Evaluation of Vectors based on group B adenoviruses

描述（由申请人提供）：大多数实体癌是上皮起源的。上皮细胞的一个特征是紧密的粘附连接。紧密和粘附的连接封闭了细胞间隙，并显著限制了抗肿瘤药物（如药物、抗体和肿瘤内的免疫细胞）的灌注，从而严重降低了这种治疗方式的疗效。癌细胞的上皮表型也代表了一种屏障，可以抵抗针对CD46或柯萨奇-腺病毒受体（CAR）的常用腺病毒（Ads）的感染，因为这些受体被困在紧密和粘附的连接中，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种腺病毒，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，例如最近爆发的高致病性新Ad14染色剂（Ad14a）也使用受体x。此外，我们已经证明重组Ad3十二面体（PtDd）通过12个penton碱基与突出的纤维相互作用形成，可以进入上皮癌细胞并促进Ads（以及潜在的其他肿瘤药物）的摄取，而紧密和粘附的连接代表了一种屏障。基于Ad3、7、11和14作为病原体和潜在基因治疗载体的重要性，本提案的中心目标是鉴定受体X，描述AdB- 2组和PtDd在正常和恶性上皮细胞中的摄取机制，并开发AdB- 2组载体和PtDd衍生物作为基因或药物递送到上皮癌症的载体。

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. PUBLIC HEALTH RELEVANCE: In cancers of epithelial origin, tight and adherens junctions seal intercellular spaces and severely diminish the efficacy of anti-tumor agents. The central goals of this proposal are to understand how adenovirus serotypes Ad3, Ad7, Ad11, and Ad14 infect normal and malignant epithelial cells and to develop derivatives of these adenoviruses as vehicles for gene or drug delivery into epithelial cancers.