期刊
ONCOTARGET
卷 7, 期 19, 页码 27926-27937出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.8545
关键词
adenovirus; re-targeting; neutralizing antibody; ovarian cancer; alpha v beta 6 integrin
资金
- Cancer Research Wales
- Cardiff University School of Medicine
- Life Science Research Network Wales
- HEFCW
- Cancer Research UK
Encouraging results from recent clinical trials are revitalizing the field of oncolytic virotherapies. Human adenovirus type 5 (HAdV-C5/Ad5) is a common vector for its ease of manipulation, high production titers and capacity to transduce multiple cell types. However, effective clinical applications are hindered by poor tumor-selectivity and vector neutralization. We generated Ad5/kn48 by pseudotyping Ad5 with the fiber knob domain from the less seroprevalent HAdV-D48 (Ad48). The vector was shown to utilize coxsackie and adenovirus receptor (CAR) but not CD46 for cell entry. A 20-amino acid peptide NAVPNLRGDLQVLAQKVART (A20) was inserted into the Ad5. Luc HI loop (Ad5. HI. A20) and Ad5/kn48 DG loop (Ad5/kn48. DG. A20) to target a prognostic cancer cell marker, beta v beta 6 integrin. Relative to the Ad5.Luc parent vector, Ad5.HI.A20, Ad5.KO1.HI.A20 (KO1, ablated CAR-binding) and Ad5/kn48.DG.A20 showed similar to 160-, 270-and 180-fold increased transduction in BT-20 breast carcinoma cells (beta v beta 6(high)). Primary human epithelial ovarian cancer (EOC) cultures derived from clinical ascites provided a useful ex vivo model for intraperitoneal virotherapy. Ad5.HI.A20, Ad5.KO1.HI.A20 and Ad5/kn48.DG.A20 transduction was similar to 70-, 60- and 16-fold increased relative to Ad5. Luc in EOC cells (beta v beta 6(high)), respectively. A20 vectors transduced EOC cells at up to similar to 950-fold higher efficiency in the presence of neutralizing ovarian ascites, as compared to Ad5. Luc. Efficient transduction and enhanced cancer-selectivity via a non-native beta v beta 6-mediated route was demonstrated, even in the presence of pre-existing anti-Ad5 immunity. Consequently, beta v beta 6-targeted Ad vectors may represent a promising platform for local intraperitoneal treatment of ovarian cancer metastases.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据