ANTIBODY-CHELATE CONJUGATES

该项目的具体目标是与项目1和项目2互动 开发改进的双功能螯合剂技术， 用途，并不仅通过标准方法表征免疫缀合物， 而且还通过确定双官能的连接的确切位点， 螯合剂与单克隆抗体。 我们下一次拨款的计划 期间为： 1. 开发大规模的临床预标签， 双功能螯合剂DOTA-肽和-异硫氰酸酯， 治疗量的90 Y可以给予患者， 抗体的量。 研究一组合理选择的肽接头 来优化这些分子的生物学特性。 前- 标记方法有望大大改善生物学特性 钇免疫缀合物，以及其他。 2. 探讨TETA-肽试剂测定67 Cu的优势 放射免疫疗法 预期肽接头可以导致 肝脏中的放射性水平低于目前获得的AR 与2-亚氨基硫杂环戊烷连接体连接。 3. 利用本报告所述期间开发的方法， 在抗体上的肽位点与过程中使用的试剂缀合， 下一个补助期。 这种程度的特征化将使我们能够 将生物分布模式和修饰位点联系起来。 4. 开始对我们现有的工程蛋白进行生物测试 制作。 这将导致靶向分子与选定的 特性，其可以针对每个目标的生理学而定制。 许多金属离子形成螯合物。 金属离子的稳定附着 通过“双功能”螯合剂与抗体结合， 金属元素的核、物理和化学性质， 这些目标选择性蛋白质。 由于放射性标记的 单克隆抗体的进展，一些抗体已被发现， 可用于人类患者的体内诊断和治疗。 一个主要 例如，抗体Lym-1。 这种小鼠IgG 2a（k）抗体， 针对伯基特淋巴瘤，结合到膜结合糖蛋白， 在许多人类淋巴瘤和淋巴细胞白血病中强烈表达 细胞 我们已经成功地对患有这些疾病的患者进行了成像， 该抗体用131 I、67 Cu、111 In标记。 我们还提供了 有效的放射免疫疗法对这种抗体的淋巴瘤患者使用 131 I和67 Cu。

The specific aims of this project is to interact with Projects 1 and 2 to develop improved bifunctional chelating agent technology for clinical use, and to characterize immunoconjugates not only by standard methods, but also by determining the exact sites of attachment of bifunctional chelating agents to monoclonal antibodies. Our plans for the next grant period are: 1. To develop large-scale clinical pre-labeling with the new bifunctional chelating agents DOTA-peptide and -isothiocyanate, so that therapeutic amounts of 90Y can be administered to patients with minimal amounts of antibody. To study a set of rationally chosen peptide linkers to optimize the biological properties of these molecules. The pre- labeling approach promises to greatly improve the biological properties of yttrium immunoconjugates, and others as well. 2. To explore the advantages of TETA-peptide reagents for 67Cu radioimmunotherapy. It is expected that the peptide linker can lead to lower levels of radioactivity in the liver than ar currently obtained with the 2-iminothiolane linker. 3. Using the methods developed during the current period, to map the peptide sites on the antibodies conjugated with reagents employed during the next grant period. This degree of characterization will allow us to correlate biodistribution patterns and modified sites. 4. To begin biological testing of engineered proteins that we have produced. This will lead to targeting molecules with selected properties, which may be tailored to the physiology of each target. Many metal ions form chelate complexes. Stable attachment of metal ions to antibodies by means of "bifunctional" chelating agents can add the nuclear, physical, and chemical properties of the metallic elements to these target-selective proteins. As the clinical use of radiolabeled monoclonal antibodies proceeds, a few antibodies have been found to be useful in vivo for both diagnosis and therapy of human patients. A prime example is the antibody Lym-1. this mouse lgG2a(k) antibody, produced against Burkitt's lymphoma, binds to a membrane-bound glycoprotein which is strongly expressed on many human lymphoma and lymphocytic leukemia cells. We have successfully imaged patients with these diseases using this antibody labeled with 131I, 67Cu, 111In. We have also delivered effective radioimmunotherapy on this antibody to lymphoma patients using 131I and 67Cu.