Eren Rachel, Landstein Dorit, Terkieltaub Dov, Nussbaum Ofer, Zauberman Arie, Ben-Porath Judith, Gopher Judith, Buchnick Rachel, Kovjazin Riva, Rosenthal-Galili Ziva, Aviel Sigal, Ilan Ehud, Shoshany Yariv, Neville Lewis, Waisman Tal, Ben-Moshe Ofer, Kischitsky Alberto, Foung Steven K H, Keck Zhen-Yong, Pappo Orit, Eid Ahmed, Jurim Oded, Zamir Gidi, Galun Eithan, Dagan Shlomo
XTL Biopharmaceuticals Ltd., Rehovot, Israel.
J Virol. 2006 Mar;80(6):2654-64. doi: 10.1128/JVI.80.6.2654-2664.2006.
Passive immunotherapy is potentially effective in preventing reinfection of liver grafts in hepatitis C virus (HCV)-associated liver transplant patients. A combination of monoclonal antibodies directed against different epitopes may be advantageous against a highly mutating virus such as HCV. Two human monoclonal antibodies (HumAbs) against the E2 envelope protein of HCV were developed and tested for the ability to neutralize the virus and prevent human liver infection. These antibodies, designated HCV-AB 68 and HCV-AB 65, recognize different conformational epitopes on E2. They were characterized in vitro biochemically and functionally. Both HumAbs are immunoglobulin G1 and have affinity constants to recombinant E2 constructs in the range of 10(-10) M. They are able to immunoprecipitate HCV particles from infected patients' sera from diverse genotypes and to stain HCV-infected human liver tissue. Both antibodies can fix complement and form immune complexes, but they do not activate complement-dependent or antibody-dependent cytotoxicity. Upon complement fixation, the monoclonal antibodies induce phagocytosis of the immune complexes by neutrophils, suggesting that the mechanism of viral clearance includes endocytosis. In vivo, in the HCV-Trimera model, both HumAbs were capable of inhibiting HCV infection of human liver fragments and of reducing the mean viral load in HCV-positive animals. The demonstrated neutralizing activities of HCV-AB 68 and HCV-AB 65 suggest that they have the potential to prevent reinfection in liver transplant patients and to serve as prophylactic treatment in postexposure events.
被动免疫疗法在预防丙型肝炎病毒（HCV）相关性肝移植患者的肝移植再感染方面可能有效。针对不同表位的单克隆抗体组合对于像HCV这样高度变异的病毒可能具有优势。开发了两种针对HCV E2包膜蛋白的人源单克隆抗体（HumAbs），并测试了它们中和病毒及预防人肝感染的能力。这些抗体命名为HCV-AB 68和HCV-AB 65，识别E2上不同的构象表位。对它们进行了体外生化和功能特性分析。两种HumAbs均为免疫球蛋白G1，对重组E2构建体的亲和常数在10^(-10) M范围内。它们能够从感染患者的不同基因型血清中免疫沉淀HCV颗粒，并对HCV感染的人肝组织进行染色。两种抗体都能固定补体并形成免疫复合物，但它们不激活补体依赖性或抗体依赖性细胞毒性。补体固定后，单克隆抗体诱导中性粒细胞对免疫复合物的吞噬作用，提示病毒清除机制包括内吞作用。在体内，在HCV-Trimera模型中，两种HumAbs都能够抑制人肝片段的HCV感染，并降低HCV阳性动物的平均病毒载量。HCV-AB 68和HCV-AB 65所表现出的中和活性表明，它们有潜力预防肝移植患者的再感染，并可作为暴露后事件的预防性治疗药物。
