New bifunctional ligands for radioimmunotherapy

用于放射免疫治疗的新型双功能配体

• 批准号: 7259383
• 负责人: HYUN-SOON CHONG
• 金额: $ 13.84万
• 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/7259383
• 关键词: 90Y; Achievement; Address; Adverse effects; Antibodies; Arsenazo III; Binding; Biodistribution; Biological Assay; Blood; Cancer Patient; Cells; Clinical; Collaborations; Colon Carcinoma; Column Chromatography; Community Health Nurse Specialist; Complex; Condition; Coupling; Data; Development; Dialysis procedure; Drug Kinetics; Drug usage; ERBB2 gene; Edetic Acid; Effectiveness; Evaluation; Exhibits; Exposure to; External Beam Radiation Therapy; High Pressure Liquid Chromatography; Human; Immunoconjugates; In Vitro; Investigation; Ions; Isothiocyanates; Kinetics; Label; Laboratories; Life; Ligand Binding; Ligands; Literature; Mass Spectrum Analysis; Measures; Metals; Methods; Modification; Mus; Nude Mice; Numbers; Organ; Organic Chemistry; Physical Dialysis; Preparation; Principal Investigator; Property; Purpose; Radioactivity; Radioimmunoassay; Radioimmunoconjugate; Radioimmunotherapy; Radioisotopes; Radiolabeled; Reaction; Research; Research Personnel; Roche brand of trastuzumab; Roentgen Rays; Route; Scheme; Screening procedure; Serum; Serum Proteins; Side; Structure; Students; Testing; Therapeutic; Thermodynamics; Time; Titrations; Upper arm; Week; Work; X-Ray Crystallography; Xenograft procedure; antibody conjugate; base; cancer therapy; cytotoxic; design; direct application; functional group; immunoreactivity; in vivo; metal complex; neoplastic cell; novel; programs; radiotracer; research study; success; tumor; uptake

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）：放射免疫疗法（RIT）采用靶向肿瘤的抗体来选择性递送细胞毒性放射性核素向肿瘤细胞，从而最大程度地减少对健康细胞的暴露。这种疗法的成功至关重要的是，外部放射治疗中的众多癌症患者患有明显的放射性副作用，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。与MAB结合后，足够的配体的发展是有效固定放射性核素的，这是增强RIT功效的关键步骤。拟议的研究的长期目标是开发在RIT中直接应用的临床可行的放射免疫共轭物。在当前的建议中，我们将重点介绍双功能配体的设计和评估，这些配体可能满足RIT的主动临床探索需求。提出的新配体既有大环腔，也具有一个无环形结合组。基于新配体设计的假设是，使用大环环和无环形吊坠的合作结合可能会在金属络合中提供增强的动力学，同时保持较高的复杂稳定性。该提案的目的是研究新配体的双峰结合特性，并根据具有90-Y，212-BI，213-BI，212-PB，212-PB，177-LU和225-AC标记的新配体对有用的放射免疫共轭物进行鉴定。我们的初步数据表明，一种结构上的新配体首次结合86-y，具有出色的动力学，体外和体内稳定性。新的配体还形成了一个非常稳定的复合物，在人血清或小鼠中具有205/6-Bi，203-Pb和177-LU。我们将通过评估使用拟议金属的新配体进行络合动力学和热力学研究以及X射线晶体学研究的新配体，进一步研究提出的假设。将制备使用新的双功能配体的放射标记抗体偶联物，并将研究其络合动力学和稳定性在血清中结合放射性核素时的稳定性。使用无胸腺小鼠的体内研究，将进一步评估从体外评估中筛选出的最佳放射免疫共轭物。拟议研究的结果可能有可能有助于使用实用和轻松的放射性标记条件发展毒性较小，更安全，更有效的RIT药物。