Targeted immunotherapy program

靶向免疫治疗方案

• 批准号: 6228600
• 负责人: ALBERT F LOBUGLIO
• 金额: $ 9.95万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2004-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6228600
• 关键词: clinical research; disease /disorder model; dosage; female; human subject; human therapy evaluation; injection /infusion; laboratory mouse; monoclonal antibody; neoplasm /cancer immunotherapy; neoplasm /cancer radiation therapy; neoplasm /cancer radionuclide therapy; ovary neoplasms; peritoneum; pharmacokinetics; radionuclides; women's health

DESCRIPTION: (Applicant's Description) 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 delta CH2) radiolabeled with 188Re and administered by the intraperitoneal route (IP). Our prior phase I studies with 177Lu-CC49 have shown evidence of anti- tumor 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 to the small size of the antibody construct. The construct will be radiolabeled with 188Re, which have shown superior results in animal studies and is predicted to reduce marrow radiation in analysis of clinical data. This new radiolabeled product 188Re-HuCC49 delta CH2 will be possible due to availability of 188Re from a generator and a stable trisuccin chelator synthesized and tested by our team. Our initial phase I trial will establish the maximum tolerated dose (MTD) of 188Re-HuCC49 delta 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 details of designing two subsequent clinical trials aimed to further improve the tumor to normal tissue ratios of IP radioimmunotherapy with 188Re-HuCC49 delta 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.

（申请人描述）本项目的目的是利用局部放射免疫治疗优化卵巢癌腹膜受累患者的有效治疗方法。这些研究将利用一种新设计的重组单克隆抗体，该抗体带有缺失的CH2区域（HuCC49 δ CH2），用188Re放射性标记，并通过腹腔注射途径（IP）给药。我们之前对177Lu-CC49的I期研究已经显示出抗肿瘤作用的证据（客观反应和延长无病生存期），但试验受到小鼠单克隆抗体的免疫原性和剂量限制性骨髓抑制的限制。新设计的分子应该很少或没有免疫原性，允许重复疗程的治疗。此外，动物研究已经证实，由于抗体结构的小尺寸，预测的肿瘤穿透性提高和血浆半衰期缩短。该构建体将用188Re进行放射性标记，该放射性标记在动物研究中显示出优异的结果，预计在临床数据分析中可以减少骨髓辐射。这个新的放射性标记产品188Re- hucc49 δ CH2将是可能的，因为我们的团队合成和测试了一个稳定的三绿素螯合剂，并从发电机和稳定的三绿素螯合剂中获得188Re。我们的初始I期试验将确定188Re-HuCC49 δ CH2的最大耐受剂量（MTD），并包括免疫反应、成像、剂量学、药代动力学、肿瘤反应和肿瘤标志物的研究。Donald Buchsbaum博士将同时分析动物模型中的重复剂量计划和放射增敏剂的整合。动物模型结果将用于设计后续两项临床试验的细节，旨在进一步提高188Re-HuCC49 δ CH2放射免疫治疗的肿瘤与正常组织的比率。这些研究应该为标准治疗后复发的卵巢癌患者提供有效的新疗法，或者可能作为一线治疗的辅助策略。