A novel monoclonal antibody to fibroblast growth factor 2 effectively inhibits growth of hepatocellular carcinoma xenografts.
A novel monoclonal antibody to fibroblast growth factor 2 effectively inhibits growth of hepatocellular carcinoma xenografts.
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DOI：
10.1158/1535-7163.mct-11-0813
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发表时间：
2012-04
影响因子：
5.7
通讯作者：
Kim KJ
中科院分区：
文献类型：
--
作者：
Wang L;Park H;Chhim S;Ding Y;Jiang W;Queen C;Kim KJ
成纤维细胞生长因子 2 (FGF2) 的表达被认为是多种肿瘤类型生长的促进因素，包括肝细胞癌 (HCC)。然而，临床试验尚未探索中和 FGF2 的单克隆抗体治疗癌症患者的潜力。因此，我们生成了一种新型单克隆抗体 (mAb)，即 GAL-F2，对 FGF2 具有特异性，并在体外和体内表征了其特性。 GAL-F2 与之前测试的几种抗 FGF2 mAb 结合的表位不同：这种新表位是使用嵌合 FGF1/FGF2 蛋白和丙氨酸扫描诱变定义的，并显示在 FGF2 的氨基和羧基区域均包含氨基酸。 GAL-F2 阻断 FGF2 与其四种细胞受体中每一种的结合，强烈抑制 HUVEC 中 FGF2 诱导的增殖和下游信号传导，并抑制两种 HCC 细胞系的增殖和下游信号传导。此外，GAL-F2以5mg/kg腹腔注射施用。每周两次，可有效抑制裸鼠中 SMMC-7721、HEP-G2 和 SK-HEP-1 人类 HCC 细胞系异种移植物的生长，并且在某些模型中与抗 VEGF 单克隆抗体或索拉非尼具有很强的相加效应。 GAL-F2 治疗还可阻断异种移植物中的血管生成并抑制下游细胞信号传导，表明其抗肿瘤作用机制。我们的报告支持对 GAL-F2 mAb 人源化形式用于治疗 HCC 和其他潜在癌症的临床测试。
Expression of Fibroblast Growth Factor 2 (FGF2) is believed to be a contributing factor to the growth of a number of tumor types, including hepatocellular carcinoma (HCC). However, the potential of monoclonal antibodies that neutralize FGF2 for treatment of cancer patients has not yet been explored in clinical trials. We therefore generated a novel monoclonal antibody (mAb), GAL-F2, specific for FGF2 and characterized its properties in vitro and in vivo. GAL-F2 binds to a different epitope than several previous anti-FGF2 mAbs tested: this novel epitope was defined using chimeric FGF1/FGF2 proteins and alanine scanning mutagenesis and shown to comprise amino acids in both the amino and carboxy regions of FGF2. GAL-F2 blocked binding of FGF2 to each of its four cellular receptors, strongly inhibited FGF2-induced proliferation and downstream signaling in HUVEC, and inhibited proliferation and downstream signaling in two HCC cell lines. Moreover, GAL-F2, administered at 5 mg/kg i.p. twice weekly, potently inhibited growth of xenografts of the SMMC-7721, HEP-G2 and SK-HEP-1 human HCC cell lines in nude mice, and in some models had a strong additive effect with an anti-VEGF mAb or sorafenib. Treatment with GAL-F2 also blocked angiogenesis and inhibited downstream cellular signaling in xenografts, indicating its anti-tumor mechanism of action. Our report supports clinical testing of a humanized form of the GAL-F2 mAb for treatment of HCC and potentially other cancers.