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，但癌症仍造成了所有死亡的20％以上，并将很快超过心脏病，成为西方世界的主要杀手。第一代腺病毒载体通过肿瘤内给药显示了局部晚期癌症的希望。但是，由于效率有限和特异性，这些第一代载体不太可能适合治疗大型市场，转移性癌症。因此，靶向腺病毒载体的开发可以有效，特异性地将有效的抗癌基因传播到传播肿瘤，这将是癌症治疗的重大进展。 该赠款中的初步数据详细介绍了一种腺病毒载体，该腺病毒载体被消融到与其天然受体结合并重定向到与高度肿瘤选择性受体Alpha-V-Beta-6结合。与非靶向载体相比，证明该载体显着提高了基因转移到皮下α-V-Beta-6表达肺癌的特异性。虽然肿瘤基因转移的特异性大大改善，但数据表明，矢量所达到的特异性可能需要进一步增强。先前的工作表明，如上所述，将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，对腺病毒载体的其他修饰，以减少其伸长外套蛋白（纤维）的长度和/或改变其组成，也大大降低了基因转移到非靶向器官，从而提高了特异性。该阶段I SBIR的主要目的是通过减少其纤维外套蛋白的长度进一步提高当前肿瘤靶向载体的特异性。 该应用的长期目的是基于腺病毒载体为临床发育创建突破性的癌症治疗性，该腺病毒载体有效，专门针对促进抗肿瘤基因的转移性肿瘤。