Development of a Highly Tumor-Specific Adenovirus Vector

高度肿瘤特异性腺病毒载体的开发

• 批准号: 6787911
• 负责人: DAVID A EINFELD
• 金额: $ 9.67万
• 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: 2004-03-12 至 2005-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6787911
• 关键词: Adenoviridae; athymic mouse; biotechnology; gene delivery system; green fluorescent proteins; laboratory mouse; neoplastic cell; polymerase chain reaction; protein engineering; protein reconstitution; protein sequence; receptor binding; technology /technique development; transfection /expression vector; tumor necrosis factor alpha; virus protein; virus receptors

DESCRIPTION (provided by applicant): Despite a number of newly approved drugs, cancer is responsible for over 20% of all deaths and will soon overtake heart disease as the main killer in the Western world. First generation adenovirus vectors have shown promise in the treatment of locally advanced cancer via intratumoral administration. However, these first generation vectors are not likely to be suitable for treating large-market, metastatic cancers due to their limited efficiency and specificity. Therefore, the development of targeted adenovirus vectors that can efficiently and specifically deliver potent anti-cancer genes to disseminated tumors would be a major advance in the treatment of cancer. The preliminary data in this grant detail an adenovirus vector that is ablated for binding to its native receptors and redirected for binding to the highly tumor-selective receptor, alpha-v-beta-6. Compared to an untargeted vector, it is demonstrated that this vector significantly improved the specificity of gene transfer to a subcutaneous alpha-v-beta-6-expressing lung carcinoma. While the specificity of tumor gene transfer is dramatically improved, the data suggests that the specificity achieved by the vector may require further enhancement. Previous work has shown that modifications that ablate the binding of adenovirus to its native receptors, as highlighted above, are critical for improving specificity. However, recently published research has shown that additional modifications to the adenovirus vector that reduce the length and/or alter the composition of its elongated coat protein, fiber, also significantly reduce gene transfer to non-target organs and thereby improve specificity. The primary objective of this phase I SBIR is to further improve the specificity of the current tumor targeted vector through reducing the length of its fiber coat protein. The long-term objective of this application is to create a breakthrough cancer therapeutic for clinical development based upon an adenovirus vector that efficiently and specifically targets potent antitumor genes to metastatic tumors.

描述（由申请人提供）：尽管有许多新批准的药物，但癌症仍占所有死亡的 20% 以上，并且很快将超过心脏病成为西方世界的主要杀手。第一代腺病毒载体已显示出通过瘤内给药治疗局部晚期癌症的前景。然而，这些第一代载体由于其有限的效率和特异性，不太可能适合治疗大市场的转移性癌症。因此，开发能够高效、特异地将有效抗癌基因传递至播散性肿瘤的靶向腺病毒载体将是癌症治疗的重大进展。 该资助中的初步数据详细介绍了一种腺病毒载体，该载体被消融以结合其天然受体，并重定向以结合高度肿瘤选择性受体 alpha-v-beta-6。与非靶向载体相比，该载体被证明显着提高了基因转移至皮下表达α-v-β-6的肺癌的特异性。虽然肿瘤基因转移的特异性显着提高，但数据表明载体实现的特异性可能需要进一步增强。先前的工作表明，如上所述，消除腺病毒与其天然受体结合的修饰对于提高特异性至关重要。 然而，最近发表的研究表明，对腺病毒载体进行额外的修饰，减少长度和/或改变其延长的外壳蛋白纤维的组成，也显着减少向非靶器官的基因转移，从而提高特异性。该一期SBIR的主要目标是通过减少纤维外壳蛋白的长度来进一步提高当前肿瘤靶向载体的特异性。 该应用的长期目标是基于腺病毒载体创造一种用于临床开发的突破性癌症治疗方法，该载体可有效且特异性地将有效的抗肿瘤基因靶向转移性肿瘤。