Targeted, Alternate Serotype Vector for Ovarian Cancer

卵巢癌的靶向替代血清型载体

• 批准号: 6942316
• 负责人: C. RICHTER KING
• 金额: $ 24.56万
• 依托单位: GENVEC, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-23 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6942316
• 关键词: Adenoviridae; athymic mouse; binding sites; biotechnology; gene therapy; green fluorescent proteins; integrins; laboratory mouse; luciferin monooxygenase; molecular cloning; neoplasm /cancer therapy; neutralizing antibody; nonhuman therapy evaluation; ovary neoplasms; receptor binding; therapy design /development; transfection /expression vector; tumor necrosis factor alpha

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.

描述（由申请人提供）：尽管卵巢癌的管理有了显著改善，但预计美国每年约有13，900名妇女最终无法接受标准治疗并死亡。对于卵巢癌的治疗，广泛使用的5型腺病毒（Ad 5）基因治疗载体具有两个显著的缺点：1）向卵巢癌细胞的基因转移效率或特异性不足，和2）预先存在的针对基于Ad 5的载体的中和抗体通常存在于40-60%的人群中。我们最近通过创建靶向在卵巢癌中高度表达的α v β 3和α v β 5整联蛋白受体（α v β 3/5）的基于Ad 5的载体克服了第一个缺点。我们的研究结果表明，这种alphavbeta 3/-靶向载体是高效和特异性的基因转移到肿瘤细胞存在于腹腔。此外，我们证明了与标准的非靶向Ad 5载体相比，从alphavbeta 3/5靶向载体表达肿瘤坏死因子-α（TNF）具有改善的安全性和增强的抗肿瘤活性。然而，初步数据显示，通过靶向载体的有效体内肿瘤递送受到预先存在的对Ad 5的免疫力的严重损害。在所提出的I期研究中，我们将通过产生基于腺病毒35型（Ad 35）的载体来克服对Ad 5的预先存在的免疫力的缺点，对于Ad 35，只有一小部分人具有预先存在的免疫力。该SBIR的总体目标是将先前测试和有效的肿瘤靶向和肿瘤杀伤元件整合到基于Ad 35的载体中，以开发卵巢癌的新治疗方法。在本SBIR的I期部分，将生成并测试电极导线，以便（可能）推进临床试验。我们将构建一个ava 35整合素靶向的Ad 35载体。为了有资格作为先导药物，靶向α v β 35整联蛋白的基于Ad 35的载体必须在存在预先存在的Ad 5中和抗体的情况下满足预定义的递送和安全性（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）的里程碑。