Monoclonal anti-envelope antibody AP33 protects humanized mice against a patient-derived hepatitis C virus challenge.
Monoclonal anti-envelope antibody AP33 protects humanized mice against a patient-derived hepatitis C virus challenge.
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DOI：
10.1002/hep.28428
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发表时间：
2016-04
期刊：
影响因子：
--
通讯作者：
Meuleman P
中科院分区：
文献类型：
--
作者：
Desombere I;Fafi-Kremer S;Van Houtte F;Pessaux P;Farhoudi A;Heydmann L;Verhoye L;Cole S;McKeating JA;Leroux-Roels G;Baumert TF;Patel AH;Meuleman P
丙型肝炎病毒感染引起的终末期肝病是肝移植的主要适应症。然而，移植后，病毒感染患者的肝移植立即普遍被循环病毒感染，导致肝脏疾病加速发展。目前可用的直接作用抗病毒疗法降低了终末期肝病患者的疗效，预防丙型肝炎复发的预防策略仍然非常必要。在这项研究中，我们比较了两种广泛反应的单抗(MAbs)，命名为3/11和AP33，识别病毒E2糖蛋白中不同但重叠的表位的能力，以保护人源化小鼠免受患者来源的丙型肝炎病毒的攻击。使用表达多个患者来源包膜的HCVpp和HCVcc系统和人-肝嵌合小鼠模型评估它们的中和活性。在用患者来源的丙型肝炎病毒1b分离株攻击的所有对照组小鼠中，很容易检测到丙型肝炎病毒RNA，而四只接受AP33治疗的小鼠中有三只完全保护。相比之下，在整个观察期内，四只接受3/11治疗的小鼠中只有一只保持丙型肝炎病毒RNA阴性，而其他三只小鼠的病毒载量与对照组几乎没有区别。AP33体内药效的增强与其较高的亲和力和体外中和能力相一致。虽然单抗AP33和3/11针对的是E2中的同一区域，但只有单抗AP33能有效地保护体内异源丙型肝炎病毒群体的攻击。由于单抗AP33有效地中和了逃脱体液免疫反应并再次感染移植患者的肝移植的病毒变体，因此它可能是防止丙型肝炎复发的有价值的候选者。此外，我们的数据对预防性疫苗的设计也很有价值。
End-stage liver disease caused by hepatitis C virus (HCV) infection is a major indication for liver transplantation. However, immediately after transplantation the liver graft of viremic patients universally becomes infected by circulating virus, resulting in accelerated liver disease progression. Currently available direct-acting antiviral therapies have reduced efficacy in patients with end-stage liver disease and prophylactic strategies to prevent HCV recurrence are still highly needed. In this study we compared the ability of two broadly reactive monoclonal antibodies (mAbs), designated 3/11 and AP33, recognizing a distinct but overlapping epitope in the viral E2 glycoprotein to protect humanized mice from a patient-derived HCV challenge. Their neutralizing activity was assessed using the HCVpp and HCVcc systems expressing multiple patient-derived envelopes and a human-liver chimeric mouse model. HCV RNA was readily detected in all control mice challenged with a patient-derived HCV genotype 1b isolate, while three out of four AP33-treated mice were completely protected. In contrast, only one out of four 3/11-treated mice remained HCV RNA negative throughout the observation period, while the other three had a viral load that was indistinguishable from that in the control group. The increased in vivo efficacy of AP33 was in line with its higher affinity and neutralizing capacity observed in vitro. Although mAbs AP33 and 3/11 target the same region in E2, only mAb AP33 can efficiently protect from challenge with a heterologous HCV population in vivo. Since mAb AP33 efficiently neutralizes viral variants that escaped the humoral immune response and re-infected the liver graft of transplant patients, it may be a valuable candidate to prevent HCV recurrence. In addition our data is valuable for the design of a prophylactic vaccine.
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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：
29.4
作者：
Charlton, Michael;Gane, Edward;Terrault, Norah A.
通讯作者：
Terrault, Norah A.
影响因子：
25.7
作者：
Lacek, Krzysztof;Vercauteren, Koen;Nicosia, Alfredo
通讯作者：
Nicosia, Alfredo
影响因子：
13.5
作者：
Ciesek, Sandra;von Hahn, Thomas;Steinmann, Eike
通讯作者：
Steinmann, Eike
影响因子：
82.9
作者：
Law, Mansun;Maruyama, Toshiaki;Burton, Dennis R.
通讯作者：
Burton, Dennis R.