NOVEL RADIOIMMUNOTHERAPY FOR OVARIAN CANCER

卵巢癌的新型放射免疫疗法

• 批准号: 6038198
• 负责人: ALBERT F LOBUGLIO
• 金额: $ 17.97万
• 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 2003-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6038198
• 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 immunotherapy; neoplasm /cancer radionuclide therapy; 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：(改编自调查人员的摘要)目的 该项目旨在优化腹膜透析患者的有效治疗 区域放射免疫治疗对卵巢癌的影响。这些研究 将利用一种新设计的带有缺失的重组单抗 用188Re放射性标记的CH2区(HuCC49 CH2) 腹膜腔内途径(IP)。他们之前对177Lu-CC49的I期研究已经 显示有抗肿瘤作用的证据(客观反应和持续时间 无病存活)，但试验受到免疫原性的限制 鼠源单抗与剂量限制性骨髓抑制。最新的 设计的分子应该具有很小的免疫原性或没有免疫原性，允许重复 疗程的治疗。此外，动物研究也证实了预测的改善 肿瘤穿透性和较短的血浆半衰期，部分原因是体积小 抗体结构。该结构将被放射性标记为188Re，这 在动物研究中显示出优越的结果，并被预测会减少骨髓 临床资料分析中的放射作用。这是一种新的放射性标签产品 由于发电机提供了188Re，将有可能实现188Re-HuCC49 CH2 他们的团队合成并测试了一种稳定的三糖素络合剂。他们的 最初的I期试验将确定最大耐受剂量(MTD)或 188Re-HuCC49 CH2经IP途径给药，包括免疫研究 反应、成像、剂量学、药代动力学、肿瘤反应和肿瘤 记号笔。唐纳德·布赫斯鲍姆博士将同时分析重复剂量计划 以及动物模型中放射增敏剂的整合。动物模型 结果将被用于后续临床试验的设计，目的是 估计有效率或进一步提高IP的抗肿瘤作用 188Re-HuCC49 CH2放射免疫治疗。这些研究应该提供 卵巢癌术后复发的有效新疗法 标准治疗或可能作为一线治疗的辅助策略。