Core--Radiopharmaceutical development

核心--放射性药物开发

• 批准号: 6347315
• 负责人: SALLY J DENARDO
• 金额: $ 18.05万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 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 2001-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6347315
• 关键词: biomedical facility; chelating agents; data management; drug design /synthesis /production; human tissue; immunoconjugates; immunological substance; laboratory mouse; monoclonal antibody; pharmacokinetics; protein purification; radiopharmacology; radiotracer

Core C supports Projects 1, 2, and 3 by (1) preparing radiolabeled antibodies for preclinical and clinical studies; (2) translating Project 3 chemistry to standard operation methods to conjugate and radiolabel radiopharmaceuticals with optimized yields and quality; (3) assisting in the selection of Project 3 reagents for human pharmaceutical development on the basis of evaluation in mice; and (4) record keeping in accordance with FDA and radiation use regulatory agencies. During the current funded period, Core C developed simplified procedures to radiolabel MoAbs with Y-90 with yields and radiopharmaceutical quality comparable to 131l- MoAbs, using macrocyclic chelating agents developed in Project 3. Core C has also performed evaluations of DOTA-peptide chelating agents under development in Project 3. The chelating agents incorporate peptide linkers which remain uncleaved in circulation and at the tumor target, but should be readily cleaved intracellularly and clear the liver, kidney, and other non-target sites. Digestion of a prototypical DOTA-peptide chelate was demonstrated in vitro and improved clearance from the liver was subsequently demonstrated in the tumored mouse model and in pilot clinical studies. A library of new peptide linkers has been generated in Project 3, and three linkers subject to digestion have been identified. Core C has demonstrated the stability of the linkers in vitro in human plasma and has performed autoradiography studies of one peptide in mice that demonstrated favorable biodistribution. The proposal for Core C includes preparing radiopharmaceuticals for Project 1 and 2 preclinical and clinical studies, using simplified, high yield procedures already developed to minimize expense and radiation exposure. Core C will continue to evaluate DOTA-peptide chelating agents from the existing and proposed combinatorial libraries in Project 3 by biodistribution studies in the tumored mouse model, to assess tumor uptake and hepatic, renal, and total body clearance. The peptide(s) exhibiting the most favorable bjodistribution results according to predetermined, statistically evaluable criteria for radiation dose to liver, kidneys, and tumor, will be examined further for characterization of metabolites. Core C will continue to develop conjugation, radiolabeling , and purification of MoAb fragments and peptides to prepare novel radiopharmaceuticals.

核心C通过(1)制备用于临床前和临床研究的放射性标记抗体来支持项目1、2和3；(2)将项目3化学转化为标准操作方法，以优化收率和质量的方式偶联和标记放射性药物；(3)在小鼠评价的基础上，协助选择项目3人药开发试剂；(4)按照FDA和辐射使用监管机构的规定进行记录。在目前的资助期内，C核心开发了简化的程序，使用项目3开发的大环螯合剂，用Y-90对MoAbs进行放射性标记，其产量和放射性药物质量与131l- MoAbs相当。Core C还对Project 3正在开发的dota肽螯合剂进行了评估。螯合剂包含肽连接物，其在循环中和肿瘤靶点处保持不裂解，但应易于在细胞内裂解并清除肝脏、肾脏和其他非靶点。在体外证明了原型dota肽螯合物的消化，随后在肿瘤小鼠模型和初步临床研究中证明了肝脏清除的改善。项目3中生成了一个新的肽连接物库，并确定了三个需要消化的连接物。Core C已经在体外证明了连接体在人血浆中的稳定性，并在小鼠中进行了一种肽的放射自显影研究，显示出良好的生物分布。核心C的提案包括为项目1和项目2的临床前和临床研究准备放射性药物，使用已经开发的简化、高产量的程序，以尽量减少费用和辐射暴露。Core C将继续通过肿瘤小鼠模型的生物分布研究来评估项目3中现有和拟议的组合文库中的dota肽螯合剂，以评估肿瘤摄取和肝脏、肾脏和全身清除。根据预先确定的、统计上可评估的肝脏、肾脏和肿瘤辐射剂量标准，显示出最有利的bjodistribution结果的肽将被进一步检查以表征代谢物。Core C将继续开发偶联、放射性标记和纯化MoAb片段和肽，以制备新型放射性药物。