ANTIBODY CHELATES AND CONJUGATES

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。 新型双功能螯合物 是基于大环DOTA和纳入新的悬垂功能 基团以增强抗体缀合物上的金属离子结合。 的 官能团包括羧基、巯基、酰肼和 乙酰异羟肟酸盐 预计这些群体将形成紧密的“I型” 与In-111、Y-90、Cu-64形成配合物。 选择放射性金属是为了 它们在放射免疫成像和治疗中的效用。 pH值条件， 温度，和transchelator的选择将被优化， 共轭的每种金属离子，和稳定常数的“I型” 将在血清中测量复合物。 此外，稳定常数 对于“II型”复合物，将在10 mM DTPA中测量。 简化 已经为每种双官能螯合剂设计了合成路线。 的 产品将通过离子交换色谱法纯化，并通过 质谱和NMR。 双功能螯合剂将连接到 具有或不具有与完整片段和抗体片段的接头， 项目2. 非特异性连接将是赖氨酸残基和位点 特异性连接将是在铰链区的半胱氨酸残基上， 那些被工程化到CH 3结构域中的，以及由 工程化糖基残基的高碘酸盐氧化。 化学不稳定 提高肿瘤与血液比率而不降低肿瘤对 连接基中的硫原子。 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， 肾脏和肿瘤。 整体方法预计将导致临床 具有改进的标记和生物分布特性的产品。 的 组装团队在化学，抗体结合， 以及使用动物模型评估放射性标记的抗体， 临床前和临床研究。

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.