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.

新型双功能螯合物和金属离子配合物将合成 并与抗CEA（癌症抗原抗原）抗体共轭 改善了CEA阳性肿瘤的靶向。 新的双功能螯合物 基于大环DOTA，并包含新的吊坠功能 组以增强对抗体结合物上的金属离子结合。 这 功能组包括羧基，硫赖尔，氢氮化物和 乙醛氨基酸盐。 这些组有望形成紧密的“ I型” IN-1111，Y-90，ND CU-64的复合物。 选择辐射图 它们在放射免疫模仿和治疗方面的效用。 pH的条件， 温度和选择的选择将优化 每种金属离子的共轭和“ I型”的稳定性常数 复合物将以血清测量。 另外稳定性常数 对于“ II型”复合物，将以10 mM DTPA进行测量。 简化 已经为每个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纯化，并通过 质谱和NMR。 双功能螯合剂将附加 有或没有连接到整体和抗体片段的连接器， 项目2。非特异性附件将是赖氨酸残留物和现场 具体的附件将是铰链区域中的半胱氨酸残留物或 那些被设计到CH3域，以及由 工程糖基残基的周期氧化。 化学上不稳定 改善肿瘤与血比的衬里而不降低肿瘤的吸收 接头中的硫原子。 动物研究将进行 确定金属络合物的最终代谢命运INA肝脏， 肾脏和肿瘤。 总体方法有望导致临床 具有改进的标记和生物分布特性的产品。 这 组装团队在化学，抗体共轭方面具有独特的专业知识， 并使用动物模型评估放射性标记的抗体 临床前和临床研究。