Metal Chelate Conjugated Monoclonal Antibodies for Tumor Diagnosis and Therapy

用于肿瘤诊断和治疗的金属螯合物缀合单克隆抗体

• 批准号: 6433345
• 负责人: MARTIN W BRECHBIEL
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6433345
• 关键词: Primates; antitumor antibody; bismuth; chelating agents; cytotoxicity; diethylenetriaminepentaacetate; disease /disorder model; immunoconjugates; laboratory mouse; metastasis; monoclonal antibody; neoplasm /cancer immunodiagnosis; neoplasm /cancer immunotherapy; neoplasm /cancer radiodiagnosis; neoplasm /cancer radionuclide therapy; radionuclide diagnosis; radionuclide imaging /scanning; radionuclides; radiopharmacology; yttrium

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.

肿瘤相关单克隆抗体（mAb）是潜在的治疗剂，作为恶性细胞的细胞毒性剂的选择性载体。 这一假设在动物模型系统中进行了测试，其中使用了针对多种恶性肿瘤相关抗原的单克隆抗体。所使用的杀细胞剂是各种放射性核素。 分析了它们与单克隆抗体 (mAb) 缀合时的相对功效，并与单独的 mAb 进行比较。 选择用于研究的放射性核素涵盖了可用的放射性核素特性范围，从而分析了发射能量、半衰期和发射物理特性的影响。 研究继续集中于扩大 Y-90 的临床使用以及使用 α 粒子发射放射性核素 Bi-212、Bi-213、Ac-225 和 At-211 进行临床前研究。 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 或 Tiuxetan）来螯合 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成果已经产生了迄今为止最稳定的 Ac-225 双功能螯合剂，Ac-225 是 HEHA 的对异硫氰酸苄基类似物。 已在两个小鼠模型中评估了评估该配体的体内稳定性以及 Ac-225 作为放射免疫缀合物中放射性核素成分的潜在功效的努力。 肺肿瘤模型的治疗实验结果治愈了所有动物，但也证明 0.5 微居里的剂量具有 100% 的放射性毒性。然而，以相似的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受到抑制，表明需要在多个肿瘤模型系统中广泛研究该同位素。 Bi-213 使用人源化、CH2 结构域缺失的工程版本 mAb CC49 进行的临床前结果产生了显着的结果，约 60% 的接受 750 微居里剂量治疗的小鼠要么实现了部分反应，其中肿瘤生长被抑制，要么完全完全缓解。肿瘤的反应基本上被消除了。 Bi-213 的研究也已扩大到包括对预靶向方案使用的调查。人源化抗 Tac 和 B3 单克隆抗体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，以待母体放射性核素的可用性。 计划扩展该技术以重新检验 Pb-212 的效用，并在相同的小鼠系统中评估 Pb-212/Bi-212 的体内发生器系统。