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）：尽管卵巢癌的治疗取得了显着进步，但预计美国每年约有 13,900 名女性最终因标准治疗失败而死亡。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着的缺点：1) 向卵巢癌细胞的基因转移效率或特异性不足；2) 现有的针对基于 Ad5 的载体的中和抗体是通常存在于 40-60% 的人口中。我们最近通过创建一种基于 Ad5 的载体克服了第一个缺点，该载体针对在卵巢癌中高表达的 alphavbeta3 和 alphavbeta5 整合素受体 (alphavbeta3/5)。我们的结果表明，这种 alphavbeta3/-靶向载体在将基因转移到腹膜腔中存在的肿瘤细胞方面具有高效性和特异性。此外，我们证明，与标准的非靶向 Ad5 载体相比，αvbeta3/5 靶向载体表达的肿瘤坏死因子-α (TNF) 具有改进的安全性和增强的抗肿瘤活性。然而，初步数据表明，预先存在的对 Ad5 的免疫力严重损害了靶向载体在体内的有效肿瘤递送。在拟议的第一阶段研究中，我们将通过生成基于 35 型腺病毒 (Ad35) 的载体来克服 Ad5 预先存在的免疫力的缺点，对于这种病毒，只有一小部分人群具有预先存在的免疫力。该SBIR的总体目标是将先前测试的有效肿瘤靶向和肿瘤杀伤元件整合到基于Ad35的载体中，以开发卵巢癌的新疗法。在此 SBIR 的第一阶段部分，将生成并测试先导化合物（可能）推进到临床试验。我们将构建一个靶向 ava3/5 整合素、基于 Ad35 的载体。为了获得领先资格，以 alphavbeta3/5 整合素为靶点、基于 Ad35 的载体必须满足预定义的交付和安全里程碑（第 1 年的具体目标 1 和 2）以及抗肿瘤活性（第 2 年的具体目标 3）。预先存在的 Ad5 中和抗体的存在。