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.

肿瘤相关单抗(MAbs)是一种潜在的治疗药物，可作为细胞毒药物对肿瘤细胞的选择性载体。这一假设在动物模型系统中得到了验证，mAb针对的是与各种恶性肿瘤相关的抗原。所使用的杀细胞剂是各种放射性核素。检测它们与单抗结合时的相对效力，并与单抗进行比较。所选用于研究的放射性核素跨越现有的放射性核素性质范围，从而分析发射能量、半衰期和发射的物理特性的影响。研究继续侧重于扩大Y-90的临床应用，并对发射放射性核素的阿尔法粒子进行临床前研究。正在进行的临床试验目前使用第二代双功能螯合剂1B4M-DTPA(又名MX-DTPA或Tiuxetan)来隔离Y-90，计划中的未来试验将使用CHX-A‘’DTPA。螯合设计技术的最新成果为Ac-225生产了迄今为止最稳定的双官能团螯合剂，即HEHA的对异硫氰基苯基类似物。已经在两个小鼠模型中评估了该配体的体内稳定性和Ac-225作为放射免疫结合物中放射性核素成分的潜在疗效。肺肿瘤模型的治疗实验结果治愈了所有动物，但也被证明是100%的放射毒性，剂量为0.5微立方米。然而，对实体结肠癌异种移植瘤的治疗，在类似的剂量下，几乎完全抑制了肿瘤的生长，这表明需要在多个肿瘤模型系统中广泛研究这种同位素。使用人源化、CH2结构域缺失的mAbCC49的临床前结果显示，使用750微居里剂量治疗的小鼠中，约60%的小鼠获得了部分反应，其中肿瘤生长被阻止，或对肿瘤的完全反应基本上被根除。对Bi-213的研究也已扩大到包括对预靶向方案的使用进行调查。人源化抗Tac和B3单抗的初步结果都显示出有希望的结果。这些研究将继续优化剂量和时间表，等待母体放射性核素的供应。计划扩展这项技术，以重新检查铅-212的用途，并在相同的小鼠系统中评估体内铅-212/铋-212的发生器系统。