PRETARGETING STRATEGIES FOR CENTRAL NERVOUS MALIGNANCY RADIOIMMUNOTHERAPY

这项建议的总体目标是提高临床实用性。 放射性标记单抗在中枢神经系统治疗中的应用 肿瘤。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单抗标记方法 都被使用过。在过去的几年里，我们开发了新的战略 用于用放射免疫疗法标记单抗，并释放β粒子 组织的最大射程为102毫米。~(211)At因排放而衰变 阿尔法粒子，它的范围只有几个细胞直径和一个 比β粒子具有更高的相对生物学效应。这种核素 可能是治疗肿瘤性颌下炎的理想选择。氟-18综合征 一个正电子发射器，和标记有18F的单抗提供了诱人的 用正电子发射断层扫描(PET)定量检测 标记单抗的分布。PET成像可以提供更准确的 肿瘤和正常组织的剂量测定，极大地方便了 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，如 尽可能快。这些研究将使用嵌合体进行 MEL-14及其碎片。这种单抗之所以被选中，是因为它的潜力 用于治疗胶质瘤和黑色素瘤，特别是通过 瘤内和鞘内分娩。此外，评选 嵌合体MEL-14得到了#年取得的令人鼓舞的结果的支持。 我们有广泛的临床前工作和临床试点研究 用小鼠MEL-14F(ab‘)2. 该项目的具体目标是：a)标记完整的嵌合体MEL-14 用N-琥珀酰亚胺基[131I]结合~(131)I、~(211)At和~(18)F的免疫球蛋白及其片段 [~(211)At]碘苯甲酸酯和[18F]氟苯甲酸酯， 分别在不影响免疫反应性的情况下；b)确定 放射性卤化完整嵌合体Mel-14的药代动力学 人类皮下、颅内和肿瘤性脑膜炎的碎片 异种移植瘤模型；c)体外放射毒性研究 ~(131)I和~(211)At标记的人完整嵌合体Mel-14及其片段 肿瘤2细胞系；d)评价~(131)I和~(211)At标记的毒性 正常和正常小鼠中完整的嵌合Mel-14及其片段；和e) 确定完整嵌合体Mel-14及其基因的治疗潜力 皮下131I和211At等毒性剂量标记的碎片， 颅内和肿瘤性脑膜炎人肿瘤异种移植模型。

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.