METAL CHELATE CONJUGATED MONOCLONAL ANTIBODIES FOR TUMOR DIAGNOSIS AND THERAPY

用于肿瘤诊断和治疗的金属螯合单克隆抗体

• 批准号: 6290746
• 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/6290746
• 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) 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,

肿瘤相关单克隆抗体（mAb）是潜在的治疗剂，作为恶性细胞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，并与单独使用 I-131 放射性标记或与毒素缀合的 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 的临床使用以及完成发射 α 粒子的放射性核素 Bi-212、Bi-213 和 At-211 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，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 Pb(II) 同位素 (TCMC) 和 HEHA 的新配体，HEHA 是目前唯一与 Ac-225 形成复合物的配体，该复合物表现出体内数据的稳定性。在适当的小鼠模型系统中正在努力评估每个版本的双功能版本。目前，α发射体 Bi-213 与人源化 CH2 结构域缺失的工程抗体 CC49 的临床前结果已经产生了显着的结果。与无法用α发射体放射免疫缀合物治疗已建立的肿瘤的传统范例相反，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。这一系列的实验继续扩大到更大的人群并略微增加剂量。与此同时，计划在同一小鼠系统中使用 Pb-212/Bi-212 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、放射免疫疗法、