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类重新暴露于腺病毒后就具有快速中和抗体(NAb)的反应。 NAb的诱导会严重限制腺病毒基因治疗的全身性重新给药的疗效。我们假设改变光纤旋钮可以克服NAb。将具有免疫能力的小鼠暴露于血清型5腺病毒(Ad5)(GL),Ad5 / 3luc1,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,肺脏和脾脏的功能降低。暴露于衣壳修饰的病毒对Ad5(GL)基因转移的影响要小得多。抗Ad5(GL)NAb阻断了静脉内Ad5(GL)基因向原位肺癌异种移植的转移,而衣壳修饰的病毒则不受影响。当分析基因转移到新鲜癌症和正常肺外植体时,我们发现衣壳修饰的病毒可以在存在抗Ad5(GL)NAb的情况下有效地将基因传递给肿瘤,而Ad5(GL)被阻断。相反,由不同病毒诱导的NAb交叉阻断影响了基因向正常人肺外植体的传递,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,改变腺病毒纤维瘤足以使相对存在的NAb逃逸程度。如果在试验中得到证实,这种方法可能会提高腺病毒基因疗法对人类的重新给药效果。

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