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（由申请人提供）：放射免疫治疗（RIT）采用肿瘤靶向抗体，将细胞毒性放射性核素选择性递送至肿瘤细胞，从而最大限度地减少对健康细胞的暴露。这种疗法的成功是至关重要的，因为许多癌症患者在外部放射治疗中遭受显著的放射毒性副作用，而不是接受癌症治疗。90 Y、177 Lu、212 Bi、213 Bi、212 Pb和225 Ac是RIT的有效放射性核素。开发适当的配体以在与mAb缀合后有效地保持放射性核素是增强RIT功效的关键步骤。拟议研究的长期目标是开发临床上可行的放射免疫缀合物，直接应用于RIT。在目前的提案中，我们将重点放在双功能配体的设计和评价，可能会解决迫切需要积极的临床探索RIT。所提出的新配体同时具有一个大环空腔和一个无环的侧基结合基团。基于新配体的设计的假设是，使用大环和无环侧臂两者的合作结合可以提供增强的金属络合动力学，同时保持高水平的络合物稳定性。本研究的目的是研究新配体的双峰结合特性，并鉴定基于90-Y，212-Bi，213-Bi，212-Pb，177-Lu和225-Ac标记的新配体的有用的放射免疫缀合物。我们的初步数据表明，结构上的新配体结合86-Y的第一次，具有良好的动力学，在体外和体内的稳定性。新的配体还与205/6-Bi，203-Pb和177-Lu在人血清或小鼠中形成非常稳定的络合物。我们将进一步研究所提出的假设，通过评估新的配体的络合动力学和热力学研究和X射线晶体学研究使用拟议的金属。将制备使用新的双功能配体的放射性标记的抗体缀合物，并且将研究它们在血清中结合放射性核素的络合动力学和稳定性。从体外评价中筛选出的最佳放射免疫缀合物将在使用无胸腺小鼠的体内研究中进一步评价。拟议研究的结果可能有助于开发毒性更小，更安全，更有效的RIT药物，使用实用和简便的放射性标记条件。