Core--Radiopharmaceutical development

CORE C通过以下方式为项目1、2和3提供支持：(1)为临床前和临床研究准备放射性标记抗体；(2)将项目3的化学转化为标准操作方法，以最佳产量和质量结合和标记放射性药物；(3)在小鼠评估的基础上协助选择项目3用于人类药物开发的试剂；以及(4)根据FDA和辐射使用管理机构的要求进行记录保存。在当前的资助期间，Core C使用项目3中开发的大环络合剂开发了用Y-90放射性标记MoAbs的简化程序，其产量和放射性药物质量与131L-MoAbbs相当。Core C还对项目3中正在开发的DOTA-多肽螯合剂进行了评估。这些螯合剂包含了在循环中和肿瘤靶点仍未切割的多肽连接物，但应该容易在细胞内切割，并清除肝、肾和其他非靶点。在体外证明了典型的DOTA多肽螯合物的消化，随后在肿瘤小鼠模型和试点临床研究中证明了改善了从肝脏的清除。在项目3中已经生成了一个新的多肽连接子文库，并且已经鉴定了三个可被消化的连接子。Core C已经证明了连接物在体外在人血浆中的稳定性，并在小鼠身上进行了一种肽的放射自显影研究，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的高产量程序，将费用和辐射暴露降至最低。Core C将通过在肿瘤小鼠模型中的生物分布研究，继续评估项目3中现有和建议组合文库中的DOTA-多肽螯合剂，以评估肿瘤摄取和肝、肾和全身清除情况。根据预先确定的、可统计评估的肝、肾和肿瘤辐射剂量标准，表现出最有利的生物分布结果的肽(S)将被进一步检查以确定代谢物的特征。核心C将继续开发偶联、放射性标记和纯化Moab片段和多肽，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.