PRETARGETING STRATEGIES FOR CENTRAL NERVOUS MALIGNANCY RADIOIMMUNOTHERAPY

中枢神经恶性肿瘤放射免疫治疗的预先靶向策略

• 批准号: 6474096
• 负责人: Michael Rod Zalutsky
• 金额: $ 31.4万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6474096
• 关键词: antitumor antibody; athymic mouse; biotin; central nervous system neoplasms; combination cancer therapy; disease /disorder model; drug screening /evaluation; glioma; hybrid antibody; immunoconjugates; iodine; laboratory mouse; method development; monoclonal antibody; neoplasm /cancer radioimmunotherapy; neoplasm /cancer transplantation; nonhuman therapy evaluation; pharmacokinetics; radiation therapy dosage; radionuclides; radiopharmacology; tenascin

The overall objective of this proposal is to improve the clinical utility of radiolabeled monoclonal antibodies (MAbs) for the treatment of CNS tumors. Our hypothesis is that the efficacy of radioimmunotherapy is critically dependent on the type of nuclide and MAb labeling method that are used. During the past few years, we have developed novel strategies for labeling MAbs with the radioimmunotherapy and emits beta-particles with a maximum range in tissue of 102 mm. Astatine-211 decays by the emission of alpha-particles, which have a range of only a few cell diameters and a higher relative biological effectiveness than beta-particles. This nuclide might be ideal for the treatment of neoplastic maningitis. Fluorine-18 sis a positron emitter, and MAbs labeled with 18F offer the attractive possibility of using positron emission tomography (PET) to quantitate the distribution of labeled MAbs. PET imaging could provide more accurate dosimetry for both tumor and normal tissues and greatly facilitate radioimmunotherapy planning. The goal of this work is to be able to transfer our radiohalogenation technologies to the clinical domain as expeditiously as possible. These studies will be performed using chimeric Mel-14 and its fragments. This MAb was selected because of its potential utility for the treatment of gliomas and melanomas, particularly via intratumoral and intrathecal delivery. In addition, the selection of chimeric Mel-14 is supported by the encouraging results obtained in extensive preclinical work and clinical pilot studies that we have performed with murine Mel-14 F(ab')2. The specific aims of this project are: a) to label intact chimeric Mel-14 IgG and its fragments with 131I, 211At, and 18F using N-succinimidyl [131I] iodobenzoate, [211At] astatobenzoate, and [18F] fluorobenzoate, respectively, without compromising immunoreactivity; b) to determine the pharmacokinetics of radiohalogenated intact chimeric Mel-14 and its fragments in subcutaneous, intracranial, and neoplastic meningitis human tumor xenograft models; c) to investigate the in vitro radiotoxicity of 131I- and 211At-labeled intact chimeric mel-14 and its fragments in human tumor 2 cell lines; d) to evaluate the toxicity of 131I- and 211At-labeled intact chimeric Mel-14 and its fragments in normal and athymic mice; and e) to determine the therapeutic potential of intact chimeric Mel-14 and its fragments labeled with equitoxic doses of 131I and 211At in subcutaneous, intracranial, and neoplastic meningitis human tumor xenograft models.

该提案的总体目的是改善临床公用事业 用于治疗中枢神经系统的放射性标记的单克隆抗体（mAb） 肿瘤。 我们的假设是放射免疫疗法的功效是 至关依赖于核素和mAb标记方法的类型 使用。 在过去的几年中，我们制定了新颖的策略 用于用放射免疫疗法标记mAb并用 102毫米的组织最大范围。 Astatine-211发射衰减 α粒子的绘制，它们的范围仅为几个细胞直径和一个 比β颗粒更高的相对生物学有效性。 这个核素 可能是治疗肿瘤性人道炎的理想选择。 氟-18 SIS 正电子发射极，并标有18F的mabs提供了吸引力 使用正电子发射断层扫描（PET）定量的可能性 标记的mAb的分布。 宠物成像可以提供更准确的 肿瘤和正常组织的剂量测定法，并极大地促进 放射免疫疗法计划。 这项工作的目的是能够 将我们的放射性化技术转移到临床领域 尽快。 这些研究将使用嵌合 Mel-14及其碎片。 选择此mAb是因为它的潜力 治疗神经胶质瘤和黑色素瘤的实用程序，特别是通过 肿瘤内和鞘内递送。 另外，选择 Chimeric MEL-14得到了获得的令人鼓舞的结果 我们拥有的广泛的临床前工作和临床试验研究 用Merine Mel-14 F（AB'）2进行。 该项目的具体目的是：a）标记完整的嵌合mel-14 IgG及其碎片，使用N-核酰亚胺基[131i]，具有131i，211AT和18F 碘苯甲酸盐，[211AT] astatobenzoate和[18f]氟苯甲酸盐， 分别不损害免疫反应性； b）确定 放射线式完整嵌合MEL-14的药代动力学及其 皮下，颅内和肿瘤性脑膜炎的碎片 肿瘤异种移植模型； c）研究体外放射性毒性的 131II和211AT标记的完整嵌合MEL-14及其在人类中的碎片 肿瘤2细胞系； d）评估131i和211at标记的毒性 完整的嵌合MEL-14及其在正常和无胸腺小鼠中的碎片；和e） 确定完整嵌合MEL-14及其的治疗潜力 在皮下，标记为131i和211AT的片段， 颅内和肿瘤性脑膜炎人类肿瘤异种移植模型。