Broad neutralization of hepatitis C virus-resistant variants by Civacir hepatitis C immunoglobulin.
Broad neutralization of hepatitis C virus-resistant variants by Civacir hepatitis C immunoglobulin.
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DOI：
10.1002/hep.28767
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发表时间：
2016-11
期刊：
影响因子：
--
通讯作者：
Baumert TF
中科院分区：
文献类型：
--
作者：
Tawar RG;Heydmann L;Bach C;Schüttrumpf J;Chavan S;King BJ;McClure CP;Ball JK;Pessaux P;Habersetzer F;Bartenschlager R;Zeisel MB;Baumert TF
丙型肝炎病毒（HCV）诱导的终末期肝脏疾病是肝移植（LT）的主要适应症。然而，肝移植物的再感染仍然很常见，特别是在移植时可检测到病毒载量的患者中。有限的数据是可用的直接作用抗病毒药物（DAA）在移植设置为预防移植物感染。人丙型肝炎免疫球蛋白（HCIG）Civacir®是一种研究药物，目前正在进行的III期临床试验中开发，评估在美国肝移植后预防HCV复发的安全性和有效性。使用在LT期间选择的充分表征的患者来源的HCV变体，我们旨在研究Civacir®作用的分子机制。使用感染性HCV模型研究了HCV感染的抑制，包括HCV假颗粒（HCVpp）和细胞培养衍生的HCV病毒（HCVpp），其中含有来自LT前后患者分离的22种HCV变体的患者衍生病毒包膜糖蛋白。此外，我们研究了不同HCV基因型和DAA耐药病毒的中和作用。我们的研究结果表明，Civacir可有效、广泛和剂量依赖性地中和HCVpp和HCVpp试验中检测的所有患者变体，包括对宿主中和抗体和抗病毒单克隆抗体显示耐药性的变体。半数最大抑制浓度与病毒变体的表型无关，表明Civacir的病毒中和不受病毒选择的影响。此外，Civacir对细胞培养物中测试的DAA抗性HCV分离株具有同等活性。结论：总的来说，这些结果证明了Civacir对耐药病毒的广泛中和活性，并支持其用于预防肝移植物感染的进一步临床开发。Civacir的广泛中和活性可能是由于来自不同患者供体的抗HCV抗体之间的协同作用。
Hepatitis C virus (HCV)-induced end-stage liver disease is the major indication for liver transplantation (LT). However, re-infection of the liver graft is still common, especially in patients with detectable viral load at the time of transplantation. Limited data is available with direct-acting antivirals (DAAs) in the transplant setting for prevention of graft infection. The human hepatitis C immune globulin (HCIG) Civacir® is an investigational drug that is currently developed in an ongoing phase III clinical trial assessing safety and efficacy to prevent the HCV recurrence after liver transplant in the US. Using well characterized patient-derived HCV variants selected during LT we aimed to study the molecular mechanism of action of Civacir®. Inhibition of HCV infection was studied using infectious HCV models including HCV pseudoparticles (HCVpp) and cell culture-derived HCV viruses (HCVcc) containing patient-derived viral envelope glycoproteins from 22 HCV variants isolated from patients before and after LT. Additionally, we studied neutralization of different HCV genotypes and of DAA-resistant viruses. Our results indicate that Civacir potently, broadly and dose-dependently neutralizes all tested patient variants in HCVpp and HCVcc assays including variants displaying resistance to host neutralizing antibodies and anti-viral monoclonal antibodies. The half maximal inhibitory concentrations were independent of the phenotype of the viral variant indicating that virus neutralization by Civacir is not affected by viral selection. Furthermore, Civacir is equally active against tested DAA-resistant HCV isolates in cell culture. Conclusion: Collectively, these results demonstrate broad neutralizing activity of Civacir against resistant viruses and support its further clinical development for prevention of liver graft infection. The broad neutralizing activity of Civacir is likely due to synergy between anti-HCV antibodies derived from different patient donors.
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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：
13.5
作者：
Lawitz, Eric;Poordad, Fred;Brainard, Diana M.;Hyland, Robert H.;An, Di;Dvory-Sobol, Hadas;Symonds, William T.;McHutchison, John G.;Membreno, Fernando E.
通讯作者：
Membreno, Fernando E.
影响因子：
13.5
作者：
Meuleman, Philip;Bukh, Jens;Leroux-Roels, Geert
通讯作者：
Leroux-Roels, Geert
使用Claudin-1靶向单克隆抗体的人源化小鼠中持续性丙型肝炎病毒感染的清除。
影响因子：
46.9
作者：
Mailly, Laurent;Xiao, Fei;Lupberger, Joachim;Wilson, Garrick K.;Aubert, Philippe;Duong, Franois H. T.;Calabrese, Diego;Leboeuf, Celine;Fofana, Isabel;Thumann, Christine;Bandiera, Simonetta;Luergehetmann, Marc;Volz, Tassilo;Davis, Christopher;Harris, Helen J.;Mee, Christopher J.;Girardi, Erika;Chane-Woon-Ming, Beatrice;Ericsson, Maria;Fletcher, Nicola;Bartenschlager, Ralf;Pessaux, Patrick;Vercauteren, Koen;Meuleman, Philip;Villa, Pascal;Kaderali, Lars;Pfeffer, Sebastien;Heim, Markus H.;Neunlist, Michel;Zeisel, Mirjam B.;Dandri, Maura;McKeating, Jane A.;Robinet, Eric;Baumert, Thomas F.
通讯作者：
Baumert, Thomas F.
影响因子：
3.7
作者：
Law JL;Chen C;Wong J;Hockman D;Santer DM;Frey SE;Belshe RB;Wakita T;Bukh J;Jones CT;Rice CM;Abrignani S;Tyrrell DL;Houghton M
通讯作者：
Houghton M