A Novel Monoclonal Antibody to Fibroblast Growth Factor 2 Effectively Inhibits Growth of Hepatocellular Carcinoma Xenografts
Menée in vitro et in vivo à l'aide de xénogreffes de carcinome hépatocellulaire, cette étude évalue l'activité antitumorale d'un anticorps monoclonal ciblant le facteur fibroblastique de croissance 2
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.
http://mct.aacrjournals.org/content/early/2012/02/16/1535-7163.MCT-11-0813.abstract