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）作为细胞毒药物的选择性载体，是一种潜在的治疗药物。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。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）偶联时的相对效力，并与单独的mAb、I-131放射性标记的mAb或与毒素偶联的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，并完成α粒子发射放射性核素Bi-212、Bi-213和At-211的临床前研究。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）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已经产生了新的Pb（II）同位素（TCMC）和HEHA的配体，HEHA是目前唯一与Ac-225形成复合物的配体，其证明了体内数据的稳定性。在适当的鼠模型系统中，正在努力评估每种的双功能版本。目前使用具有人源化CH 2结构域缺失的工程化抗体CC 49的α发射体Bi- 213的临床前结果已经产生了显著的结果。与不能用α发射体放射免疫缀合物治疗已建立的肿瘤的传统观点相反，用750微居里剂量治疗的约60%的小鼠产生部分反应，其中肿瘤生长被阻止，或者产生完全反应，其中肿瘤基本上被根除。然而，无论剂量如何，约30%的治疗无效。这一系列的实验继续扩大到更大的人群，剂量略有增加。同时，计划在相同的鼠系统中使用Pb-212/Bi-212的体内发生器系统，以提供更大的剂量和延长的半衰期，从而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，