RAIT OF LUNG CANCER WITH RESIDUALIZING LABELS

描述：放射免疫疗法（赖特）原则上是一种有吸引力的 癌症治疗的方式。 然而，许多不确定因素仍然存在 关于这种模式的最佳实施，它正在成为 越来越明显的是， 当设计有效的抗体偶联物时， 免疫疗法 这对于放射性碘标记的单克隆抗体尤其重要。 抗体（MAbs），因为放射性碘标记的MAbs的催化剂， 催化剂从靶细胞中扩散出来， 同位素在肿瘤部位的停留时间短。 整体 本研究的目的是开发一种简单有效的 将放射性碘标记的残基化形式引入单克隆抗体中以 在放射免疫治疗中的应用，并比较靶向和治疗性 残留放射性碘对常规碘的效果 和放射性金属（90 Y用于治疗或111 In用于成像）。 我们特别 将开始寻求找到一种替代的共轭化学， 将保留我们迄今为止工作中使用的DLT方法的优点 (i.e.,被捕获在细胞内的能力，没有MAb-缀合物的聚集， 改进的靶向和治疗），但将提供增加的产量， 高比活度产品。 其次，我们将分析 将碎片的使用融入到研究中 这是适当的，因为 片段允许改善肿瘤对肿瘤的渗透， Behr等人，已经表明肾毒性的增加， 在过去使用的放射性标记的单克隆抗体片段，可以减少 使用阳离子氨基酸及其衍生物。 除了这些 实验室研究，计划进行一项试点临床靶向研究。 我们 先前的研究已经显示出在动物模型中的显著优势， 残留标记物（钇和碘-DLT）用于靶向和治疗的用途 非小细胞肺癌 本临床研究将 评估这些结果是否可以转化为临床管理 非小细胞肺癌，这是国家癌症计划的主要目标。 我们的工作假设是，增强肿瘤靶向和治疗 快速内化和缓慢内化MAb的功效可 通过使用优化的缀合物获得， 放射性同位素

DESCRIPTION: Radioimmunotherapy (RAIT) is, in principle, an attractive modality for cancer treatment. However, many uncertainties remain concerning the optimal implementation of this modality, and it is becoming increasingly apparent that the processing of antibodies after antigen binding must be considered when designing effective antibody conjugates for immunotherapy. This is especially important for radioiodinated monoclonal antibodies (MAbs), because catabolism of radioiodinated MAbs followed by diffusion of the catabolites out of the target cells leads to a relatively short residence time of the isotope at the tumor site. The overall objective of this research proposal is to develop a simple and efficient method to introduce a residualizing form of radioiodine label into MAbs for application in radioimmunotherapy, and to compare targeting and therapeutic efficacy of the residualizing radioiodine to those of conventional iodine and radiometal (90Y for therapy or 111In for imaging). Specifically, we will begin by seeking to find an alternative conjugation chemistry which will retain the benefits of the DLT methodology used in our work thus far (i.e., ability to be trapped inside cells, no aggregation of MAb-conjugates, improved targeting and therapy), yet will afford an increased yield of a higher specific activity product. Secondly, we will incorporate an analysis of the use of the fragments into the study. This is now appropriate since fragments allow improved tumor penetration into tumors, and the recent work of Behr, et al., has shown that elevated kidney toxicity, which has resulted in the past from the use of the radiolabeled MAb fragments, can be reduced using cationic amino acids and their derivatives. In addition to these laboratory studies, a pilot clinical targeting study is planned. Our previous studies have shown a marked advantage in the animal model in the use of residualizing labels (yttrium and iodo-DLT) for targeting and therapy of non-small cell carcinoma of the lung. This proposed clinical study will evaluate whether these results can be translated to the clinical management of non-small lung cancer, which is a major goal of the National Cancer Plan. Our working hypothesis is that enhanced tumor targeting and therapeutic efficacy with both rapidly internalizing and slowly internalizing MAbs may be obtained by using optimized conjugates, prepared with residualizing radioisotopes.