New bifunctional ligands for radioimmunotherapy

描述（由申请人提供）：放射免疫疗法（RIT）采用肿瘤靶向抗体，选择性地向肿瘤细胞递送细胞毒性放射性核素，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，因为许多接受外部放射治疗的癌症患者遭受了明显的放射毒性副作用，而不是接受癌症治疗。90Y、177Lu、212Bi、213Bi、212Pb和225Ac是RIT的有效放射性核素。开发足够的配体来有效地保留与单克隆抗体结合后的放射性核素是提高RIT疗效的关键步骤。该研究的长期目标是开发临床可行的放射免疫偶联物，直接应用于RIT。在目前的建议中，我们将重点关注双功能配体的设计和评估，这可能会解决RIT临床探索的迫切需要。提出的新配体具有大环空腔和无环垂坠结合基。基于新配体设计的假设是，使用大环和非环垂臂的协同结合可以在保持高水平配合物稳定性的同时提高金属配合的动力学。本研究的目的是研究新配体的双峰结合特性，并基于90-Y、212-Bi、213-Bi、212-Pb、177-Lu和225-Ac标记的新配体鉴定有用的放射免疫偶联物。我们的初步数据表明，其中一个结构上新的配体首次与86-Y结合，具有良好的动力学，体外和体内稳定性。新配体在人血清或小鼠中与205/6-Bi、203-Pb和177-Lu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所提出的金属。本文将利用该新型双功能配体制备放射性标记抗体偶联物，并研究其在血清中与放射性核素结合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偶联物将进一步用于胸腺小鼠的体内研究。这项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，并使用实用和方便的放射性标记条件。

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.