Targeted, Alternate Serotype Vector for Ovarian Cancer

卵巢癌的靶向替代血清型载体

• 批准号: 6827574
• 负责人: C. RICHTER KING
• 金额: $ 23.26万
• 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 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6827574
• 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着改善，但预计美国每年约有13,900名妇女最终将失败标准疗法并死亡。为了治疗卵巢癌，广泛使用的5型腺病毒（AD5）基因治疗载体具有两个重要缺点：1）在40-60％的40-60％中，对基于AD5的载体的中和抗体通常存在于AD5基于AD5的载体中的中和抗体不足或特异性基因转移。最近，我们通过创建针对Alphavbeta3和Alphavbeta5整合素受体（alphavbeta3/5）的基于AD5的向量来克服了第一个缺点，该向量在卵巢癌中高度表达。我们的结果表明，该α3/靶向的载体在基因转移到腹膜腔中存在的肿瘤细胞方面非常有效且具有特异性。此外，我们证明了与标准的，未经预定的AD5载体相比，Alphavbeta3/5靶向载体的肿瘤坏死因子-Alpha（TNF）具有提高的安全性和抗肿瘤活性的提高。然而，初步数据表明，靶向载体的有效体内肿瘤递送会严重损害对AD5的免疫力。在拟议的第一阶段研究中，我们将通过基于腺病毒35型（AD35）产生载体来克服对AD5的免疫力的缺点，为此，只有一小部分人口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素纳入基于AD35的载体，以开发针对卵巢癌的新治疗方法。在该SBIR的第一阶段部分中，将生成并测试（可能的）临床试验的（可能）进步。我们将构建一个基于AD35的AVA3/5整合素靶向的向量。为了获得铅的资格，基于AD35的矢量必须符合预定义的里程碑，以实现交付和安全性（具体目的1和2，1年级）和抗肿瘤活性（特定目标3，特定目标3，第二年），在预先存在对AD5的中和抗体的情况下，基于AD35的矢量必须达到预定义的里程碑。