Evaluation of Vectors based on group B adenoviruses

描述(申请人提供)：大多数实体癌起源于上皮癌。上皮细胞的一个标志是紧密和粘连连接。紧密和粘连的连接封闭了细胞间隙，并显著限制了抗肿瘤药物、抗体和免疫细胞在肿瘤内的灌流，从而严重降低了此类治疗方法的疗效。癌细胞的上皮表型也代表了一种针对CD46或柯萨奇-腺病毒受体(CAR)的常用腺病毒(ADS)感染的屏障，这是由于这些受体被捕获在紧密和粘连的连接上，这在一定程度上解释了为什么这些血清型在癌症基因治疗中无效。然而，我们发现，特定的人类B型腺病毒，即AD3，AD7，AD11和AD14(ADB组2)，使用一种未知的受体(受体X)，不同于CAR和CD46，有效地感染上皮癌细胞。这使得这些血清型成为癌症病毒治疗以及将基因转移到正常上皮组织的潜在工具。此外，这些血清型是重要的病原体，最近爆发的一种也使用X受体的高致病性新AD14菌株(Ad14a)就是例证。此外，我们已经证明，通过12个五元碱基与突出的纤维相互作用形成的重组AD3十二面体(PtDd)可以进入上皮癌细胞，并促进ADS(和潜在的其他肿瘤因子)的摄取，对这些细胞来说，紧密和粘连的连接是一种屏障。基于AD3、7、11和14作为病原体和潜在载体在基因治疗中的重要性，本研究的中心目标是确定X受体，阐明ADB组2和PtDd在正常和恶性上皮细胞中摄取的机制，并开发ADB组2载体和PtDd衍生物作为基因或药物输送到上皮性肿瘤的载体。

DESCRIPTION (provided by applicant): The majority of solid cancers are of epithelial origin. A hallmark of epithelial cells are tight and adherens junctions. Tight and adherens junctions seal intercellular spaces and significantly limit the perfusion of anti- tumor agents such as drugs, antibodies, and immune cells within the tumor, thus severely diminishing the efficacy of such therapeutic modalities. The epithelial phenotype of cancer cells also represents a barrier to infection with commonly used adenoviruses (Ads) that target CD46 or the coxsackie-adenovirus receptor (CAR), due to trapping of these receptors in tight and adherens junctions which explains, in part, why these serotypes are inefficient in cancer gene therapy. We found however, that specific human species B adenoviruses, namely Ad3, Ad7, Ad11, and Ad14 (AdB-group 2) that use a yet unknown receptor (receptor X), which is different from CAR and CD46, efficiently infect epithelial cancer cells. This makes these serotypes potential tools for virotherapy of cancer as well as for gene transfer into normal epithelial tissue. In addition, these serotypes are important pathogens, exemplified by recent outbreaks of a highly pathogenic new Ad14 stain (Ad14a) that also uses receptor X. Furthermore, we have shown that recombinant Ad3 dodecahedra (PtDd) formed through interaction of 12 penton bases with protruding fibers can enter epithelial cancer cells and faciliate uptake of Ads (and potentially other tumor agents) for which tight and adherens junctions represent a barrier. Based on the importance of Ad3, 7, 11, and 14 as pathogens and potential vectors for gene therapy, the central goals of this proposal are to identify receptor X, to delineate the mechanism of AdB- group 2 and PtDd uptake in normal and malignant epithelial cells, and to develop AdB-group 2 vectors and PtDd-derivatives as vehicles for gene or drug delivery into epithelial cancers.