METAL CHELATE CONJUGATED MONOCLONAL ANTIBODIES FOR TUMOR DIAGNOSIS AND THERAPY

肿瘤相关单克隆抗体（Tumor associated mon克隆antibody， mAb）作为肿瘤细胞毒性药物的选择性载体，是潜在的治疗药物。这一假设在动物模型系统中进行了测试，其中单克隆抗体针对与各种恶性肿瘤相关的抗原。所使用的细胞杀灭剂是各种放射性核素。测定它们与单克隆抗体（mab）结合时的相对疗效，并与单克隆抗体单独、用I-131放射标记或与毒素结合时的相对疗效进行比较。选择用于研究的放射性核素跨越了可用的放射性核素性质范围，从而分析了发射能量、半衰期和发射物理特性的影响。研究继续侧重于扩大Y-90的临床应用，并完成放射放射性核素Bi-212、Bi-213和At-211的α粒子的临床前研究。目前正在进行的临床试验使用第二代双功能螯合剂1B4M-DTPA（又名MX-DTPA）来隔离Y-90，未来计划的试验将使用CHX-A DTPA。螯合设计技术的最新成果已经产生了铅（II）同位素（TCMC）和HEHA的新配体，HEHA是目前唯一与Ac-225形成络合物的配体，数据显示其在体内具有稳定性。在适当的小鼠模型系统中，正在努力评估每种功能的双功能版本。目前，α发射器Bi- 213与人源化CH2结构域缺失工程抗体CC49的临床前研究结果已经产生了显著的结果。与传统的肿瘤不能用α发射器放射免疫偶联物治疗的范式相反，用750微居里剂量治疗的约60%的小鼠要么产生部分反应，其中肿瘤生长被阻止，要么产生完全反应，其中肿瘤基本上被根除。然而，无论剂量如何，约30%的治疗未能产生积极反应。这一系列的实验将继续扩大到更大的人群，并略微增加剂量。同时，计划在相同的小鼠系统中使用Pb-212/Bi-212的体内发生器系统，以提供更大的剂量和更长的半衰期，以改善靶向药代动力学。-成像，金属螯合物，单克隆抗体，放射，放射免疫治疗，

Tumor associated monoclonal antibodies (mAb) are potential therapeutic agents as selective carriers of cytotoxic agents to malignant cells. This hypothesis is tested in animal model systems with mAbs directed toward antigens associated with a variety of malignancies. The cytocidal agents being employed are various radionuclides. Their relative efficacy when conjugated to monoclonal antibodies (mAbs) is assayed and compared to that of mAbs alone, radiolabeled with I-131, or conjugated to toxins. The radionuclides chosen for study span the range of radionuclidic properties available thereby assaying the effects of energy of emission, half-life, and physical characteristics of emission. Research continues to focus on expanding clinical use of Y-90 and on completing pre-clinical studies with the alpha-particle emitting radionuclides Bi-212, Bi-213, and At-211. Ongoing clinical trials currently employ the second generation bifunctional chelating agent 1B4M-DTPA (aka MX-DTPA) for sequestering Y-90 and future trials being planned will use the CHX-A DTPA. Recent results in chelate design technology have yielded new ligands for Pb(II) isotopes (TCMC), and HEHA, currently the only ligand that forms a complex with Ac-225 that demonstrates stability in vivo to data. Efforts at evaluating the bifunctional versions of each are ongoing in the appropriate murine model systems. Current pre-clinical results with the alpha emitter Bi- 213 with the humanized CH2 domain deleted engineered antibody CC49 has generated remarkable results. Contrary to the conventional paradygm that established tumors can not be treated with an alpha emitter radioimmunoconjugate, ~60% of mice treated with a 750 microcurie dose either produced a partial respose wherein the tumor growth was arrested or a complete response wherein the tumor was essentially eradicated. However, regardless of dose, ~30% treated failed to respond positively. This series of experiments continues to be expanded to a larger population and slightly increased doses. In parallel, use of the in vivo generator system of Pb-212/Bi-212 in the same murine system is planned in provide both a greater dose and an enhanced half-life to improve targeting pharmacokinetics. - imaging, metal chelates, monoclonal antibodies, radiation, radioimmunotherapy,