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; 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.

Core C支持项目1、2和3的（1）制备用于临床前和临床研究的放射标记抗体； （2）将项目3化学转换为标准操作方法，以相结合和放射性标记的放射性药物具有优化的产率和质量； （3）在小鼠评估的基础上协助选择3个项目3剂进行人类药物开发； （4）根据FDA和辐射使用监管机构的记录。在当前资助的期间，核心C制定了简化的程序，以使用项目3中开发的大环螯合剂与131l-MoAb相当的Y-90具有Y-90的放射性标记摩押，可与131l-MoAb相当。核心C在Project 3中的旋转型固定型固定型固定型固定型固定型核心也对速度固定在3号旋转的旋转剂进行了评估。肿瘤靶标，但应容易细胞内切割并清除肝脏，肾脏和其他非目标部位。在体外证明了原型DOTA肽螯合的消化，并在肿瘤的小鼠模型和试验临床研究中证明了肝脏的清除率的改善。项目3中已经生成了新的肽接头库，并确定了三个受消化的接头。 Core C已证明了连接器在人血浆中体外的稳定性，并对显示出有利的生物分布的小鼠中的一只肽​​进行了自显影研究。 Core C的建议包括为项目1和2临床前和临床研究准备放射性药物，并使用已经开发出的简化的高产量程序来最大程度地减少费用和辐射暴露。 Core C将继续通过在肿瘤小鼠模型中的生物分布研究中评估项目3中现有和拟议组合库中的DOTA肽螯合剂，以评估肿瘤的吸收和肝，肾脏，肾脏和全身清除率。根据预定的，可评估对肝脏，肾脏和肿瘤的统计评估标准，表现出最有利的双分裂结果的肽，将进一步检查代谢物的表征。核心C将继续发展摩押碎片和肽的共轭，放射性标记和纯化，以制备新型的放射性药物。