Metal Chelate Conjugated Monoclonal Antibodies for Tumor Diagnosis and Therapy

肿瘤相关单克隆抗体（mAb）是作为针对恶性细胞的细胞毒性剂的选择性载体的潜在治疗剂。 在动物模型系统中用针对与多种恶性肿瘤相关的抗原的mAb测试该假设。所使用的杀细胞剂是各种放射性核素。 测定它们与单克隆抗体（mAb）缀合时的相对效力，并与单独的mAb进行比较。 选择用于研究的放射性核素涵盖可用的放射性核素特性范围，从而分析发射能量、半衰期和发射物理特性的影响。 研究继续侧重于扩大Y-90的临床使用，并对发射α粒子的放射性核素Bi-212、Bi-213、Ac-225和At-211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1B 4 M-DTPA（又名MX-DTPA或Tiuxetan）螯合Y-90，计划中的未来试验将使用CHX-A“DTPA。 螯合物设计技术的最新结果产生了迄今为止最稳定的Ac-225双功能螯合剂，HEHA的对异硫氰酸苄类似物。 已在两种小鼠模型中评价了该配体的体内稳定性和Ac-225作为放射性免疫偶联物中放射性核素组分的潜在功效。 在肺肿瘤模型中的治疗实验结果治愈了所有动物，但也证明了0.5微居里剂量的100%放射毒性。然而，以类似剂量治疗实体结肠癌异种移植肿瘤导致肿瘤生长几乎完全抑制，表明需要在多种肿瘤模型系统中广泛研究该同位素。 使用mAb CC 49的人源化、CH 2结构域缺失的工程化版本的Bi-213的临床前结果产生了显著的结果，其中约60%的用750微居里剂量处理的小鼠实现了部分响应，其中肿瘤生长被阻止，或者肿瘤基本上被根除的完全响应。 Bi-213的研究也已扩展到包括对预靶向方案使用的研究。使用单克隆抗体人源化抗Tac和B3的初步结果均显示出有希望的结果。 这些研究将继续优化剂量和时间表，以待获得母体放射性核素。 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价Pb-212/Bi-212的体内发生器系统。

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.