Morin Trevor J, Broering Teresa J, Leav Brett A, Blair Barbra M, Rowley Kirk J, Boucher Elisabeth N, Wang Yang, Cheslock Peter S, Knauber Michael, Olsen David B, Ludmerer Steve W, Szabo Gyongyi, Finberg Robert W, Purcell Robert H, Lanford Robert E, Ambrosino Donna M, Molrine Deborah C, Babcock Gregory J
MassBiologics, University of Massachusetts Medical School, Boston, Massachusetts, United States of America.
PLoS Pathog. 2012;8(8):e1002895. doi: 10.1371/journal.ppat.1002895. Epub 2012 Aug 30.
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 log(10) 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.
丙型肝炎病毒（HCV）感染是肝移植的主要原因，迫切需要开发疗法以降低移植肝脏的HCV感染率。已批准的HCV治疗药物耐受性差，对该患者群体疗效有限。人单克隆抗体HCV1识别HCV E2包膜糖蛋白的高度保守线性表位（氨基酸412 - 423），并中和多种HCV基因型。在黑猩猩模型中，在输注1a基因型H77 HCV前30分钟给予250 mg/kg的单剂量HCV1可提供完全的HCV感染保护，而50 mg/kg的剂量则无保护作用。此外，一只急性感染的黑猩猩在接触病毒42天后给予250 mg/kg HCV1，病毒载量迅速降至检测限以下，14天后反弹。出现的病毒显示出赋予对HCV1中和抗性的E2突变（N415K/D）。最后，三只慢性HCV感染黑猩猩接受单剂量40 mg/kg HCV1治疗，一只黑猩猩的病毒载量降至检测限以下21天，反弹病毒显示出抗性突变（N417S）。另外两只黑猩猩的病毒载量降低了0.5 - 1.0 log(10)，没有证据表明病毒对HCV1有抗性。使用HCV假病毒（HCVpp）的体外试验表明，反应不佳的黑猩猩血清抑制了HCV1中和HCVpp的能力。对慢性感染黑猩猩抗体反应的测量表明，尽管其他因素也可能起作用，但E2的内源性抗体和对HCV1中和的干扰有关。这些数据表明，人单克隆抗体HCV1可能是预防接受肝移植的HCV感染患者发生移植物感染的有效治疗方法。
