Efficacy of a recombinant single-chain fragment variable region,VasSF, as a new drug for vasculitis
Efficacy of a recombinant single-chain fragment variable region,VasSF, as a new drug for vasculitis
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DOI：
10.2147/dddt.s188651
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发表时间：
2019-01-01
影响因子：
4.8
通讯作者：
Suzuki, Kazuo
中科院分区：
文献类型：
--
作者：
Kameoka, Yosuke;Kishi, Fukuko;Suzuki, Kazuo
背景资料：抗中性粒细胞胞浆抗体（ANCA）相关性血管炎是一种以小血管炎症为主要表现的寡免疫性疾病。抗体药物诱导治疗血管炎的疗效因病例而异。在这里，我们开发了一种新的具有血管炎特异性治疗潜力的单链Fv区（ScFv）克隆。材料和方法：该克隆称为VasSF，是从我们的重组人ScFv的大肠杆菌表达文库中选择的，其基于在MPO-ANCA相关血管炎（MAAV）的SCG/Kj小鼠模型中的治疗功效，例如改善尿评分和减少肾小球中的新月体形成，结果：我们鉴定了血管炎相关的载脂蛋白A-II（VAP 2）作为克隆的靶分子，并证实独立建立的VAP 2抗体在SCG/Kj小鼠中也是治疗性的。在MAAV中，MPO-ANCA和细胞因子通过促进VAP 2与HDL中载脂蛋白A-I形成异源二聚体来刺激中性粒细胞。结论：VasSF可能通过抑制载脂蛋白A-I形成异源二聚体而成为治疗血管炎的新型抗体药物。
Background: Anti-neutrophil cytoplasmic autoantibodies (ANCA) associated vasculitis is a pauci-immune disease with the inflammation of the small blood vessels. The efficacies of antibody drugs for induction therapies of vasculitis vary among cases. Here, we developed a novel clone of a single chain Fv region (ScFv) with vasculitis-specific therapeutic potential.Materials and methods: The clone, termed VasSF, was selected from our Escherichia coil expression library of recombinant human ScFv based on the therapeutic efficacy in an SCG/Kj mouse model of MPO-ANCA-associated vasculitis (MAAV), such as improvement of the urinary score and decreased crescent formation in glomeruli, granulomatous in lung, MPO-ANCA biomarkers, the anti-moesin antibody, and some cytokine levels.Results: We identified vasculitis-associated apolipoprotein A-II (VA P2) as a target molecule of the clone and confirmed the independently-established VAP2 antibodies were also therapeutic in SCG/Kj mice. In MAAV, MPO-ANCA and cytokines stimulate neutrophils by facilitating heterodimer formation of VAP2 with apolipoprotein A-I in HDL.Conclusion: VasSF would constitute a novel antibody drug for vasculitis by suppressing the heterodimer formation of the apolipoproteins.