TARGETED IMMUNOTHERAPY FOR TUMOR EXPRESSING GRP RECEPTOR

针对表达 GRP 受体的肿瘤的靶向免疫治疗

• 批准号: 6073849
• 负责人: Tibor P Keler
• 金额: $ 10万
• 依托单位: MEDAREX, INC.
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6073849
• 关键词: antibody receptor; breast neoplasms; cell mediated cytotoxicity; chimeric proteins; drug design /synthesis /production; enzyme linked immunosorbent assay; flow cytometry; gastrin releasing peptide; genetically modified animals; human tissue; immunoglobulin A; immunological substance; laboratory mouse; monoclonal antibody; neoplasm /cancer immunotherapy; neuropeptide receptor; pharmacokinetics; small cell lung cancer

Gastrin-Releasing Protein (GRP) is the mammalian analog of bombesin, a 14- amino acid peptide initially isolated from the skin of the frog Bombina bombina. GRP receptors are expressed on a variety of human tumors including small cell carcinoma of the lung (SCCL), and breast cancer, but are rarely present on normal cells. Previous studies have shown that an immunoconjugate between CRP and a monoclonal antibody against the receptor for immunoglobulin (expressed on normal monocytes, macrophages, and lymphocytes) can solicit a specific antibody-dependent cell-mediated cytotoxicity (ADCC) directed towards SCCL cells. The mechanism of action is to bring into proximity targeted tumor cells and immune competent elements in the patient. The category of bifunctional proteins can be produced by different methods, such as fusion of the monoclonal antibody and GRP molecule, or by chemically linking the structures together. It is also possible that other surface makers can be used in the linkage. Thus, the specific aim for this Phase I SBIR application is to investigate whether or not different methods for producing the bifunctional molecules [fusion versus chemical linkage, and receptor for immunoglobulins (Fc-gamma-RI versus Fc-alpha-R)] can affect the effectiveness of the conjugates. PROPOSED COMMERCIAL APPLICATIONS: This research will lead to potentially therapeutic and minimally toxic agents for the treatment of small cell carcinomas of the lung and other GRP-receptor expressing tumors. Development of such therapeutics are greatly needed for SCCL for which currently available treatments provide only short-term remissions.

胃泌素释放蛋白（GRP）是蛙皮素（bombesin）的哺乳动物类似物，蛙皮素是一种最初从青蛙Bombina bombina皮肤中分离出来的14个氨基酸的肽。 GRP受体在多种人类肿瘤上表达，包括肺小细胞癌（SCCL）和乳腺癌，但很少存在于正常细胞上。 先前的研究表明，CRP和针对免疫球蛋白受体（在正常单核细胞、巨噬细胞和淋巴细胞上表达）的单克隆抗体之间的免疫缀合物可以引起针对SCCL细胞的特异性抗体依赖性细胞介导的细胞毒性（ADCC）。作用机制是使靶向肿瘤细胞与患者体内的免疫活性成分接近。 双功能蛋白的种类可以通过不同的方法产生，例如单克隆抗体和GRP分子的融合，或通过化学连接结构在一起。也可以在连接中使用其它表面标记。因此，该I期SBIR申请的具体目的是研究用于产生双功能分子[融合与化学连接，以及免疫球蛋白受体（Fc-γ-RI与Fc-α-R）]的不同方法是否会影响缀合物的有效性。拟议的商业应用：这项研究将导致潜在的治疗和最低毒性的药物治疗小细胞肺癌和其他GRP受体表达肿瘤。SCCL非常需要开发此类治疗剂，目前可用的治疗仅提供短期缓解。