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: 6354776
• 负责人: Michael Rod Zalutsky
• 金额: $ 28.83万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2001-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6354776
• 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 immunotherapy; neoplasm /cancer radionuclide therapy; 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.

本提案的总体目标是提高临床实用性 放射性标记的单克隆抗体（MAb）用于治疗CNS 肿瘤的 我们的假设是放射免疫疗法的疗效是 严重依赖于核素的类型和MAb标记方法， 被使用。 在过去的几年里，我们制定了新的战略， 用于用放射免疫疗法标记单克隆抗体，并发射β-颗粒， 在组织中的最大范围为102 mm。 α粒子，其范围仅为几个细胞直径， 比β粒子更高的相对生物有效性。 这种核素 可能是治疗肿瘤性脑膜炎的理想药物 氟-18sis 一个正电子发射体，用18F标记的单克隆抗体提供了有吸引力的 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。 PET成像可以提供更准确的 肿瘤和正常组织的剂量测定， 放射免疫治疗计划 这项工作的目标是能够 将我们的放射性卤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。 选择该单克隆抗体是因为其潜在的 用于治疗神经胶质瘤和黑色素瘤，特别是通过 肿瘤内和鞘内递送。 此外，选择 嵌合Mel-14得到了令人鼓舞的结果的支持 广泛的临床前工作和临床试点研究， 用鼠Mel-14 F（ab ′）2进行。 本项目的具体目标是：a）标记完整的嵌合Mel-14 使用N-琥珀酰亚胺基[131 I]的IgG及其131 I、211 At和18 F片段 碘苯甲酸盐、[211 At]阿司他苯甲酸盐和[18F]氟苯甲酸盐， B）测定免疫反应性， 放射性卤化的完整嵌合Mel-14的药代动力学及其 人类皮下、颅内和肿瘤性脑膜炎中的碎片 肿瘤异种移植模型; c）研究 131 I和211 At标记的人体完整嵌合mel-14及其片段 肿瘤2细胞系; d）评估131 I-和211 At-标记的毒性 正常和无胸腺小鼠中的完整嵌合Mel-14及其片段;和e） 为了确定完整嵌合Mel-14的治疗潜力， 用等毒性剂量的131 I和211 At标记的片段， 颅内和肿瘤性脑膜炎人肿瘤异种移植物模型。