ANTIBODY CHELATES AND CONJUGATES

抗体螯合物和缀合物

• 批准号: 6300283
• 负责人: John Ernest Shively
• 金额: $ 15.65万
• 依托单位: CITY OF HOPE NATIONAL MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6300283
• 关键词: Mammalia; antitumor antibody; carcinoembryonal antigen; chelating agents; chemical synthesis; crosslink; hybrid antibody; immunochemistry; immunoconjugates; immunoglobulin structure; ion exchange chromatography; mass spectrometry; metal complex; monoclonal antibody; nuclear magnetic resonance spectroscopy; pharmacokinetics; protein engineering; radionuclides

Novel bifunctional chelates and metal ion complexes will be synthesized and conjugated to anti-CEA (carcinoembryonic antigen) antibodies for their improved targeting in CEA positive tumors. The new bifunctional chelates are based on the macrocycle DOTA and incorporate new pendant functional groups to enhance metal ion binding on the antibody conjugate. the functional groups include carboxyl, sulfhydryl, hydrazides, and acetohydroxamates. these groups are expected to form tight "type I" complexes with In-111, Y-90, nd Cu-64. The radiometals were chosen for their utility in radioimmuno-imaging and therapy. Conditions of pH, temperature, and choice of transchelator will be optimized for the conjugate for each metal ion, and stability constants for the "type I" complexes will be measured in serum. in addition the stability constants for the "type II" complexes will be measured in 10 mM DTPA. Simplified synthetic routes have been devised for each bifunctional chelator. The products will be purified by ion exchange chromatography and analyzed by mass spectrometry and NMR. The bifunctional chelators will be attached with or without linkers to whole and antibody fragments, engineered in Project 2. Non-specific attachment will be to lysine residues and site specific attachment will be to cysteine residues in the hinge region or those engineered into the CH3 domain, and to aldehydes produced by periodate oxidation of engineered glycosyl residues. Chemically labile liners that improve tumor to blood ratios without lowering tumor uptake of the sulfur atom in the linker. Animal studies will be performed to determine the ultimate metabolic fate of the metal complex ina the liver, kidney, and tumor. The overall approach is expected to lead to clinical products with improved labeling and biodistribution properties. The assembled team has unique expertise in chemistry, antibody conjugation, and the use of animal models for evaluating radiolabeled antibodies in pre-clinical and clinical studies.

将合成新型双功能螯合物和金属离子配合物 并与抗 CEA（癌胚抗原）抗体缀合 改善 CEA 阳性肿瘤的靶向性。 新型双功能螯合物 基于大循环DOTA并融入新的挂件功能 基团以增强金属离子在抗体缀合物上的结合。 这 官能团包括羧基、巯基、酰肼和 乙酰羟肟酸盐。 这些群体预计将形成紧密的“I 型” 与 In-111、Y-90 和 Cu-64 形成络合物。 无线电金属被选为 它们在放射免疫成像和治疗中的用途。 pH 条件， 温度和转螯合剂的选择将针对 每种金属离子的缀合物，以及“I 型”的稳定常数 将在血清中测量复合物。 另外稳定常数 对于“II 型”复合物，将在 10 mM DTPA 中进行测量。 简化版 已经为每种双功能螯合剂设计了合成路线。 这 产品将通过离子交换色谱法纯化并通过以下方法进行分析 质谱和核磁共振。 双功能螯合剂将被附加 带有或不带有完整片段和抗体片段的接头，经过工程设计 项目 2. 非特异性附着将针对赖氨酸残基和位点 特定的连接将是铰链区的半胱氨酸残基或 那些被工程化到 CH3 结构域以及由 工程糖基残基的高碘酸盐氧化。 化学不稳定 改善肿瘤与血液比率而不降低肿瘤摄取的衬垫 连接子中的硫原子。 将进行动物研究 确定金属络合物在肝脏中的最终代谢命运， 肾、肿瘤。 总体方法预计将导致临床 具有改进的标签和生物分布特性的产品。 这 组建的团队在化学、抗体偶联、 以及使用动物模型来评估放射性标记抗体 临床前和临床研究。