RAIT OF LUNG CANCER WITH RESIDUALIZING LABELS

带有剩余化标签的肺癌类型

基本信息

批准号：
6150144
负责人：
RHONA N STEIN
金额：
$ 35.87万
依托单位：
CTR FOR MOLECULAR MEDICINE/IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-07-20 至 2002-01-31
项目状态：
已结题

项目摘要

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.

描述：放射免疫疗法（RAIT）原则上是一个有吸引力的癌症治疗的方式。但是，仍然存在许多不确定性关于这种模式的最佳实现，它正在成为越来越明显的是抗原后的抗体加工设计有效的抗体偶联物时必须考虑绑定免疫疗法。这对于放射性固定区的单克隆尤其重要抗体（mAb），因为放射性施加的mAb的分解代谢，然后是分解代谢物从靶细胞中扩散导致相对同位素在肿瘤部位的停留时间很短。总体该研究建议的目的是开发一个简单有效的将放射碘标签的残留形式引入mab的方法应用放射免疫疗法，并比较靶向和治疗剩余放射碘对常规碘的功效和放射线仪（治疗90Y或111英寸用于成像）。具体来说，我们将首先寻求寻找一种替代性结合化学反应将保留迄今为止我们工作中使用的DLT方法的好处（即，能够被困在细胞内，没有mab偶联物的聚集，改进的靶向和治疗），但将获得提高的收益较高的特异性活动产物。其次，我们将结合分析将片段使用到研究中。现在这是合适的碎片可以改善肿瘤渗透到肿瘤中，最近的工作 Behr等人的肾脏毒性升高，这已导致过去，由于使用放射性标记的MAB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了一项试点临床靶向研究。我们的先前的研究表明，动物模型中的优势显着使用剩余标签（YTTrium和Iodo-DLT）进行靶向和治疗肺的非小细胞癌。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肺癌是国家癌症计划的主要目标。我们的工作假设是增强的肿瘤靶向和治疗性快速内在化和缓慢内在化mAb的功效可能可以通过使用优化的缀合物来获得，以差异制备放射性同位素。