MAB-CYTOKINE R-ALPHA FUSIONS TO DELIVER ARMED LIGAND

MAB-细胞因子 R-α 融合以提供武装配体

• 批准号: 2772057
• 负责人: JACK D BURTON
• 金额: $ 16.12万
• 依托单位: CTR FOR MOLECULAR MEDICINE/IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2772057
• 关键词: autoimmune disorder; breast neoplasms; chemotherapy; chimeric proteins; colon neoplasms; cytokine; cytokine receptors; diabetes mellitus; diabetes mellitus therapy; diagnosis design /evaluation; drug delivery systems; gastrointestinal disorder chemotherapy; immunotherapy; inflammatory bowel diseases; ligands; lung neoplasms; monoclonal antibody; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; prostate neoplasms; rheumatoid arthritis; skeletal disorder chemotherapy; transplantation; tumor antigens

DESCRIPTION (Adapted from the applicant's abstract): Traditional approaches to administration of drugs and other therapeutic agents for the treatment of disease often use a systemic route. This exposes pathologic cell populations and normal tissues nonspecifically to these agents. If active agents for a given disease have only a low therapeutic index, treatment may either be ineffective or be associated with serious side effects. This situation obtains for a wide range of malignancies (such as cancers of the lung, breast, prostate and colon), as well as for a variety of immune-mediated and inflammatory conditions. Among these latter conditions are disease states such as autoimmune diabetic states, organ transplantation, bone marrow transplantation, inflammatory bowel disease, and other autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis). The problem is addressed in this application with an innovative approach to intracellular delivery of drugs or other agents that could ultimately be applied to the diagnosis and therapy of the diseases listed above. This approach involves the utilization of fusion molecule consisting of a single chain monoclonal antibody and the ligand-binding domain of selected cytokine receptors. This fusion protein will be used to target pathogenic cell populations. Therapeutic or diagnostic agents linked to the cognate cytokine will then be given. This capitalizes on the specificity of the ligand/receptor interactions; the rapid, efficient internalization of these receptors, and allows for a high-level cell surface antigen to be targeted to substantially increase the number of cytokine receptors over their low background level. This application, specifically, seeks to advance the initial efforts made by researchers by constructing and expressing antibody-receptor fusion proteins as well as armed forms of the cognate ligands. After construction and expression, their function will be tested in vitro on an ultimate path towards pre-clinical and clinical evaluation in a variety of disease models and conditions.

描述（改编自申请人摘要）：传统方法 涉及用于治疗以下疾病的药物和其它治疗剂的给药 疾病通常通过全身途径传播。 这暴露了病理细胞 人群和正常组织对这些试剂无特异性。 如果活动 对于给定的疾病，药剂仅具有低的治疗指数，治疗可 要么无效，要么有严重的副作用。 这 对于广泛的恶性肿瘤（如乳腺癌）， 肺、乳腺、前列腺和结肠），以及各种 免疫介导的和炎性病症。 在后一种情况中， 是疾病状态，例如自身免疫性糖尿病状态、器官 移植，骨髓移植，炎症性肠病， 和其它自身免疫性疾病（例如，系统性红斑狼疮， 类风湿性关节炎）。 在本申请中，通过创新的方法来解决该问题， 药物或其它试剂的细胞内递送， 应用于上述疾病的诊断和治疗。 这 该方法涉及利用由单个 单链单克隆抗体和所选细胞因子的配体结合结构域 受体。 该融合蛋白将用于靶向致病细胞 人口。 与同源物相关的治疗或诊断剂 然后给予细胞因子。 这充分利用了 配体/受体相互作用;这些相互作用的快速，有效的内化 受体，并允许高水平的细胞表面抗原被靶向 以显著增加细胞因子受体的数量， 背景水平。 本申请具体地寻求推进 研究人员通过构建和表达 抗体-受体融合蛋白以及同源物的武装形式 配体。 在构建和表达后，将测试它们的功能 在体外进行临床前和临床评价， 各种疾病模型和条件。