ANTIBODY CHELATES AND CONJUGATES

将合成新型双功能络合物和金属离子络合物 并与抗CEA(癌胚抗原)抗体偶联，用于其 改进了CEA阳性肿瘤的靶向。新型双功能络合物 是基于大环DOTA，并结合了新的吊坠功能 增强抗体结合物上金属离子结合的基团。这个 官能团包括羧基、巯基、肼和 乙酰异羟氨酸盐。预计这些群体将形成紧密的“第一类”。 In-111、Y-90和铜-的络合物。放射性金属被选择用于 它们在放射免疫成像和治疗中的应用。PH值的条件， 温度和传络剂的选择将进行优化 每种金属离子的共轭，以及“第一类”的稳定常数 复合体将在血清中进行测量。此外，稳定常数 对于“第二类”复合体，将以10毫米DTPA测量。简化 已经为每种双功能螯合剂设计了合成路线。这个 产品将通过离子交换层析进行纯化，并通过 质谱学和核磁共振。双功能的螯合剂将被附着 带有或不带有完整和抗体片段的连接子，在 项目2.与赖氨酸残基和部位的非特异性连接 特异性结合在铰链区的半胱氨酸残基或 那些被改造成CH3结构域的化合物，以及由 工程糖基残基的高碘酸氧化。化学不稳定 在不降低肿瘤摄取的情况下改善肿瘤与血液的比率的衬垫 连接物中的硫原子。将进行动物研究，以 决定了金属络合物在肝脏中的最终代谢命运， 肾脏和肿瘤。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。这个 组队在化学、抗体偶联、 以及评估放射性标记抗体的动物模型的使用 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.