New bifunctional ligands for radioimmunotherapy

用于放射免疫治疗的新型双功能配体

• 批准号: 7145822
• 负责人: HYUN-SOON CHONG
• 金额: $ 18.24万
• 依托单位: ILLINOIS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7145822
• 关键词: ligands; radionuclides; radiotracer

DESCRIPTION (provided by applicant): Radioimmunotherapy (RIT) employs tumor-targeting antibody for selective delivery of a cytotoxic radionuclide to tumor cells thereby minimizing exposure to healthy cells. The success of this therapy is critical in that numerous cancer patients in external radiation treatment suffer from significant radiotoxic side effects rather than receive cancer therapy. 90Y, 177Lu, 212Bi, 213Bi, 212Pb, and 225Ac are effective radionuclides for RIT. The development of the adequate ligands to effectively hold the radionuclides after being conjugated with mAbs is a critical step for enhancing the efficacy of RIT. The long-term objective of the proposed research is to develop clinically viable radioimmunoconjugates that have direct applications in RIT. In the current proposal we will focus on the design and evaluation of bifunctional ligands that may address the pressing needs for active clinical exploration of RIT. The proposed new ligands possess both a macrocyclic cavity and an acyclic pendant binding group. The hypothesis based on the design of the new ligands is that the cooperative binding using both a macrocyclic ring and an acyclic pendant arm may provide enhanced kinetics in metal complexation while maintaining a high level of complex stability. The objective of this proposal is the investigation of bimodal binding property of the new ligands and identification of the useful radioimmunoconjugates based on the new ligand labeled with 90-Y, 212-Bi, 213-Bi, 212-Pb, 177-Lu, and 225-Ac. Our preliminary data indicate that one of the structurally new ligands binds 86-Y for the first time, with excellent kinetics, and in vitro and in vivo stability. The new ligand also forms a very stable complex with 205/6-Bi, 203-Pb, and 177-Lu in human serum or mice. We will further investigate the proposed hypothesis by evaluating the new ligands for complexation kinetics and thermodynamics studies and x-ray crystallographic studies using the proposed metals. The radiolabeled antibody conjugates using the new bifunctional ligands will be prepared, and their complexation kinetics and stability in binding the radionuclides in serum will be investigated. The best radioimmunoconjugates screened from in vitro evaluations will be further evaluated for in vivo studies using athymic mice. The results of the of the proposed research may potentially contribute to the development of less toxic, safer, and more potent RIT drugs using practical and facile radiolabeling condition.

描述(申请人提供)：放射免疫疗法(RIT)使用肿瘤靶向抗体选择性地将细胞毒性放射性核素输送到肿瘤细胞，从而最大限度地减少对健康细胞的暴露。这种疗法的成功至关重要，因为许多癌症患者在接受外照射治疗时会出现明显的放射毒性副作用，而不是接受癌症治疗。~(90)Y、~(177)Lu、~(212)Bi、~(213)Bi、~(212)Pb和~(225)Ac是有效的放射性核素。发展足够的配体与单抗结合后有效地固定放射性核素是提高RIT疗效的关键一步。这项拟议研究的长期目标是开发临床上可行的、可直接应用于RIT的放射免疫结合物。在目前的提案中，我们将集中于双功能配体的设计和评估，以满足积极的RIT临床探索的迫切需求。所提出的新配体同时具有大环腔和非环侧基团。基于新配体设计的假设是，同时使用大环环和非环悬臂的协同结合可以在保持高水平络合稳定性的同时提供增强的金属络合动力学。本建议的目的是研究新配体的双峰结合性质，并鉴定基于标记了90-Y、212-Bi、213-Bi、212-Pb、177-Lu和225-Ac的新配体的有用的放射免疫结合物。我们的初步数据表明，其中一个结构上的新配体首次与86-Y结合，具有良好的动力学和体内外稳定性。新配体还与205/6-铋、203-铅和177-Lu在人血清或小鼠体内形成了非常稳定的络合物。我们将通过评估用于络合动力学和热力学研究的新配体以及使用所建议的金属进行的x射线结晶学研究来进一步研究所提出的假设。将制备使用新的双功能配体的放射性标记抗体结合物，并研究它们的络合动力学和与血清中放射性核素结合的稳定性。从体外评估中筛选出的最好的放射免疫结合物将被进一步评估，用于在体内使用无菌小鼠进行研究。拟议研究的结果可能有助于利用实用和简便的放射性标记条件开发毒性更低、更安全和更有效的RIT药物。