IMMUNOCHEMOTHERAPY FOR OVARIAN CANCER

卵巢癌的免疫化学治疗

• 批准号: 7002709
• 负责人: JINDRICH H. KOPECEK
• 金额: $ 3.91万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7002709
• 关键词: antireceptor antibody; apoptosis; combination cancer therapy; copolymer; cytokine receptors; cytotoxicity; disease /disorder model; doxorubicin; drug design /synthesis /production; drug resistance; drug screening /evaluation; human tissue; immunoconjugates; laboratory mouse; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; neoplasm /cancer pharmacology; ovary neoplasms; pharmacokinetics; polymethacrylate; tissue /cell culture; tumor necrosis factor alpha; xenotransplantation

DESCRIPTION (provided by applicant) We propose to use water-soluble synthetic copolymers based on N-(2 hydroxypropyl) methacrylamide (HPMA) as carriers for pharmacologically active molecules. Specifically, we will synthesize an agonistic antibody - i.e. anti-TRAIL receptor (anti-DR4 or anti-DR5)-HPMA copolymer conjugates designed to induce selective apoptotic death in TRAIL-sensitive ovarian cancer cells. The agonistic antibodies resemble the cytokine and death ligand TRAIL. After binding to DR4 and DR5 death receptors they induce selective apoptotic death in a number of different cancer cells, including ovarian cancer cells. In this application, the agonistic antibody serves both as a death-inducing (cytotoxic) molecule and a targeting moiety. The development of multiple drug resistance (frequently seen in ovarian carcinoma) is a consequence of conventional cancer chemotherapy and remains the major obstacle in its treatment. Since the drug (doxorubicin) and TRAIL death-signaling pathways cross-sensitize each other, we suggest to use HPMA copolymer conjugates containing two molecules that act in synergy (agonistic anti-DR4 and/or anti-DR5 antibody plus doxorubicin) or HPMA copolymer-bound antibody and HPMA copolymer-bound drug for combination immunochemotherapy. This is intended to overcome both TRAIL- and drug-resistance in ovarian cancer. This HPMA copolymer carrier-based therapy should stabilize the agonistic antibody, increase its proapoptotic activity, decrease its immunogenicity, prolong its availability in the blood stream, and allow a dosage reduction, thereby minimizing unwanted side effects while simultaneously enhancing cytotoxicity.

描述（由申请人提供） 我们建议将基于N-（2个羟丙基）甲基丙烯酰胺（HPMA）的水溶性合成共聚物作为药理活性分子的载体。具体而言，我们将合成一种激动剂抗体 - 即抗Trail受体（抗DR4或抗DR5）-HPMA共聚物共轭物，旨在在径向敏感的卵巢癌细胞中诱导选择性凋亡死亡。激动剂抗体类似于细胞因子和死亡配体步道。与DR4和DR5死亡受体结合后，它们在包括卵巢癌细胞在内的许多不同癌细胞中诱导选择性凋亡死亡。在此应用中，激动抗体既用作死亡（细胞毒性）分子和靶向部分。 多种耐药性的发展（在卵巢癌中经常出现）是常规癌症化疗的结果，并且仍然是其治疗的主要障碍。由于药物（阿霉素）和跟踪死亡信号途径相互交叉敏感性，我们建议使用HPMA共聚物共轭物，其中包含两个在Synergy中起作用的分子（激动剂抗DR4和/或抗-DR4和/或抗DR5抗体加毒抗体加doxorubody Plus doxorubicin）或HPMA共聚抗体抗体和HPMA抗体抗体和HPMA-HPMAN-HPMAN-BOND-BOND-BOND-BOND-BOND-BONDORMERING互联体。这旨在克服卵巢癌中的越野越野性和抗药性。 这种基于HPMA共聚物载体的治疗应稳定激动剂抗体，增加其促凋亡活性，降低其免疫原性，延长其在血液中的可用性，并降低剂量，从而最大程度地减少不需要的副作用，同时增强细胞毒性。