Evaluation of Vectors based on group B adenoviruses

描述(申请人提供)：在初步研究中，我们发现一种小的重组腺病毒血清3型衍生蛋白(Ad3K-K又名JO-1)在上皮性肿瘤中触发细胞间连接的瞬时开放。上皮性连接是获得抗癌治疗药物和在肿瘤内传播的物理障碍，例如曲妥珠单抗/赫赛汀，一种用于治疗Her2/neu阳性乳腺癌患者的商用单抗。我们证明，JO-1增加了捕获在上皮连接中的治疗性靶受体(例如Her2/neu)的可及性，并显著改善了使用单抗在小鼠异种移植瘤模型中的癌症治疗。这项建议的目标是产生足够的临床前疗效和安全性数据，以允许提交JO-1和曲妥珠单抗联合治疗进展期乳腺癌患者的IND前申请。由于JO-1不与小鼠DSG2相互作用，我们将使用基于人DSG2转基因小鼠的乳腺癌模型(DSG2/neu模型)。具体目的是：1.评价JO-1对DSG2/neu转基因小鼠的毒性，寻找最大耐受量。2.研究和优化JO-1与治疗性单抗联合治疗乳腺癌的参数。3对非人类灵长类动物进行毒性研究。新的联合治疗JO-1有可能改进曲妥珠单抗治疗。它也与包括过继T细胞治疗或脂质体化疗药物在内的癌症治疗有关。 公共卫生相关性：这项建议的目标是产生足够的临床前疗效和安全性数据，允许提交IND申请，用于对患有进展性疾病的乳腺癌患者进行重组上皮连接开放剂和曲妥珠单抗/赫赛汀的联合治疗。

DESCRIPTION (provided by applicant): In preliminary studies we found that a small, recombinant adenovirus serotype 3 derived protein (Ad3K-K aka JO-1) triggers transient opening of intercellular junctions in epithelial tumors. Epithelial junctions represent physical obstacles for access and intratumoral dissemination of anti-cancer therapeutics, such as trastuzumab/Herceptin, a commercial monoclonal antibody that is used for the treatment of patients with Her2/neu-positive breast cancer. We demonstrated that JO-1 increases access to therapeutic target receptors (e.g. Her2/neu) which are trapped in epithelial junctions and significantly improves cancer therapy with monoclonal antibodies in mouse models with xenograft tumors. The goal of this proposal is to generate sufficient preclinical efficacy and safety data that allow the submission of a pre-IND application for a combination therapy of JO-1 and trastuzumab in breast cancer patients with progressing disease. Because JO-1 does not interact with murine DSG2, we will use a breast cancer model based on human DSG2-transgenic mice (DSG2/neu model). The Specific Aims are: 1. asses JO-1 toxicity in DSG2/neu transgenic mice and find a maximal tolerated dose. 2. Study and optimize parameters for a co-therapy of JO-1 and a therapeutic monoclonal antibody (mAb) for breast cancer. 3 perform toxicity studies in non-human primates. The new co-therapeutic JO-1 has the potential to improve trastuzumab therapy. It is also relevant for cancer therapies involving adoptive T-cell therapy or liposomal chemotherapy drugs. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to generate sufficient preclinical efficacy and safety data that allow the submission of an IND application for a combination therapy of a recombinant epithelial junction opener and trastuzumab/Herceptin in breast cancer patients with progressing disease.