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.

产品说明：（申请人的描述）本项目的目的是使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。这些研究将使用新设计的CH 2区缺失的重组单克隆抗体（HuCC 49 delta CH 2），用188 Re放射性标记，并通过腹膜内途径（IP）给药。 我们先前使用177 Lu-CC 49的I期研究已经显示出抗肿瘤作用的证据（客观反应和延长的无病生存期），但是这些试验受到鼠单克隆抗体的免疫原性和剂量限制性骨髓抑制的限制。 新设计的分子应该具有很少或没有免疫原性，允许重复治疗过程。 此外，动物研究已经证实了由于抗体构建体的小尺寸所预测的改善的肿瘤穿透和短的血浆半衰期。 该结构将用188 Re进行放射性标记，其在动物研究中显示出上级结果，并在临床数据分析中预测可减少骨髓辐射。 这种新的放射性标记产品188 Re-HuCC 49 delta CH 2将是可能的，因为我们的团队合成并测试了来自发生器的188 Re和稳定的三琥珀酰亚胺螯合剂。 我们最初的I期试验将确定通过IP途径给予188 Re-HuCC 49 Δ CH 2的最大耐受剂量（MTD），并包括免疫应答、成像、剂量测定、药代动力学、肿瘤应答和肿瘤标志物的研究。 Donald Buchsbaum博士将同时分析重复给药方案和放射增敏剂在动物模型中的整合。 动物模型结果将用于设计两项后续临床试验的细节，旨在进一步提高188 Re-HuCC 49 delta CH 2 IP放射免疫治疗的肿瘤与正常组织比率。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，或可能作为一线治疗的辅助策略。