Laboratory of Molecular Biology and Biochemistry, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Anticancer Res. 2012 Apr;32(4):1145-52.
Pre-existing anti-adenovirus neutralizing antibodies (AdNAbs) are a major barrier in clinical gene therapy using adenovirus vectors; however, the transduction profile of adenovirus vectors in the presence of AdNAbs following intratumoral injection has not been fully examined, although such vectors are often intratumorally injected in clinical studies. In this study, we evaluated the correlation between the titer of AdNAbs in the serum and the transduction profiles in the tumor and the liver following intratumoral administration into mice possessing various titers of AdNAbs. Adenovirus vector-mediated transduction in the tumor was inhibited by AdNAbs; however, when the titer of AdNAbs was less than 200, the levels of inhibition in the transduction efficiencies within the tumor ranged from approximately 2- to 100-fold. A more than 2500-fold reduction of adenovirus vector-mediated transduction was found in most of the mice when the titers of AdNAbs were >200. On the other hand, the transduction efficiencies in the liver were largely reduced almost to the levels of the mock-transduced mice even at the low titers of AdNAbs. These results provide crucial information for the clinical use of adenovirus vectors.
预先存在的抗腺病毒中和抗体（AdNAb）是使用腺病毒载体进行临床基因治疗的主要障碍；然而，尽管此类载体在临床研究中经常瘤内注射，但在存在 AdNAb 时腺病毒载体在肿瘤内的转导情况尚未得到充分检查。在这项研究中，我们评估了血清中 AdNAb 滴度与携带各种 AdNAb 滴度的小鼠瘤内给药后肿瘤和肝脏中转导谱之间的相关性。腺病毒载体介导的肿瘤内转导被 AdNAb 抑制；然而，当 AdNAb 滴度低于 200 时，肿瘤内转导效率的抑制水平在 2 到 100 倍之间。当 AdNAb 滴度>200 时，大多数小鼠的腺病毒载体介导的转导水平下降了 2500 多倍。另一方面，即使在低滴度的 AdNAb 时，肝脏中的转导效率也大大降低，几乎降至 mock 转导小鼠的水平。这些结果为腺病毒载体的临床应用提供了重要信息。
