Human monoclonal antibody HCV1 effectively prevents and treats HCV infection in chimpanzees.
Human monoclonal antibody HCV1 effectively prevents and treats HCV infection in chimpanzees.
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DOI：
10.1371/journal.ppat.1002895
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Babcock GJ
中科院分区：
文献类型：
--
作者：
Morin TJ;Broering TJ;Leav BA;Blair BM;Rowley KJ;Boucher EN;Wang Y;Cheslock PS;Knauber M;Olsen DB;Ludmerer SW;Szabo G;Finberg RW;Purcell RH;Lanford RE;Ambrosino DM;Molrine DC;Babcock GJ
丙型肝炎病毒(丙型肝炎病毒)感染是肝移植的主要原因，迫切需要开发治疗方法来降低移植肝的丙型肝炎病毒感染率。已批准的治疗丙型肝炎病毒的药物耐受性很差，在这类患者中疗效有限。人类单抗HCV1识别一个高度保守的丙型肝炎病毒包膜糖蛋白(氨基酸412-423)的线性表位，并中和广泛的丙型肝炎病毒基因。在黑猩猩模型中，在输注1a H77型丙型肝炎病毒前30分钟单次注射250毫克/公斤的丙型肝炎病毒可完全预防丙型肝炎病毒的感染，而50毫克/公斤的丙型肝炎病毒却不能起到保护作用。此外，一只急性感染的黑猩猩在接触病毒42天后注射250毫克/公斤的HCV1病毒后，病毒载量迅速下降到低于检测极限，14天后反弹。新出现的病毒表现出对HCV1中和耐药的E2突变(N415K/D)。最后，对三只慢性感染丙型肝炎病毒的黑猩猩单次注射40 mg/kg的HCV1，其中一只病毒反弹显示耐药突变(N417S)的黑猩猩的病毒载量在21天内降至检测下限以下。另外两只黑猩猩的病毒载量减少了0.5-1.0log10，但没有证据表明对HCV1有病毒耐药性。用丙型肝炎病毒假病毒(HCVpp)进行的体外试验表明，来自低应答黑猩猩的血清抑制了HCV1中和HCVpp的能力。对慢性感染的黑猩猩的抗体反应的测量表明，内源性的E2抗体和干扰了HCV1的中和，尽管其他因素也可能起作用。这些数据表明，人源单抗HCV1可能是预防肝移植术后丙型肝炎病毒感染患者移植物感染的有效方法。大多数感染丙型肝炎病毒(丙型肝炎病毒)的人会成为慢性感染者，许多人会继续发展为肝功能衰竭，需要肝移植。不幸的是，在几乎100%的移植患者中，移植肝脏感染了丙型肝炎病毒。目前对丙型肝炎病毒的治疗在肝移植后耐受性差，移植物健康受到感染的影响。我们已经开发出一种名为HCV1的单抗，它可以阻止培养中的丙型肝炎病毒感染肝细胞。利用黑猩猩作为丙型肝炎病毒感染的模型，我们证明了HCV1具有预防丙型肝炎病毒感染的能力。我们还表明，HCV1可以治疗慢性感染丙型肝炎病毒的黑猩猩，并在7至21天的时间内将血浆病毒载量降至检测水平以下。在接受治疗的黑猩猩体内重新出现的病毒对HCV1中和具有抵抗力，显示出靶向结合。鉴于HCV1保护黑猩猩免受丙型肝炎病毒感染的能力，我们推测HCV1对接受肝移植的丙型肝炎病毒感染患者可能是有益的。
Hepatitis C virus (HCV) infection is a leading cause of liver transplantation and there is an urgent need to develop therapies to reduce rates of HCV infection of transplanted livers. Approved therapeutics for HCV are poorly tolerated and are of limited efficacy in this patient population. Human monoclonal antibody HCV1 recognizes a highly-conserved linear epitope of the HCV E2 envelope glycoprotein (amino acids 412–423) and neutralizes a broad range of HCV genotypes. In a chimpanzee model, a single dose of 250 mg/kg HCV1 delivered 30 minutes prior to infusion with genotype 1a H77 HCV provided complete protection from HCV infection, whereas a dose of 50 mg/kg HCV1 did not protect. In addition, an acutely-infected chimpanzee given 250 mg/kg HCV1 42 days following exposure to virus had a rapid reduction in viral load to below the limit of detection before rebounding 14 days later. The emergent virus displayed an E2 mutation (N415K/D) conferring resistance to HCV1 neutralization. Finally, three chronically HCV-infected chimpanzees were treated with a single dose of 40 mg/kg HCV1 and viral load was reduced to below the limit of detection for 21 days in one chimpanzee with rebounding virus displaying a resistance mutation (N417S). The other two chimpanzees had 0.5–1.0 log10 reductions in viral load without evidence of viral resistance to HCV1. In vitro testing using HCV pseudovirus (HCVpp) demonstrated that the sera from the poorly-responding chimpanzees inhibited the ability of HCV1 to neutralize HCVpp. Measurement of antibody responses in the chronically-infected chimpanzees implicated endogenous antibody to E2 and interference with HCV1 neutralization although other factors may also be responsible. These data suggest that human monoclonal antibody HCV1 may be an effective therapeutic for the prevention of graft infection in HCV-infected patients undergoing liver transplantation. The majority of individuals infected with hepatitis C virus (HCV) become chronically infected and many go on to develop liver failure requiring liver transplantation. Unfortunately, the transplanted liver becomes infected with HCV in nearly 100% of transplant patients. Current treatments for HCV are poorly tolerated after liver transplantation and graft health is compromised by infection. We have developed a monoclonal antibody called HCV1 that blocks HCV from infecting liver cells in culture. Using chimpanzees as a model for HCV infection, we demonstrate that HCV1 has the ability to prevent HCV infection. We also show that HCV1 can treat chimpanzees chronically infected with HCV and reduce plasma viral load to below the level of detection for a period of 7 to 21 days. The virus that reemerges in the treated chimpanzees was resistant to HCV1 neutralization demonstrating target engagement. Given the ability of HCV1 to protect chimpanzees from HCV infection, we speculate that HCV1 may be beneficial in HCV- infected patients undergoing liver transplant.
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