TARGET ANTIGENS--IMMUNE-BASED THERAPY FOR BREAST CANCER

这个合作项目的总体目标是了解 乳腺肿瘤引起的体液反应机制 并将其用于乳腺癌治疗。 的 B细胞鉴定 参与此响应的克隆将允许使用其 产生陈旧的转染细胞系的遗传信息， 结合乳腺肿瘤抗原的人单克隆抗体。的 参与患者免疫应答的表位/抗原的鉴定 对肿瘤的识别将有助于阐明 体液和细胞免疫应答可以控制肿瘤生长， 传播. 关于抗原功能的信息可以开辟新的领域， 与乳腺癌的免疫控制、预防和治疗相关的研究 癌 该项目的具体目标是：1。定义表位结构 在乳腺粘蛋白串联重复结构域上， 放射免疫治疗和免疫识别的靶点，并确定 在乳腺肿瘤细胞中改变其加工过程的因素。2. 研究46 kDa乳腺糖蛋白，鉴定其表位结构域 为治疗提供最佳靶点，并探索其可能性 旁分泌/自分泌功能。3.表征抗原及其 产生的人和F-v移植的MoAb识别的表位。 抗乳腺粘蛋白和46 kDa HMFG糖蛋白的某些单克隆抗体 在放射免疫治疗中有效。 由于加工过程的改变 对于乳腺粘蛋白，串联重复结构域中的一些表位是 优先在乳腺癌中表达，因此某些MoAb 识别这些通常隐藏的表位比识别这些通常隐藏的表位更有效。 另一些用于乳腺癌患者的转移成像。 虽然可能性不大 在46 kDa抗原的情况下，一些抗它的单克隆抗体要多得多， 在临床前RIT研究中， 我们的cDNA克隆 研究表明，46 kDa抗原具有提示自身免疫的结构域， 或旁分泌功能：含有细胞附着的C末端结构域 和EGF样序列以及与EGF样序列同源的N-末端结构域。 人凝血因子V的磷脂结合C1-C2区和 八. 在其他项目中制备的人类单克隆抗体可以识别 如果是这样，则精确的表位将 被确定。 如果鉴定出新的抗原， cDNA将被克隆和测序。 将通过以下方法分析表位： 表位作图和重组抗原的产生及其 片段作为嵌合蛋白。 假设表位结构 知识可以预测RIT的有效性，将通过生产进行检验 使用选择性构建的表位结构， 免疫和选择。 治疗效果将是 临床前测试

The overall goal of this collaborative project is an understanding of mechanisms involved in the humoral response created by a breast tumor in its human host and employing them for breast cancer therapy. The identification of B-cell clones participating in this response will allow the use of their genetic information to produce stale transfected cell lines secreting human monoclonal antibodies binding antigens on breast tumors. The identification of epitopes/antigens involved in the patient's immune recognition of the tumor will shed light on the mechanism by which humoral and cellular immune response can control tumor growth and spread. Information on the antigens' function can open new areas of research related to immune control, prevention, and therapy of breast cancer. The Specific Aims of this project are: 1. Define the epitope structures on the breast mucin tandem repeat domain that are the most effective targets for radioimmunotherapy and immune recognition, and determine factors involved in its altered processing in breast tumor cells. 2. Study the 46 kDa breast glycoprotein, identifying its epitopic domains that provide the best targets for therapy, and explore its possible paracrine/autocrine function. 3. Characterize the antigens and their epitopes recognized by human and F-v grafted MoAbs produced. Certain MoAbs against the breast mucin and the 46 kDa HMFG glycoprotein are effective in radioimmunotherapy. Because of the altered processing of the breast mucin some epitopes in the tandem repeat domain are preferentially expressed in breast carcinomas, and thus certain MoAbs recognizing these normally cryptic epitopes are more effective than others in imaging metastases in breast cancer patients. Also, in the case of the 46 kDa antigen, some MoAbs against it are much more effective than others in preclinical RIT studies. Our cDNA cloning studies show that the 46 kDa antigen has domains suggesting an auto- or paracrine function: a C-terminal domain containing cell attachment and EGF-like sequences and a N-terminal domain homologous to the phospolipid-binding C1 C2 regions of human coagulation factors V and VIII. The human MoAbs prepared in the other projects may identify epitopes on these latter two antigens, if so, the precise epitopes will be determined. If new antigens are identified other antigens their cDNAs will be cloned and sequenced. The epitopes will be analyzed by epitope mapping and production of recombinant antigens and their fragments as chimeric proteins. The hypothesis that epitope structural knowledge can predict effectiveness in RIT will be tested by production of new MoAbs using selectively constructed epitopic structures for immunization and selection. The therapeutic effectiveness will be tested preclinically.