Core--Radiopharmaceutical Development

核心--放射性药物开发

• 批准号: 6989522
• 负责人: SALLY J DENARDO
• 金额: $ 14.12万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6989522
• 关键词: athymic mouse; biomedical facility; chelating agents; immunoconjugates; immunologic substance development /preparation; method development; neoplasm /cancer radioimmunotherapy; radiopharmacology; radiotracer; therapy design /development

The overall goal of this program is the translational development of radioisotope carrier molecules and strategies to deliver systemic radiotherapy to cancer. This core is central to the development and the translation of these molecules and supports all of the projects: (1) preparing newly constructed molecules as radioconjugates for developmental studies, in vitro analysis, in vivo mouse studies and testing preliminary pharmaceutical lots and preparing IND documents for future clinical studies; (2) translating chemistry from the projects to standard methods to conjugate and radiolabel selected constructs as radiopharmaceuticals with optimized yields, stability, and reproducible quality; (3) assuring stability and quality of reagents for pharmaceutical development based on rigorous evaluation of vitro quality controls, kinetics and tolerance in mice; and (4) maintaining records in accordance with RUC, IRB, FDA and radiation use regulatory agencies. During the current funded period, this core developed simplified procedures to radiolabel MAbs with Y-90 with high yields and radiopharmaceutical quality using macrocyclic peptide linker chelating agents developed in the third project. Enhanced hepatic clearance of radioactivity seen in mice was substantiated by the excellent tumor targeting and decrease radiation dose to liver with Lym-1 and m170 DOTA-peptide pharmaceuticals prepared by this core for clinical studies in the first and second projects. The proposal for this core for the new grant period includes transfer of chemistry of molecular agents produced by each project to allow additional pharmaceutical development, chelate conjugation, PEG lot syntheses, SHALs q.c., optimization of radiometal labeling, and studies to assure stability in vitro and in vivo. This includes preparing radiopharmaceuticals for all three projects preclinical studies, using simplified, high yield procedures already developed to minimize expense and radiation exposure. DOTA chelate linkers for "on demand" cleavage from the combinatorial libraries in the third project, DOTA-SHALs from the first project, and DOTA-(scFv)4 PEG from the second project are undergoing in vitro evaluation and studies in non tumored mice to assess stability and tolerance. This core will continue to develop the methods for pharmaceutical grade production, purification, conjugation, quality control, storage and radiolabeling and final mouse and patient lot (and dose) release criteria for these novel radiopharmaceuticals.

该计划的总体目标是放射性同位素载体分子和策略的转化发展，以提供全身放射治疗癌症。该核心是这些分子的开发和翻译的核心，并支持所有项目：(1)制备新构建的分子作为放射缀合物用于发育研究，体外分析，体内小鼠研究和测试初步药物批次，并为未来的临床研究准备IND文件；(2)将项目中的化学转化为标准方法，将选定的结构物偶联并标记为具有最佳收率、稳定性和可重复质量的放射性药物；(3)通过严格的体外质量控制、动力学和小鼠耐受性评估，确保药物开发试剂的稳定性和质量；(4)按照RUC、IRB、FDA和辐射的要求保存记录