PRETARGETING STRATEGIES FOR CENTRAL NERVOUS MALIGNANCY RADIOIMMUNOTHERAPY

该提案的总体目标是提高临床实用性 用于治疗中枢神经系统的放射性标记单克隆抗体 (MAb) 肿瘤。 我们的假设是放射免疫治疗的疗效是 很大程度上取决于核素的类型和 MAb 标记方法 被使用。 在过去的几年里，我们制定了新颖的策略 用于用放射免疫疗法标记单克隆抗体并发射 β 粒子 组织中的最大范围为 102 毫米。 砹211因发射而衰变 α粒子的范围只有几个细胞直径和 比 β 粒子具有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选择。 氟18sis 正电子发射体和 18F 标记的 MAb 提供了有吸引力的 使用正电子发射断层扫描 (PET) 来定量 标记单克隆抗体的分布。 PET 成像可以提供更准确的 肿瘤和正常组织的剂量测定，极大地方便 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 尽可能迅速。 这些研究将使用嵌合体进行 Mel-14 及其碎片。 选择该 MAb 是因为它的潜力 用于治疗神经胶质瘤和黑色素瘤，特别是通过 瘤内和鞘内递送。 此外，选择 嵌合 Mel-14 得到了以下令人鼓舞的结果的支持 我们进行了广泛的临床前工作和临床试点研究 用小鼠 Mel-14 F(ab')2 进行。 该项目的具体目标是：a) 标记完整的嵌合 Mel-14 使用 N-琥珀酰亚胺基 [131I] 分析 IgG 及其片段与 131I、211At 和 18F 碘苯甲酸酯、[211At]阿斯塔基苯甲酸酯和[18F]氟苯甲酸酯， 分别，不损害免疫反应性； b) 确定 放射性卤化完整嵌合 Mel-14 及其药代动力学 人类皮下、颅内和肿瘤性脑膜炎的碎片 肿瘤异种移植模型； c) 研究体外放射毒性 131I-和211At-标记的完整嵌合mel-14及其片段在人体内 肿瘤2细胞系； d) 评估 131I 和 211At 标记的毒性 正常和无胸腺小鼠中完整的嵌合 Mel-14 及其片段；和 e) 确定完整嵌合 Mel-14 及其治疗潜力 皮下用等毒性剂量的 131I 和 211At 标记的片段， 颅内和肿瘤性脑膜炎人类肿瘤异种移植模型。

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.