Metal Chelate Conjugated Monoclonal Antibodies for Tumor Diagnosis and Therapy

肿瘤相关单克隆抗体（mAb’s）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。它们与单克隆抗体（mAb’s）偶联时的相对功效被测定并与单克隆抗体进行比较。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，以及对放射放射性核素Bi-212、Bi-213、Ac-225和At-211的α粒子进行临床前研究。正在进行的临床试验目前使用第二代双功能螯合剂1bm4 -DTPA（又名MX-DTPA或Tiuxetan）来隔离Y-90，未来计划的试验将使用CHX-A“DTPA”。螯合剂设计技术的最新成果已经产生了迄今为止最稳定的Ac-225双功能螯合剂，一种HEHA的对异硫氰酸甲基苯类似物。在两种小鼠模型中评估了该配体的体内稳定性和Ac-225作为放射免疫偶联物中的放射性核素成分的潜在功效。肺肿瘤模型的治疗实验结果治愈了所有的动物，但也证明了0.5微居里的剂量是100%的放射性毒性。然而，以类似剂量治疗实体结肠癌异种移植肿瘤，几乎完全抑制了肿瘤生长，这表明需要在多种肿瘤模型系统中广泛研究这种同位素。使用人源化的CH2结构域缺失工程版单抗CC49的Bi-213的临床前结果产生了显著的结果，约60%的小鼠接受750微居里剂量的治疗，要么实现了部分反应，其中肿瘤生长被阻止，要么实现了完全反应，肿瘤基本上被根除。对Bi-213的研究也已扩大到包括对使用预靶向方案的调查。人源化抗tac和B3单克隆抗体的初步结果均显示出良好的效果。在母体放射性核素可用之前，这些研究将继续优化剂量和时间表。计划扩展该技术以重新检查Pb-212的效用，并在相同的小鼠系统中评估Pb-212/Bi-212的体内产生系统。

Tumor associated monoclonal antibodies (mAb's) 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 (mAb's) is assayed and compared to that of the mAb alone. 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 performing pre-clinical studies with the alpha-particle emitting radionuclides Bi-212, Bi-213, Ac-225, and At-211. Ongoing clinical trials currently employ the second generation bifunctional chelating agent 1B4M-DTPA (aka MX-DTPA or Tiuxetan) for sequestering Y-90 and future trials being planned will use the CHX-A'' DTPA. Recent results in chelate design technology have yielded the most stable bifunctional chelating agent for Ac-225 to date, a p-isothiocyanatobenzyl analog of HEHA. Efforts at evaluating the in vivo stability of this ligand and the potential efficacy of Ac-225 as the radionuclide component in a radioimmunoconjugate has been evaluated in two murine models. The results for therapy experiments in a lung tumor model cured all of the animals, yet also proved to be 100% radiotoxic with a dose of 0.5 microcuries. However, treatment of a solid, colon cancer xenograft tumor, at a similar dose, resulted in virtually complete inhibition of tumor growth indicative of need for this isotope to be extensively investigated in multiple tumor model systems. Pre-clinical results with Bi-213 using the humanized, CH2 domain deleted engineered version of mAb CC49 generated remarkable results with ~ 60% of the mice treated with a 750 microcurie dose either achieving a partial response wherein the tumor growth was arrested or a complete response with the tumor was essentially eradicated. Studies with Bi-213 have also been expanded to include investigation into use of pre-targeting protocols. Preliminary results with monoclonal antibodies humanized anti-Tac and B3 have both shown promising results. These studies will continue to optimize dose and schedule pending availability of the parent radionuclide. Plans are to expand this technology to re-examine the utility of Pb-212 and evaluate the in vivo generator system of Pb-212/Bi-212 in the same murine systems.