Evaluation of Vectors based on group B adenoviruses

描述（由申请人提供）：大多数实体癌起源于上皮。上皮细胞的标志是紧密和粘附连接。紧密连接和粘附连接密封细胞间空间，并显著限制肿瘤内抗肿瘤剂如药物、抗体和免疫细胞的灌注，从而严重降低此类治疗方式的功效。癌细胞的上皮表型也代表了对靶向CD 46或柯萨奇-腺病毒受体（CAR）的常用腺病毒（Ad）感染的屏障，这是由于这些受体被捕获在紧密和粘附连接中，这部分解释了为什么这些血清型在癌症基因治疗中效率低下。然而，我们发现特定的人类B腺病毒，即Ad 3、Ad 7、Ad 11和Ad 14（AdB组2），使用与CAR和CD 46不同的未知受体（受体X），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中的潜在工具。此外，这些血清型是重要的病原体，最近爆发的高致病性新Ad 14菌株（Ad 14 a）也使用受体X。此外，我们已经表明，通过12个五邻体碱基与突出纤维的相互作用形成的重组Ad 3十二面体（PtDd）可以进入上皮癌细胞并促进Ads（以及潜在的其他肿瘤因子）的摄取，其中紧密连接和粘附连接代表屏障。基于Ad 3、7、11和14作为病原体和基因治疗的潜在载体的重要性，本提案的中心目标是鉴定受体X，描述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衍生物作为将基因或药物递送到上皮癌中的载体。

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.