RADIOLABELED MONOCLONAL ANTIBODY IMAGING OF TUMORS

肿瘤的放射性标记单克隆抗体成像

• 批准号: 6161460
• 负责人: JORGE A. CARRASQUILLO
• 金额: --
• 依托单位: CLINICAL CENTER
• 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/6161460
• 关键词: antitumor antibody; athymic mouse; clinical research; clinical trial phase I; human subject; immunoglobulin G; monoclonal antibody; neoplasm /cancer immunotherapy; neoplasm /cancer radionuclide diagnosis; neoplasm /cancer radionuclide therapy; neoplasm /cancer transplantation; nuclear medicine; radiation therapy dosage; radionuclide imaging /scanning; radiopharmacology; xenotransplantation; yttrium

Summary of Work: These studies are designed to develop improved methods for detecting and treating malignancies. Our group performs preclinical evaluation of antibodies that appear to be promising after initial screening by various laboratories at the National Cancer Institute and develops these antibodies for clinical staff. They are then administered to patients under the supervision of a nuclear medicine physician and an assistant in the Nuclear Medicine Department. Serial blood samples, urine specimens, and often bone marrow or tumor biopsies are obtained to evaluate the distribution of the monoclonal antibody in the body. The phase I trial with B3, in collaboration with Dr. Ira Pastan, is continuing patient accrual. We have accrued 25 patients at our fourth dose level. Based on the preliminary results of our collaborative radioimmunotherapy trial with Dr. Waldmann in which we used humanized anti-tac monoclonal antibody, we have started two trials using Ca-DTPA to sequester any free Y-90 that comes from the antibody. The DTPA is expected to chelate free Y-90 on this to minimize the concentration of Y-90 in the bone marrow, which should allow higher doses of Y-90 anti- Tac to be administered. We have studied four patients. We have been developing the use of anti-Tac dsFv in collaboration with Dr. Ira Pastan and Dr. Eckelman of the Positron Emission Tomography (PET) Department. We have shown that the high renal uptake can be blocked using a commercially available amino acid solution. These studies were performed using Aminosyn bolus and infusion in baboons receiving radio-labeled dsFv. Quantitation with PET (F-18 ati-Tac dsFv) showed that renal blocking was effective. Imaging studies comparing the use of Tc-99m anti-CEA Fab (FDA approved) and F-18 deoxyglucose have been started in patients with previous history of colorectal carcinoma and rising CEA without evidence of disease by conventional radiographic modalities. In collaboration with M. Brechbiel and the NCI Radiation Oncology group, we have evaluated in a nude mice mode the stability and biodistribution of four stereoisomers of 2-(p-nitrobenzyl)-trans-CyDTPA (CHX-DTPA). We have documented that subtle differences in stereochemistry can cause significant different in stability of Y-90 labeled CHX. From the four sterosiomers we have selected the most stable for Y-90 chelation as our preferred chelate for antibody trials.

工作总结：这些研究旨在开发改进的方法 用于检测和治疗恶性肿瘤。我们组进行临床前 初步评估后似乎有希望的抗体 由国家癌症研究所的各个实验室进行筛查 为临床人员开发这些抗体。然后对它们进行管理 在核医学医师监督下的患者以及 核医学科助理。系列血样， 尿液样本，通常还获取骨髓或肿瘤活检样本 评估单克隆抗体在体内的分布。这 与 Ira Pastan 博士合作，使用 B3 进行 I 期试验 持续增加患者。我们第四次治疗已收治了 25 名患者 剂量水平。根据我们合作的初步结果 Waldmann 博士进行的放射免疫治疗试验，其中我们使用了人源化 抗-tac单克隆抗体，我们已经开始了两项使用Ca-DTPA的试验 隔离来自抗体的任何游离 Y-90。 DTPA 是 预计在其上螯合游离 Y-90，以尽量减少 Y-90 存在于骨髓中，这应该允许更高剂量的 Y-90 抗 待施用 Tac。我们研究了四名患者。我们曾经 与 Ira Pastan 博士合作开发抗 Tac dsFv 的用途 以及正电子发射断层扫描 (PET) 部门的 Eckelman 博士。 我们已经证明，可以使用以下药物来阻断高肾脏摄取： 市售氨基酸溶液。这些研究进行了 对接受放射性标记的狒狒使用 Aminosyn 丸剂和输注 dsFv。 PET（F-18 ati-Tac dsFv）定量显示肾 封锁是有效的。比较 Tc-99m 使用的影像学研究 抗 CEA Fab（FDA 批准）和 F-18 脱氧葡萄糖已于 有结直肠癌病史且 CEA 升高的患者 通过常规放射线照相方式没有疾病证据。在 与 M. Brechbiel 和 NCI 放射肿瘤学小组合作， 我们在裸鼠模式下评估了稳定性和生物分布 2-(对硝基苄基)-反式-CyDTPA (CHX-DTPA) 的四种立体异构体。我们 已经证明立体化学的细微差异可能会导致 Y-90 标记的 CHX 的稳定性存在显着差异。从四 我们选择了最稳定的 Y-90 螯合立体异构体作为我们的 抗体试验的首选螯合物。