IMMUNOCHEMOTHERAPY FOR OVARIAN CANCER

描述(由申请人提供) 我们建议使用基于N-(2-羟丙基)甲基丙烯酰胺(HPMA)的水溶性合成共聚物作为药物活性分子的载体。具体地说，我们将合成一种激动型抗体，即抗TRAIL受体(抗DR4或抗DR5)-HPMA共聚结合物，旨在诱导TRAIL敏感的卵巢癌细胞选择性凋亡。激动型抗体类似于细胞因子和死亡配体TRAIL。在与DR4和DR5死亡受体结合后，它们诱导包括卵巢癌细胞在内的许多不同癌细胞选择性的凋亡性死亡。在这一应用中，激动型抗体既可以作为死亡诱导(细胞毒)分子，也可以作为靶向部分。 多药耐药(常见于卵巢癌)的形成是传统癌症化疗的结果，仍然是其治疗的主要障碍。由于药物(阿霉素)和TRAIL死亡信号通路相互交叉敏感，我们建议使用含有两个分子协同作用的HPMA共聚物结合物(激动型抗DR4和/或抗DR5抗体加阿霉素)或HPMA共聚物结合抗体和HPMA共聚物结合药物进行联合免疫化疗。这是为了克服卵巢癌的TRAIL和耐药性。 这种基于HPMA共聚物载体的疗法应该稳定激动型抗体，增加其促凋亡活性，降低其免疫原性，延长其在血流中的可利用度，并允许减少剂量，从而最大限度地减少不良副作用，同时增强细胞毒性。

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.