NEW ANTIBODY TARGETS IN HUMAN BREAST CANCER STROMA

人类乳腺癌基质中的新抗体靶点

基本信息

批准号：
3201819
负责人：
WOLFGANG J RETTIG
金额：
$ 0.03万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-12-16 至 1994-01-31
项目状态：
已结题

项目摘要

Our objective in this proposal is to apply immunologic techniques and principles to the study, detection, and therapy of breast cancer as part of an integrated laboratory and clinical effort combining immunologic, biochemical, molecular, and cell biologic approaches. In the past, the search for monoclonal antibody (mAb) targets in breast cancer focused on surface molecules of transformed mammary epithelium, but most of these epithelial markers show shortcomings related to variable expression in tumors (heterogeneity), presence in normal tissues or serum, or poor accessibility to circulating mAbs. Recently, new emphasis has been placed on alternative mAb targets in th abundant stromal compartment of breast carcinomas, including antigens of reactive stromal fibroblasts and of tumor capillary endothelial cells. Aim I focuses on the identification of new antigenic targets in breast cancer stoma, i.e. cell surface antigens of reactive stromal fibroblast and tumor capillaries. Prototypes for this category of tumor stromal antigens are the fibroblast activation protein, FAP, abundantly expressed in reactive fibroblasts of >90% of breast cancers; and endosialin, expressed in tumor capillaries of 60-70% of malignant solid tumors; additional stromal antigens are likely to be identified. The normal tissue distribution of tumor stromal antigens and their expression in benign, premalignant, and malignant breast lesions in patients in various stages of their disease will be documented by immunohistochemistry. Aim II will define the molecular structure of FAP, endosialin, and other antigens in breast cancer stroma, based on biochemical and gene cloning studies. For selected molecules, homologues in other species will be identified to design xenograft models of tumor stromal targeting. Aim III will explore stromal antigen function and mAb antigen interactions through cell biologic approaches. The newly derived serologic and DNA probes will be used to study the regulation of tumor stroma formation and activation, with emphasis on the role of soluble factors produced by malignant breast epithelial cells. The function of tumor stromal antigens may be discovered through sequence analysis or through blocking experiments with mAbs and antisense oligonucleotides in cultured cell models. The effects of first and second-generation mAbs and mAb-conjugates mediating immunologic and nonimmunologic effector functions, the fate of bound mAbs (internalization, processing), and imaging characteristics of radiolabeled mAbs in mouse xenograft models will also be examined. One of the main objectives is to develop a cocktail of humanized mAbs that can be used to target breast cancers, including existing mAbs against malignant epithelial cells and mAbs against reactive fibroblast or tumor capillary antigens. These mAbs may be used as adjuvant therapy in patients with minimal residual disease after surgery or chemotherapy. Pursuing these three aims should result in new concepts, new reagents, and new approaches to the detection and therapy of breast cancer.

我们在此提案中的目标是应用免疫学技术和作为研究，检测和治疗乳腺癌的原则一种结合免疫学的综合实验室和临床工作，生化，分子和细胞生物学方法。过去，在乳腺癌中搜索乳腺癌中的单克隆抗体（MAB）靶标转化的乳腺上皮的表面分子，但大多数上皮标记显示与可变表达相关的缺点肿瘤（异质性），正常组织或血清或较差循环mAb的可访问性。最近，新的重点已放置在乳房大量基质室中的替代mAb靶癌，包括反应性基质成纤维细胞和肿瘤的抗原毛细管内皮细胞。目的我专注于新的识别乳腺癌造口的抗原靶标，即反应性基质成纤维细胞和肿瘤毛细血管。原型肿瘤基质抗原的类别是成纤维细胞激活蛋白， FAP，以> 90％的乳房的反应性成纤维细胞表达大量表达癌症；和内塞林，以60-70％的肿瘤毛细血管表达恶性实体瘤；其他基质抗原可能是确定。肿瘤基质抗原的正常组织分布和它们在良性，预先预先和恶性乳房病变中的表达处于疾病各个阶段的患者将记录在案免疫组织化学。 AIM II将定义FAP的分子结构，基于生化和基因克隆研究。对于选定的分子，同源物在其他物种中，将确定设计肿瘤的异种移植模型基质靶向。 AIM III将探索基质抗原功能和mAb 通过细胞生物学方法进行抗原相互作用。新得出的血清学和DNA探针将用于研究肿瘤的调节基质形成和激活，重点是可溶性的作用恶性乳房上皮细胞产生的因素。功能可以通过序列分析或通过阻断用mAb和反义寡核苷酸的实验培养的细胞模型。第一代和第二代mab的影响以及 mab偶联的介导免疫学和非免疫效应子功能，绑定mab的命运（内部化，处理）和成像小鼠异种移植模型中放射性标记的mAb的特征也将是检查。主要目标之一是开发人源化的鸡尾酒可以用来靶向乳腺癌的mAB，包括现有mAb 针对恶性上皮细胞和mAb反对反应性成纤维细胞或肿瘤毛细血管抗原。这些mAb可以用作辅助治疗手术或化学疗法后残留疾病最小的患者。追求这三个目标应导致新概念，新试剂和乳腺癌检测和治疗的新方法。