態Published - 5月 2020

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