Core--Radiopharmaceutical development

核心C通过以下方式支持项目1、2和3：（1）制备用于临床前和临床研究的放射性标记抗体;（2）将项目3化学转化为标准操作方法，以优化产量和质量的方式偶联和放射性标记放射性药物;（3）根据小鼠评价，协助选择用于人类药物开发的项目3试剂;以及（4）按照FDA和辐射使用监管机构的要求保存记录。在本资助期内，核心C开发了用Y-90放射性标记单克隆抗体的简化程序，其产率和放射性药物质量与131-单克隆抗体相当，使用项目3中开发的大环螯合剂。核心C还对项目3中正在开发的DOTA-肽螯合剂进行了评价。螯合剂掺入肽接头，所述肽接头在循环中和在肿瘤靶标处保持未裂解，但应易于在细胞内裂解并清除肝、肾和其它非靶标位点。原型DOTA-肽螯合物的消化在体外得到证实，随后在肿瘤小鼠模型和初步临床研究中得到证实，从肝脏的清除率提高。在项目3中已经产生了新的肽接头的文库，并且已经鉴定了三个经受消化的接头。Core C已证明了接头在体外人血浆中的稳定性，并对小鼠中的一种肽进行了放射自显影研究，证明了良好的生物分布。核心C的提案包括为项目1和2临床前和临床研究制备放射性药物，使用已经开发的简化的高产程序，以最大限度地减少费用和辐射暴露。核心C将通过肿瘤小鼠模型中的生物分布研究，继续评价项目3中现有和拟定组合文库中的DOTA-肽螯合剂，以评估肿瘤摄取以及肝、肾和全身清除率。根据预先确定的、对肝脏、肾脏和肿瘤的辐射剂量的统计学可评价标准，将进一步检查表现出最有利的双分布结果的肽，以表征代谢物。核心C将继续开发MoAb片段和肽的偶联、放射性标记和纯化，以制备新型放射性药物。

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.