ANTIBODY FUSION PROTEINS FOR THE THERAPY OF CANCER

用于癌症治疗的抗体融合蛋白

• 批准号: 2758242
• 负责人: Joseph David Rosenblatt
• 金额: $ 22.98万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-15 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2758242
• 关键词: SCID mouse; T cell receptor; antibody specificity; antigen antibody reaction; antitumor antibody; autoimmunity; cellular immunity; chemokine; chimeric proteins; cytotoxic T lymphocyte; genetically modified animals; laboratory mouse; leukocyte activation /transformation; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; nonhuman therapy evaluation; protein engineering; receptor binding; synthetic tumor antigen; tumor antigens

DESCRIPTION: (Applicant's Abstract) Minimal residual disease is a serious problem in the therapy of many common malignancies including breast, lung, ovarian and gastrointestinal cancer. More effective therapies are required to target minimal residual disease and micrometastases. The applicant believes that combined recruitment and costimulation using antibody fusion proteins may act synergistically to amplify host response to tumors. The applicant will synthesize antibody fusion molecules with variable domains directed against tumor associated antigens, such as CEA or her2/neu, linked to sequences encoding the chemokine RANTES and/or to the extracellular domain of the B7.1 T-cell costimulatory ligand. RANTES, a C-C chemokine acts to recruit T-cells and other immune effector cells to sites of inflammation. B7.1, the ligand for the CD28 costimulatory receptor acts to deliver a second signal required for T-cell activation following engagement of the T-cell receptor (TCR). Fusion with RANTES is designed to increase transendothelial migration and recruitment of the immune effector cells, while fusion with B7.1 is expected to activate a specific host response to tumor from effector cell population. The applicant will construct and purify novel antibody fusion proteins specific for the tumor-associated antigens, her2/neu and CEA, linked to the chemokine RANTES and/or the extracellular domain of the B7.1 costimulatory ligand. Two promising fusions to RANTES and to B7.1 have already been constructed and are being actively characterized. He will evaluate the immunoreactivity, receptor binding properties and biological activity of fusion proteins in vitro. RANTES fusions will be studied for antigen binding, binding to cellular receptors, and for ability to elicit chemotaxis. B7.1 fusion proteins will be characterized for ability to bind to antigen, cognate cellular receptors (CTLA4 and CD28), and to deliver a co-stimulatory signal in vitro. He will characterize the properties of the recombinant fusion proteins in vivo and their effectiveness in causing tumor rejection. Localization of radiolabelled fusion proteins in vivo will be studied in SCID mice implanted with her2/neu or CEA expressing and non-expressing tumors. Tumor models that express the target antigens will be studied in immunologically competent syngeneic mice. Fusion proteins will be tested for efficacy in eliciting tumor rejection and a cytolytic T-cell response. Both CEA and her2/neu are expressed at low levels in certain normal tissues. Therefore, the applicant will model efficacy and potential toxicity of anti CEA fusion proteins in a transgenic CEA mouse. The use of antibody fusion proteins may overcome limitations of gene transfer and/or standard antibody therapy and represents a promising approach to the problem of minimal residual disease.

描述：（申请人的摘要）最小残留疾病是 许多常见恶性肿瘤的治疗中的严重问题 乳腺癌，肺，卵巢和胃肠道癌。更有效 靶向最小残留疾病和 微型转移。申请人认为合并招聘和 使用抗体融合蛋白进行共刺激可能会协同作用 扩增宿主对肿瘤的反应。申请人将合成抗体 具有针对肿瘤相关的可变结构域的融合分子 抗原（例如CEA或HER2/NEU）与编码的序列有关 趋化因子和/或到B7.1 T细胞的细胞外结构域 共刺激配体。 rantes，c-c趋化因子起作用招募T细胞 以及其他免疫效应细胞到炎症部位。 B7.1， CD28共刺激受体作用的配体提供了第二个 T细胞参与后T细胞激活所需的信号 受体（TCR）。与Rantes融合旨在增加 免疫效应细胞的跨内皮迁移和募集 虽然预计与B7.1的融合会激活特定的宿主响应 来自效应细胞群的肿瘤。申请人将构建和 纯化针对肿瘤相关的新型抗体融合蛋白 抗原，HER2/NEU和CEA，与趋化因子和/或 B7.1共刺激配体的细胞外结构域。两个有希望的 与Rantes和B7.1的融合已经建成，正在 被积极特征。他将评估免疫反应性， 融合蛋白的受体结合特性和生物学活性 体外。将研究Rantes融合以进行抗原结合，结合 到细胞受体，以及能够引起趋化性的能力。 B7.1融合 蛋白质的特征是与抗原结合的能力 细胞受体（CTLA4和CD28），并提供共同刺激 体外信号。他将表征重组的特性 体内融合蛋白及其在引起肿瘤的有效性 拒绝。放射性标记融合蛋白在体内的定位将 在用HER2/NEU或CEA表达的SCID小鼠中研究 非表达肿瘤。表达靶抗原的肿瘤模型 将在具有免疫学胜任的合成小鼠中进行研究。融合 将测试蛋白质在引起肿瘤排斥和 细胞溶解T细胞反应。 CEA和HER2/NEU均以低表达 在某些正常组织中的水平。因此，申请人将建模 抗CEA融合蛋白在A中的功效和潜在毒性 转基因CEA小鼠。抗体融合蛋白的使用可能会克服 基因转移和/或标准抗体疗法的局限性以及 代表了最小残留问题的一种有希望的方法 疾病。