Lutetium-177 Radiolabeled Antibodies for the Treatment of CNS Malignancies

靶向放射治疗利用一种分子载体选择性地将放射性核素输送到恶性细胞群体，目前最有希望的方法是使用放射性标记的单抗(MAb)。我们自己在新诊断和复发的胶质瘤患者中的研究表明，将131I标记的抗Tenascin 81C6单抗直接注射到手术创建的切除腔中，可以显著延长中位生存期。虽然取得了令人鼓舞的成果，但情况有了很大改善 在放射免疫治疗对中枢神经系统肿瘤患者的临床治疗产生重大影响之前，将需要进行标记单抗治疗。碘-131之所以被用作标记，是因为它的低能f3粒子与治疗相对较小的肿瘤很好地匹配；然而，它的81%丰度、364keV的伽马射线存在问题，因为它会增加对正常器官的辐射剂量，特别是大脑，延长患者的禁闭时间，并且不适合成像。这项研究计划旨在开发177Lu作为低能Beta的潜力。 用于中枢神经系统肿瘤放射免疫治疗的131I替代物。这种6.7天半衰期的放射性核素之所以吸引人，是因为它的伽马辐射在能量和丰度上都比131I低得多。它的金属特性可能被用来设计更好的标记内化单抗的方法，例如那些与突变的表皮生长因子受体变异体III(EGFRvIII)反应的单抗。我们的具体目标是：1)用177Lu标记抗Tenascin嵌合的81C6单抗和F(ab‘)2片段，并评价其作为中枢神经系统肿瘤靶向放射治疗的可能性。建议的研究包括免疫反应性的表征。 研究内容包括：1)研究EGFRvIII抗体在小鼠体内的组织分布和剂量学特性；2)研究EGFRvIII抗体在小鼠体内的组织分布和剂量学特性；2)评价抗EGFRvIII抗体在小鼠体内的组织分布和剂量学特征；2)评价其作为中枢神经系统肿瘤靶向放射治疗药物的潜能。有希望的方法将按照具体目标1)进行评估；3)通过使用多肽连接物开发改进的177Lu标记方法；以及4)研究在体外肿瘤细胞和体内肿瘤和正常组织中产生的标记分解代谢物的性质，并利用这些数据作为开发改进的177Lu标记单抗方法的指南。

Targeted radiotherapeutics utilize a molecular vehicle to selectively deliver radionuclides to malignant cell populations, with the most promising current approach being the use of radiolabeled monoclonal antibodies (MAbs). Our own studies in newly diagnosed and recurrent glioma patients have demonstrated that significant prolongation in median survival can be achieved with direct injection of 131I-labeled anti-tenascin 81 C6 MAb into surgically created resection cavities. Although encouraging results have been obtained, significant improvements in labeled MAb therapy will be required before radioimmunotherapy has a major impact on the clinical management of CNS tumor patients. Iodine-131 was utilized as the label because its low energy f3-particles are well matched to treating relatively small tumors; however, its 81%-abundant, 364-keV gamma-ray is problematic because it can increase radiation dose to normal organs, particularly the brain, prolongs patient confinement, and is not ideal for imaging. This research proposal is directed at developing the potential of 177Lu as a low-energy beta- emitting alternative to 131I for central nervous system tumor radioimmunotherapy. This 6.7-day half-life radionuclide is attractive because its gamma-emissions are considerably lower in energy and abundance than those of 131I. Its metallic character might be exploitable in designing better methods for labeling internalizing MAbs such as those reactive with the mutant epidermal growth factor receptor variant III (EGFRvIII). Our specific aims are: 1) to label anti-tenascin chimeric 81C6 MAb and F(ab')2 fragment with 177Lu and evaluate their potential as targeted radiotherapeutics for CNS tumors. The proposed studies include characterization of immunoreactivity and affinity; evaluation of tissue distribution and dosimetry in normal mice, and athymic rodents with subcutaneous, intracranial and neoplastic meningitis xenografts; and evaluation of therapeutic efficacy in these rodent xenograft models; 2) to label anti-EGFRvIII constructs with 177Lu and evaluate their potential as targeted radiotherapeutics for CNS tumors. Promising methods will be evaluated as outlined in Specific Aim 1; 3) to develop improved 177Lu labeling methodologies through the use of peptide linkers; and 4) to investigate the nature of the labeled catabolites generated in tumor cells in vitro and tumor and normal tissues in vivo and use these data as a guide for developing improved methods for labeling MAbs with 177Lu.