Objective HCV infection is a leading cause of chronic liver disease and a major indication for liver transplantation. Although direct-acting antivirals (DAAs) have much improved the treatment of chronic HCV infection, alternative strategies are needed for patients with treatment failure. As an essential HCV entry factor, the tight junction protein claudin-1 (CLDN1) is a promising antiviral target. However, genotype-dependent escape via CLDN6 and CLDN9 has been described in some cell lines as a possible limitation facing CLDN1-targeted therapies. Here, we evaluated the clinical potential of therapeutic strategies targeting CLDN1. Design We generated a humanised anti-CLDN1 monoclonal antibody (mAb) (H3L3) suitable for clinical development and characterised its anti-HCV activity using cell culture models, a large panel of primary human hepatocytes (PHH) from 12 different donors, and human liver chimeric mice. Results H3L3 pan-genotypically inhibited HCV pseudoparticle entry into PHH, irrespective of donor. Escape was likely precluded by low surface expression of CLDN6 and CLDN9 on PHH. Co-treatment of a panel of PHH with a CLDN6-specific mAb did not enhance the antiviral effect of H3L3, confirming that CLDN6 does not function as an entry factor in PHH from multiple donors. H3L3 also inhibited DAA-resistant strains of HCV and synergised with current DAAs. Finally, H3L3 cured persistent HCV infection in human-liver chimeric uPA-SCID mice in monotherapy. Conclusions Overall, these findings underscore the clinical potential of CLDN1-targeted therapies and describe the functional characterisation of a humanised anti-CLDN1 antibody suitable for further clinical development to complement existing therapeutic strategies for HCV.

中文翻译：

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一种claudin-1特异性单克隆抗体的人源化临床防治HCV感染无逃逸

目的 HCV感染是导致慢性肝病的主要原因，也是肝移植的主要适应症。尽管直接作用抗病毒药物 (DAA) 大大改善了慢性 HCV 感染的治疗，但治疗失败的患者仍需要替代策略。作为一个重要的 HCV 进入因子，紧密连接蛋白 claudin-1 (CLDN1) 是一个很有前途的抗病毒靶点。然而，通过 CLDN6 和 CLDN9 的基因型依赖性逃逸已在一些细胞系中被描述为 CLDN1 靶向治疗面临的可能限制。在这里，我们评估了针对 CLDN1 的治疗策略的临床潜力。设计 我们生成了一种适合临床开发的人源化抗 CLDN1 单克隆抗体 (mAb) (H3L3)，并使用细胞培养模型表征了其抗 HCV 活性，来自 12 个不同供体的大量原代人肝细胞 (PHH) 和人肝嵌合小鼠。结果 H3L3 泛基因型抑制 HCV 假颗粒进入 PHH，与供体无关。PHH 上 CLDN6 和 CLDN9 的低表面表达可能阻止了逃逸。一组 PHH 与 CLDN6 特异性 mAb 的共同治疗并未增强 H3L3 的抗病毒作用，证实 CLDN6 不能作为来自多个供体的 PHH 的进入因子。H3L3 还抑制抗 DAA 的 HCV 菌株，并与当前的 DAAs 协同作用。最后，H3L3 在单药治疗中治愈了人肝嵌合 uPA-SCID 小鼠的持续性 HCV 感染。结论 总体而言，