NOVEL RADIOIMMUNOTHERAPY FOR OVARIAN CANCER

卵巢癌的新型放射免疫疗法

• 批准号: 6522526
• 负责人: ALBERT F LOBUGLIO
• 金额: $ 33.64万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2004-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6522526
• 关键词: antireceptor antibody; athymic mouse; clinical research; clinical trial phase I; epidermal growth factor; female; growth factor receptors; heavy metals; human subject; human therapy evaluation; intraperitoneal injections; monoclonal antibody; neoplasm /cancer radioimmunotherapy; nonhuman therapy evaluation; ovary neoplasms; paclitaxel; pharmacokinetics; radiation therapy dosage; radionuclides; radiosensitizer; recombinant proteins; topotecan; women's health

DESCRIPTION: (adapted from the investigator's abstract) The purpose of this project is to optimize effective therapy for patients with peritoneal involvement of ovarian cancer using regional radioimmunotherapy. These studies will utilize a newly designed recombinant monoclonal antibody with a deleted Ch2 region (HuCC49 Ch2) radiolabeled with 188Re and administered by the intraperitoneal route (IP). Their prior phase I studies with 177Lu-CC49 have shown evidence of antitumor effects (objective responses and prolonged disease-free survival) but the trials were limited by the immunogenicity of the murine monoclonal antibody and dose-limiting marrow suppression. The newly designed molecule should have little or no immunogenicity allowing repeated courses of therapy. Also, animal studies have confirmed the predicted improved tumor penetration and short plasma half-life due, in part, to the small size of the antibody construct. The construct will be radiolabeled with 188Re, which has shown superior results in animal studies and is predicted to reduce marrow radiation in analysis of clinical data. This new radiolabeled product 188Re-HuCC49 Ch2 will be possible due to availability of 188Re from a generator and a stable trisuccin chelator synthesized and tested by their team. Their initial phase I trial will establish the maximum tolerated dose (MTD) or 188Re-HuCC49 Ch2 administered by IP route and include studies of immune response, imaging, dosimetry, pharmacokinetics, tumor response, and tumor markers. Dr. Donald Buchsbaum will concurrently analyze repeat dose schedules and integration of radiosensitizing agents in animal models. The animal model results will be utilized in the design of subsequent clinical trial aimed to estimate response rate or to further improve the antitumor effects of IP radioimmunotherapy with 188Re-HuCC49 Ch2. These studies should provide effective new therapy for ovarian cancer patients who have relapsed after standard therapy or possibly as an adjuvant strategy in first-line therapy.

描述：（改编自研究者的摘要）此目的 该项目旨在优化腹膜炎患者的有效治疗 使用局部放射免疫疗法治疗卵巢癌。这些研究 将利用新设计的重组单克隆抗体，其中删除了 Ch2 区域 (HuCC49 Ch2) 用 188Re 进行放射性标记并由 腹膜内途径（IP）。他们之前对 177Lu-CC49 进行的 I 期研究 显示出抗肿瘤作用的证据（客观反应和长期 无病生存），但试验受到免疫原性的限制 鼠单克隆抗体和剂量限制性骨髓抑制。新的 设计的分子应该具有很少或没有免疫原性，允许重复 治疗课程。此外，动物研究也证实了预测的改善 肿瘤渗透和血浆半衰期短，部分原因是肿瘤尺寸小 抗体构建体。该结构将用 188Re 进行放射性标记， 在动物研究中显示出优异的结果，预计会减少骨髓 临床数据分析中的辐射。这种新的放射性标记产品 由于发电机提供 188Re，188Re-HuCC49 Ch2 将成为可能 以及他们的团队合成和测试的稳定的三琥珀酸螯合剂。他们的 初始 I 期试验将确定最大耐受剂量 (MTD) 或 188Re-HuCC49 Ch2 通过 IP 途径施用，并包括免疫研究 反应、成像、剂量测定、药代动力学、肿瘤反应和肿瘤 标记。 Donald Buchsbaum 博士将同时分析重复剂量计划 以及放射增敏剂在动物模型中的整合。动物模型 结果将用于后续临床试验的设计，旨在 估计缓解率或进一步提高IP的抗肿瘤效果 使用 188Re-HuCC49 Ch2 进行放射免疫治疗。这些研究应该提供 针对卵巢癌复发的有效新疗法 标准治疗或可能作为一线治疗的辅助策略。