Prior infection has primed most adult humans for a rapid neutralizing antibody (NAb) response when re-exposed to adenovirus. NAb induction can severely limit the efficacy of systemic re-administration of adenoviral gene therapy. We hypothesized that changing the fiber knob could overcome NAb. Immune-competent mice were exposed to serotype 5 adenovirus (Ad5)(GL), Ad5/3luc1, Ad5lucRGD or Ad5pK7(GL). Mice immunized with Ad5(GL) featured reduced intravenous Ad5(GL) gene transfer to most organs, including the liver, lung and spleen. Ad5(GL) gene transfer was affected much less by exposure to capsid-modified viruses. Anti-Ad5(GL) NAb blocked intravenous Ad5(GL) gene transfer to orthotopic lung cancer xenografts, whereas capsid-modified viruses were not affected. When gene transfer to fresh cancer and normal lung explants was analyzed, we found that capsid-modified viruses allowed effective gene delivery to tumors in the presence of anti-Ad5(GL) NAb, whereas Ad5(GL) was blocked. In contrast, crossblocking by NAbs induced by different viruses affected gene delivery to normal human lung explants, suggesting the importance of non-fiber-knob-mediated infection mechanisms. We conclude that changing the adenovirus fiber knob is sufficient to allow a relative degree of escape from preexisting NAb. If confirmed in trials, this approach might improve the efficacy of re-administration of adenoviral gene therapy to humans.

译文

先前的感染已使大多数成年人在再次暴露于腺病毒时具有快速中和抗体 (NAb) 反应。NAb诱导会严重限制腺病毒基因治疗的全身性再给药的疗效。我们假设更换光纤旋钮可以克服NAb。免疫能力的小鼠暴露于血清型5腺病毒 (Ad5)(GL) 、Ad5/3lug1、Ad5lucRGD或Ad5pK7(GL)。用Ad5(GL) 免疫的小鼠的静脉内Ad5(GL) 基因转移到大多数器官,包括肝脏,肺和脾脏。暴露于衣壳修饰的病毒对Ad5(GL) 基因转移的影响要小得多。Anti-Ad5(GL) NAb阻断了静脉内Ad5(GL) 基因转移至原位肺癌异种移植物,而衣壳修饰的病毒不受影响。当分析基因转移到新鲜癌症和正常肺脏外植体时,我们发现衣壳修饰的病毒在存在anti-Ad5(GL) NAb的情况下允许有效的基因递送到肿瘤,而Ad5(GL) 被阻断。相反,由不同病毒诱导的NAbs交叉阻断会影响向正常人肺外植体的基因传递,这表明非纤维旋钮介导的感染机制的重要性。我们得出的结论是,改变腺病毒光纤旋钮足以允许从先前存在的NAb中逸出相对程度。如果在试验中得到证实,这种方法可能会提高对人类重新施用腺病毒基因疗法的疗效。

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