Metal Chelate Conjugated mAb's--Tumor Diagnosis /Therapy

金属螯合单克隆抗体--肿瘤诊断/治疗

• 批准号: 6558305
• 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/6558305
• 关键词: Primates; antitumor antibody; bismuth; chelating agents; cytotoxicity; diethylenetriaminepentaacetate; disease /disorder model; immunoconjugates; laboratory mouse; lead; metal complex; monoclonal antibody; neoplasm /cancer immunodiagnosis; neoplasm /cancer immunotherapy; neoplasm /cancer radiodiagnosis; neoplasm /cancer radionuclide therapy; ovary neoplasms; pancreas neoplasms; prostate neoplasms; radiation 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 employed are various radionuclides and their relative efficacy when conjugated to targeting vectors such as monoclonal antibodies (mAb's) is assayed. The radionuclides chosen for study span the range of radionuclidic properties available thereby assaying the effects of emission energy, half-life, and type of emission. Research continues to focus on expanding practical 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 or the CHX-A'' DTPA for Y-90 and / Bi-213. Both are suitable for imaging with either In-111 or Y-86. Recent numerous pre-clinical results in the ongoing development of novel bifunctional chelating agents and linkers for targeted radiotherapy with the alpha-emitting radionuclides Bi-213, Ac-225, and At-211 have been completed. In the case of Bi-213, a specific potential clinical application of treating prostate cancer with an antibody that targets PSMA(ext) demonstrated significant delay in tumor onset, extended life expectancy, and decreased levels of PSA in a murine model with single doses of radioimmunoconjugate. Studies addressing the possibility of using Ac-225 as a therapeutic radionuclide in targeted radiotherapy applications using the most stable in vivo chelating agent to date, HEHA, were performed in two different murine models, a vasculature targeting model and a solid tumor model. Both studies independently indicated there to be significant unacceptable toxicity originating from the decay product daughters. While this radionuclide may still be of value in a limited setting of rapid targeting and internalization, this condition in conjunction with the challenges associated with coordination chemistry eliminate this radionuclide from clinical contention. Studies with At-211 have yielded a novel protein modification reagent wherein the linking moiety has been removed from being the traditional aryl carboxylate active ester and placed several atoms away from the aryl astatine bond. Pre-clinical studies with this novel reagent termed SAPS conjugated to humanized monoclonal antibody anti-Tac indicate this agent to be stale in vivo and equivalent to the indirectly radio-iodinated protein in every regard. In the case of both Bi-213 and At-211, pre-clinical studies continue to evaluate potential therapeutic applications that may be translated into clinical protocols. Studies with Bi-213 have also been expanded to include investigation into use of pre-targeting protocols. Preliminary results of streptavidin conjugated monoclonal antibody humanized anti-Tac in a murine T-cell leukemia model have been completed with significant therapeutic levels of efficacy being obtained with single doses of Bi-213. With the recent revival in availability of both Bi-212 and Pb-212, pre-clinical evaluation of Bi-213, Bi-212, and Pb-212 for the treatment of disseminated intraperitoneal disease such as ovarian and pancreatic cancer have been initiated. Preliminary results have indicated that substantial increases in median life expectancy in murine models are possible with single doses of these isotopes conjugated to clinically relevant antibodies such as CC49 or Herceptin.

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。分解与靶向载体（如单克隆抗体（MAB））相结合时，使用的细胞固定剂是各种放射性核素及其相对功效。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，从而测定了发射能，半衰期和发射类型的影响。研究继续专注于扩大Y-90的实际临床使用，并使用Alpha-parpicle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）用于隔离Y-90和y-90和 / bi-213的Y-90和或CHX-A'DTPA。两者都适用于In-111或Y-86的成像。 最近，临床前的临床前结果是在靶向放射疗法的新型双功能螯合剂和连接器的持续发展中，并完成了α发射放射性核素BIBI-213，AC-225和AT-211。在BI-213的情况下，针对PSMA（EXT）的抗体治疗前列腺癌的特定潜在临床应用表明肿瘤发作，延长寿命延长的寿命和PSA水平降低，在鼠模型中，单剂量的PSA水平降低放射免疫共轭。解决了使用AC-225作为治疗放射性核素在靶向放射疗法应用中使用最稳定的体内螯合剂迄今为止的可能性的研究，heha是在两个不同的鼠模型中进行的，即一种脉管系统的靶向模型和实体瘤模型。两项研究都独立地表明，源自衰减产品女儿具有明显的不可接受的毒性。尽管这种放射性核素在有限的快速靶向和内在化设置中仍然具有价值，但这种条件与与协调化学相关的挑战相结合，从而消除了这种放射性核素的临床竞争。使用AT-211的研究产生了一种新型的蛋白质修饰试剂，其中将连接部分从传统的芳基羧酸酯活性酯中取出，并将几个原子远离芳基astatine键。使用这种称为人源化单克隆抗体抗TAC的SAP的新试剂进行的临床研究表明，该药物在体内是陈旧的，并且在各个方面都与间接射线固定固醇的蛋白质相当。在BI-213和AT-211的情况下，临床前研究继续评估可以转化为临床方案的潜在治疗应用。对BI-213的研究也已扩展，以包括研究使用预先定位方案的研究。在鼠T细胞白血病模型中，链霉亲和素共轭单克隆抗体抗TAC的初步结果已经完成，单剂量的BI-213获得了显着的治疗水平，可获得明显的治疗水平。随着BI-212和PB-212的可用性的近期复兴，已经启动了BI-213，BI-212和PB-212的临床前评估，用于治疗传播的腹膜内疾病，例如卵巢癌和胰腺癌。初步结果表明，通过将这些同位素的单剂量与临床相关抗体（例如CC49或Herceptin）结合在一起的单剂量，鼠模型的中值预期寿命可以大大增加。