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很大的改善，但预计美国每年约有13,900名妇女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5型腺病毒(Ad5)基因治疗载体有两个显著的缺点：1)不能有效地或特异性地将基因转移到卵巢癌细胞；2)40-60%的人中经常存在针对Ad5载体的预先存在的中和抗体。我们最近克服了第一个缺点，创建了一个基于Ad5的载体，靶向在卵巢癌中高表达的αvbeta3和alphavbeta5整合素受体(alphavbeta3/5)。我们的结果表明，这种αvbeta3/靶向载体在将基因转移到存在于腹膜腔中的肿瘤细胞方面是高效和特异的。此外，我们证明，与标准的、非靶向的Ad5载体相比，从alphavbeta3/5靶向载体表达肿瘤坏死因子-α(TNF)具有更好的安全性和增强的抗肿瘤活性。然而，初步数据显示，靶向载体的有效体内肿瘤输送受到先前存在的Ad5免疫的严重影响。在拟议的第一阶段研究中，我们将通过构建基于35型腺病毒(Ad35)的载体来克服先前对Ad5免疫的缺点，对于这种载体，只有一小部分人具有先前的免疫。这项SBIR的总体目标是将以前测试过的有效的肿瘤靶向和肿瘤杀伤元素整合到基于Ad35的载体中，以开发一种治疗卵巢癌的新方法。在这项SBIR的第一阶段，将产生一个铅并进行测试，以(可能)推进到临床试验。我们将构建一个以ava3/5整合素为靶点、Ad35为基础的载体。要符合领先条件，以alphavbeta3/5整合素为靶标的、基于Ad35的载体必须在预先存在的Ad5中和抗体存在的情况下，在交付和安全性(特异性目标1和2，第1年)和抗肿瘤活性(特异性目标3，第2年)方面达到预定的里程碑。

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.