Lutetium-177 Radiolabeled Antibodies for the Treatment of CNS Malignancies

靶向放射治疗利用分子载体选择性地向恶性细胞群递送放射性核素，目前最有前途的方法是使用放射性标记的单克隆抗体（mab）。我们自己对新诊断和复发胶质瘤患者的研究表明，通过将131i标记的抗tenascin 81 C6 MAb直接注射到手术制造的切除腔中，可以显著延长中位生存期。虽然取得了令人鼓舞的结果，但仍有重大改进

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.