RAIT OF LUNG CANCER WITH RESIDUALIZING LABELS

描述：放射免疫疗法(RAIT)原则上是一种有吸引力的 癌症治疗的方式。然而，许多不确定性依然存在。 关于这一模式的最佳实施，它正在成为 越来越明显的是，在处理抗原之后的抗体 在设计有效的抗体结合物时必须考虑结合 免疫疗法。这对于放射性碘标记的单抗来说尤其重要。 抗体(MAb)，因为放射性碘标记的MAb随后分解代谢 分解代谢产物扩散出靶细胞会导致相对的 同位素在肿瘤部位的停留时间较短。整体而言 本研究建议的目的是开发一种简单高效的 一种将残留形式的放射性碘标记引入单抗的方法 放射免疫治疗中的应用及靶向治疗与治疗的比较 放射性碘残留剂与常规碘的疗效比较 放射性金属(90y用于治疗或111in用于成像)。具体来说，我们 将从寻找一种替代的共轭化学开始 将保留我们迄今在工作中使用的DLT方法的好处 (即，被捕获在细胞内的能力，没有单抗结合物的聚集， 改进的靶向和治疗)，但将提供更高的产量 比活度较高的产品。其次，我们将结合一项分析 在研究中使用了碎片。现在这样做是合适的，因为 碎片可以改善肿瘤对肿瘤的穿透能力，最近的工作 Behr等人的研究表明，肾脏毒性增加，导致 过去使用放射性标记的单抗碎片，可以减少 使用阳离子氨基酸及其衍生物。除了这些之外， 在实验室研究的基础上，计划进行一项试点临床靶向研究。我们的 以前的研究表明，在动物模型中， 使用残留标记(Y和碘-DLT)进行靶向和治疗 非小细胞肺癌。这项拟议的临床研究将 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的靶向性和治疗性 单抗快速内化和缓慢内化的疗效可能 通过使用优化的偶合物，通过残留法制备而得到 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.