Targeted, Alternate Serotype Vector for Ovarian Cancer

描述（由申请人提供）：尽管卵巢癌的管理有了显著的改善，但在美国，每年大约有13900名妇女预计最终无法通过标准治疗而死亡。对于卵巢癌的治疗，广泛使用的腺病毒5型（Ad5）基因治疗载体有两个明显的缺点：1)不充分有效或特异性基因转移到卵巢癌细胞和2)预先存在的针对Ad5载体的中和抗体通常存在于40-60%的人群中。我们最近克服了第一个缺点，创建了一个基于ad5的载体，靶向在卵巢癌中高度表达的alphavbeta3和alphavbeta5整合素受体（alphavbeta3/5）。我们的研究结果表明，这种以alphavbeta3/-为目标的载体在将基因转移到存在于腹腔的肿瘤细胞中是高效和特异性的。此外，我们证明，与标准的非靶向Ad5载体相比，从alphavbeta3/5靶向载体中表达肿瘤坏死因子- α (TNF)具有更高的安全性和更强的抗肿瘤活性。然而，初步数据显示，预先存在的Ad5免疫严重损害了靶向载体在体内的肿瘤递送效率。在拟议的I期研究中，我们将通过生成基于35型腺病毒（Ad35）的载体来克服对Ad5预先存在免疫力的缺点，因为只有一小部分人对Ad35型腺病毒具有预先存在的免疫力。该SBIR的总体目标是将先前测试的高效肿瘤靶向和肿瘤杀伤元件整合到基于Ad35的载体中，以开发卵巢癌的新治疗方法。在这个SBIR的I期部分，将产生一个先导，并为（可能的）临床试验进行测试。我们将构建一个以ava3/5为目标，ad35为基础的整合素载体。为了获得先导药物的资格，以Ad35为基础的alphavbeta3/5整合素为目标的载体必须在预先存在Ad5中和抗体的情况下，达到预先设定的递送和安全性里程碑（特异性目标1和2，第1年）和抗肿瘤活性里程碑（特异性目标3，第2年）。

DESCRIPTION (provided by applicant): Despite significant improvements in the management of ovarian cancer, approximately 13,900 women per year in the United States are expected to ultimately fail standard therapies and die. For the treatment of ovarian cancer, the broadly used adenovirus type 5 (Ad5) gene therapy vectors have two significant disadvantages: 1) Inadequately efficient or specific gene transfer to ovarian cancer cells and 2) Pre-existing neutralizing antibodies to Ad5-based vectors are often present in 40-60% of the human population. We have recently overcome the first disadvantage by creating an Ad5-based vector targeted to the alphavbeta3 and alphavbeta5 integrin receptors (alphavbeta3/5) that are highly expressed in ovarian cancers. Our results demonstrate that this alphavbeta3/-targeted vector is highly efficient and specific in gene transfer to tumor cells present in the peritoneal cavity. Moreover, we demonstrate that expression of tumor necrosis factor-alpha (TNF) from the alphavbeta3/5-targeted vector has an improved safety profile and enhanced anti-tumor activity compared to a standard, untargeted Ad5 vector. However, preliminary data show that efficient in vivo tumor delivery by the targeted vector is severely compromised by preexisting immunity to Ad5. In the proposed phase I studies we will overcome the disadvantage of preexisting immunity to Ad5 by generating vectors based on adenovirus type 35 (Ad35), for which only a small fraction of the human population has pre-existing immunity. The overall goal of this SBIR is to incorporate the previously tested and efficient tumor targeting and tumor killing elements into an Ad35- based vector to develop a new treatment for ovarian cancer. In the phase I portion of this SBIR, a lead will be generated and tested for (possible) advancement to clinical trials. We will construct an ava3/5 integrin-targeted, Ad35-based vector. To qualify as a lead, the alphavbeta3/5 integrin-targeted, Ad35- based vector must meet predefined milestones for delivery and safety (Specific Aims 1 and 2, Year 1) and anti-tumor activity (Specific Aim 3, Year 2) in the presence of pre-existing neutralizing antibodies to Ad5.