Novel Immunoadhesin Molecule for Cancer Therapy

描述（由申请人提供）：已知肝细胞生长因子（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在各种类型的肿瘤细胞上广泛表达。因此，预期阻断HGF-Met相互作用的拮抗剂分子在癌症中具有广泛的治疗应用。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）构建融合于人IgG 1 Fc的Met胞外结构域的表达载体，在哺乳动物表达系统中表达这些粘附素分子，并纯化足够量的这些蛋白用于体外研究;（2）证明Met-Fc粘附素分子抑制HGF与膜Met受体结合的能力;和（3）证明Met-Fc阻断HGF的各种体外生物活性的能力，包括肿瘤生长促进、血管生成、细胞分散和抗凋亡活性。II期研究将包括所选专有Met-Fc粘附素分子的规模化生产、使用含/不含化疗剂的异种移植裸鼠模型的体内功效研究以及在人类患者临床试验准备中评价该分子在正常动物中的安全性和药代动力学。我们期望met-Fc将抑制肿瘤生长以及血管生成，以提供一种新的癌症治疗。

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.