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,

肿瘤相关的单克隆抗体（MAB）是潜在的治疗剂，作为对恶性细胞的细胞毒性剂的选择性载体。该假设在动物模型系统中进行了测试，其MAB针对与各种恶性肿瘤相关的抗原。所使用的胞位剂是各种放射性核素。分析与单克隆抗体（mAb）共轭的相对疗效，并与单独的mAb的相对功效进行比较，并与单独的mAb相结合，与I-131进行放射性标记或与毒素结合。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的范围，从而分析了发射能量，半衰期和发射的物理特征的影响。研究继续专注于扩大Y-90的临床使用，并使用α粒子发射放射性核素BIB-212，BI-213和AT-211完成临床前研究。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）进行隔离Y-90，并且计划的未来试验将使用CHX-A DTPA。螯合设计技术的最新结果为PB（II）同位素（TCMC）和Heha产生了新的配体，Heha目前是唯一与AC-225形成复合物的配体，该配体在体内表现出稳定性的数据。在适当的鼠模型系统中，正在进行评估每个版本的双功能版本的努力。当前与alpha发射器BI-213一起使用人源化CH2结构域删除的工程抗体CC49的临床前结果产生了出色的结果。与常规的范围相反，与alpha发射膜的放射免疫偶联物无法治疗建立的肿瘤，约60％用750个微库剂量治疗的小鼠会产生部分抑制，其中肿瘤生长被滞留或完全消除了肿瘤的完全反应。但是，无论剂量如何，接受治疗的约30％都无法做出积极反应。这一系列实验继续扩展到较大的人群，并略有增加剂量。同时，计划在同一鼠系统中使用PB-212/BI-212的体内生成器系统，以提供更大的剂量和增强的半衰期，以改善靶向药代动力学。 - 成像，金属螯合物，单克隆抗体，辐射，放射免疫疗法，