TARGET ANTIGENS--IMMUNE-BASED THERAPY FOR BREAST CANCER

该协作项目的总体目标是了解 乳腺肿瘤引起体液反应的机制 在人类宿主中，并将其用于乳腺癌治疗。这个 B细胞的鉴定 参与此响应的克隆将允许使用其 遗传信息产生陈旧的转基因细胞系分泌 乳腺肿瘤上的人源性单抗结合抗原。这个 患者免疫相关表位/抗原的鉴定 对肿瘤的识别将有助于阐明 体液和细胞免疫反应可控制肿瘤生长和 散开。有关抗原功能的信息可以开辟新的领域 关于乳房免疫控制、预防和治疗的研究 癌症。 本项目的具体目标是：1.确定表位结构 在乳房粘蛋白串联重复结构域上最有效的 放射免疫治疗和免疫识别的靶点，并确定 参与其在乳腺肿瘤细胞中改变加工的因素。2. 研究46 kDa胸膜糖蛋白，确定其表位结构域 为治疗提供最好的靶点，并探索其可能性 旁分泌/自分泌功能。3.鉴定抗原和它们的 人识别表位和F-v嫁接单抗的产生。 某些抗乳腺粘蛋白和46 kDa HMFG糖蛋白的单抗 在放射免疫治疗中是有效的。因为加工过程发生了变化 对于乳房粘蛋白，串联重复结构域中的一些表位是 在乳腺癌中优先表达，因此某些MoAbs 识别这些通常难以捉摸的表位比 其他人则在乳腺癌患者的转移成像中。此外，在 在46 kDa抗原的情况下，一些抗它的抗体要多得多 在临床前RIT研究中比其他人更有效。我们的基因克隆 研究表明，46 kDa的抗原具有暗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样序列以及与其同源的N末端结构域 人凝血因子V和磷脂结合C_1、C_2区 。其他项目中制备的人MoAbs可能会识别 这两个抗原上的表位，如果是这样的话，准确的表位将 要下定决心。如果发现新的抗原，则会发现它们的其他抗原 将克隆和测序cDNA。表位的分析将由 重组抗原及其抗原表位的定位和制备 片段作为嵌合蛋白。关于表位结构的假设 知识可以预测RIT的有效性将被生产检验 使用选择性构建的表位结构的新型MoAbs 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.