Humanisation of a claudin-1-specific monoclonal antibody for clinical prevention and cure of HCV infection without escape.
Humanisation of a claudin-1-specific monoclonal antibody for clinical prevention and cure of HCV infection without escape.
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DOI：
10.1136/gutjnl-2016-312577
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发表时间：
2018-04
期刊：
影响因子：
24.5
通讯作者：
Baumert TF
中科院分区：
文献类型：
--
作者：
Colpitts CC;Tawar RG;Mailly L;Thumann C;Heydmann L;Durand SC;Xiao F;Robinet E;Pessaux P;Zeisel MB;Baumert TF
丙型肝炎病毒感染是慢性肝病的主要原因，也是肝移植的主要指征。尽管直接作用抗病毒药物（DAAs）已经大大改善了慢性HCV感染的治疗，但对于治疗失败的患者，还需要其他策略。作为一种重要的HCV进入因子，紧密连接蛋白CLDN1是一种很有前景的抗病毒靶点。然而，在一些细胞系中，通过CLDN6和CLDN9的基因型依赖性逃逸已被描述为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。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、来自12个不同供体的大量原代人肝细胞（PHH）和人肝嵌合小鼠来表征其抗hcv活性。H3L3泛基因典型地抑制HCV假颗粒进入PHH，与供者无关。CLDN6和CLDN9在PHH表面的低表达可能阻止了逃逸。将一组PHH与一种CLDN6特异性单克隆抗体联合治疗并没有增强H3L3的抗病毒作用，这证实了CLDN6不是来自多个供者的PHH的进入因子。H3L3也抑制抗daa的HCV毒株，并与当前的daa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。总的来说，这些发现强调了cldn1靶向治疗的临床潜力，并描述了适合进一步临床开发的人源化抗cldn1抗体的功能特征，以补充现有的HCV治疗策略。
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. 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. 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. 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.
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DOI：
10.1084/jem.20090766
发表时间：
2010-08-30
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fafi-Kremer S;Fofana I;Soulier E;Carolla P;Meuleman P;Leroux-Roels G;Patel AH;Cosset FL;Pessaux P;Doffoël M;Wolf P;Stoll-Keller F;Baumert TF
通讯作者：
Baumert TF
影响因子：
158.5
作者：
Curry, M. P.;O'Leary, J. G.;Charlton, M.
通讯作者：
Charlton, M.
DOI：
10.1016/s1473-3099(16)00120-1
发表时间：
2016-06
期刊：
The Lancet. Infectious diseases
影响因子：
--
作者：
Felmlee DJ;Coilly A;Chung RT;Samuel D;Baumert TF
通讯作者：
Baumert TF
影响因子：
5.4
作者：
Koutsoudakis, George;Kaul, Artur;Bartenschlager, Ralf
通讯作者：
Bartenschlager, Ralf
影响因子：
5.4
作者：
Meertens, Laurent;Bertaux, Claire;Dragic, Tatjana
通讯作者：
Dragic, Tatjana