Keratinocyte Growth Factor (KGF): Clinical Applications

20世纪80年代末，我作为博士后提纯了角质细胞生长因子（KGF，又称FGF7），并一直参与其研究。我们实验室取得的里程碑包括生长因子的分子克隆和重组表达，其主要上皮细胞特异性的表征，酪氨酸激酶细胞表面受体的鉴定和克隆，主要局限于上皮细胞的选择性剪接产生的FGFR2IIIb亚型。几项合作研究扩大了我们对其生物活性的理解，包括第一份记录其显著细胞保护作用的报告。安进公司授权KGF开发治疗产品的专利权。安进科学家及其同事进行的临床前研究提供了进一步的证据，证明KGF在减少化疗/放疗后上皮损伤方面具有治疗潜力。一系列临床试验测试了KGF在减少接受强化癌症治疗的患者严重口腔黏膜炎的发生率和持续时间方面的安全性和有效性。这项工作在一项成功的3期试验中达到高潮，该试验涉及血液学恶性肿瘤患者，这些患者在自体外周血祖细胞移植之前接受了高剂量化疗/放疗。基于这些结果，FDA批准了KGF在该临床环境中的使用，并于2005年1月上市（商标名称为Kepivance，通用名称为palifermin）。随后两项3期临床试验的结果表明，palifermin对于接受强化化疗和放疗治疗头颈部鳞状细胞癌的类似适应症患者是安全有效的。

I purified keratinocyte growth factor (KGF, also known as FGF7) as a postdoctoral fellow in the late 1980s, and have been involved in its research ever since. Milestones achieved in our lab included molecular cloning and recombinant expression of the growth factor, characterization of its predominant epithelial cell specificity, identification and cloning of its tyrosine kinase cell surface receptors, FGFR2IIIb isoforms that arise from alternative splicing primarily confined to epithelial cells. Several collaborative studies broadened our understanding of its biological activities, including the first report documenting its remarkable cytoprotective effects. Amgen, Inc. licensed patent rights to KGF for the development of therapeutic products. Preclinical research performed by Amgen scientists and associates provided further evidence that KGF had therapeutic potential in reducing damage to epithelia following exposure to chemo/radiotherapy. A series of clinical trials tested the safety and efficacy of KGF in decreasing the incidence and duration of severe oral mucositis in patients receiving intensive cancer therapy. This work culminated in a successful phase 3 trial involving patients with hematologic malignancies who received high dose chemo/radiotherapy prior to autologous peripheral blood progenitor cell transplantation. Based on these results, the FDA approved use of KGF in this clinical context and the product went on the market in January2005 (trademark name is Kepivance, generic name is palifermin). Subsequent results from two phase 3 clinical trials suggest that palifermin would be safe and effective for a similar indication in patients who receive intensive chemotherapy and irradiation to treat head/neck squamous cell carcinoma.