文獻標(biāo)題：Human Monoclonal Antibody HCV1 Effectively Prevents and Treats HCV Infection in Chimpanzees

    文獻來源：PLoS Pathogens 2012;Aug

    得克薩斯州的生物醫(yī)學(xué)研究所馬薩諸塞州醫(yī)學(xué)院（UMMS）研究人員開發(fā)了一種新的防止丙型肝炎病毒（HCV）感染的單克隆抗體，并在動物模型上進行了測試。

    在德克薩斯州生物醫(yī)學(xué)的靈長類動物研究中心進行的一項研究中，研究人員發(fā)現(xiàn)一種新的靶向病毒的人單克隆抗體能以劑量依賴的方式保護黑猩猩免于丙型肝炎病毒感染。黑猩猩是除人類以外唯一會被HCV感染的物種，因此本研究的結(jié)果對單克隆抗體的發(fā)展至關(guān)重要。

    研究人員曾表明，單克隆抗體HCV1能阻斷丙型肝炎病毒感染實驗室組織培養(yǎng)的肝細胞。 這是一個重要的臨床前研究結(jié)論，該研究證實了高劑量的中和抗體可以保護肝臟免受感染丙型肝炎病毒。

    HCV1是一種單克隆抗體，該抗體結(jié)合HCV病毒并抑制病毒進入肝細胞的能力。HCV病毒損害肝臟，是導(dǎo)致肝移植患者死亡的主要原因，美國每年大約有6000名患者接受肝移植，但約有一半患者診斷感染丙型肝炎病毒

    abstract

    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。