Novel Immunoadhesin Molecule for Cancer Therapy

用于癌症治疗的新型免疫粘附素分子

• 批准号: 6689339
• 负责人: K Jin Kim
• 金额: $ 10.6万
• 依托单位: PANORAMA RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-16 至 2004-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6689339
• 关键词: adhesin; angiogenesis; chimeric proteins; drug design /synthesis /production; growth factor receptors; hepatocyte growth factor; human genetic material tag; immunoglobulin G; immunoglobulin structure; immunopharmacology; inhibitor /antagonist; neoplasm /cancer blood supply; neoplasm /cancer chemotherapy; neoplastic process; peptide chemical synthesis; protein protein interaction; protein purification; receptor binding; transfection /expression vector

DESCRIPTION (provided by applicant): Hepatocyte growth factor (HGF) and its receptor, c-Met, are known to play an important role in tumor growth, metastasis and angiogenesis. Met is widely expressed on various types of tumor cells. Thus, an antagonist molecule that blocks the HGF-Met interaction is expected to have wide therapeutic application in cancer. In the present study, we plan to develop a proprietary soluble Met-Fc adhesin molecule to inhibit HGF-Met interaction. We will (1) construct expression vectors for the extracellular domain of Met fused to human IgG1 Fc, express these adhesin molecules in the mammalian expression system and purify a sufficient quantity of these proteins for in vitro studies; (2) demonstrate the ability of Met-Fc adhesin molecules to inhibit the HGF binding to membrane Met receptors; and (3) demonstrate the ability of Met-Fc to block various in vitro biological activities of HGF including tumor growth promotion, angiogenesis, cell scattering and anti-apoptotic activity. The Phase II study will include scale-up production of the selected proprietary Met-Fc adhesin molecule, in vivo efficacy studies using xenograft nude mouse models with/without chemotherapeutic agents and evaluation of the safety and pharmacokinetics of this molecule in normal animals in preparation for clinical trials in human patients. We expect met-Fc will inhibit tumor growth as well as angiogenesis to provide a novel cancer therapy.

描述(申请人提供)：肝细胞生长因子(HGF)及其受体c-Met在肿瘤生长、转移和血管生成中起重要作用。MET广泛表达于多种类型的肿瘤细胞上。因此，阻断HGF-Met相互作用的拮抗剂分子有望在癌症治疗中有广泛的应用。在本研究中，我们计划开发一种专有的可溶性Met-Fc粘附素分子来抑制HGF-Met相互作用。我们将(1)构建Met胞外区与人IgG1Fc融合的表达载体，在哺乳动物表达系统中表达这些粘附素分子，并纯化足够数量的这些蛋白用于体外研究；(2)证明Met-Fc粘附素分子能够抑制HGF与膜Met受体的结合；(3)证明Met-Fc能够阻断HGF的多种体外生物学活性，包括促进肿瘤生长、血管生成、细胞散射和抗凋亡活性。第二阶段的研究将包括放大生产选定的专利Met-FC粘附素分子，使用有/没有化疗药物的异种裸鼠模型进行体内疗效研究，以及评估这种分子在正常动物中的安全性和药代动力学，为人类患者的临床试验做准备。我们预计MET-FC将抑制肿瘤生长和血管生成，从而提供一种新的癌症治疗方法。