Anti-FGF7 monoclonal antibody, clone FQS8372

Purpose: Overexpression of fibroblast growth factor receptor 2 (FGFR2) may be a causative factor of a number of human tumors, especially gastric tumors of the poorly differentiated type. We investigated whether monoclonal antibodies (mAbs) directed against FGFR2 can inhibit the growth of tumors in xenograft models. Experimental Design: We generated and characterized 3 mAbs that recognize different epitopes on FGFR2: GAL-FR21, GAL-FR22, and GAL-FR23. The ability of the mAbs to recognize the FGFR2IIIb and FGFR2IIIc isoforms of FGFR2 was determined, as was their ability to block binding of FGF ligands to FGFR2. The capability of the mAbs to inhibit FGF-induced FGFR2 phosphorylation and to downmodulate FGFR2 expression was also investigated. Finally, the ability of the anti-FGFR2 mAbs to inhibit tumor growth was determined by establishing xenografts of SNU-16 and OCUM-2M human gastric tumor cell lines in nude mice, treating with each mAb (0.5-5 mg/kg intraperitoneally twice weekly) and monitoring tumor size. Results: Of the 3 mAbs, GAL-FR21 binds only the FGFR2IIIb isoform, whereas GAL-FR22 and GAL-FR23 bind to both the FGFR2IIIb and FGFR2IIIc forms, with binding regions respectively in the D3, D2-D3, and D1 domains of FGFR2. GAL-FR21 and GAL-FR22 blocked the binding of FGF2, FGF7 and FGF10 to FGFR2IIIb. GAL-FR21 inhibited FGF2 and FGF7 induced phosphorylation of FGFR2, and both mAbs downmodulated FGFR2 expression on SNU-16 cells. These mAbs effectively inhibited growth of established SNU-16 and OCUM-2M xenografts in mice. Conclusions: Anti-FGFR2 mAbs GAL-FR21 and GAL-FR22 have potential for the treatment of gastric and other tumors. Clin Cancer Res; 16(23); 5750-58. (C)2010 AACR.

Embryonic day 13 mouse submandibular gland (E13-SMG) rudiments with two to four clefts have been commonly used in culture experiments to show that growth factors, such as epidermal growth factor (EGF)-family and fibroblast growth factor (FGF)-family ligands, are involved in branching morphogenesis. In the present study, we focused on E12 rudiments and attempted to elucidate the roles of EGF- and FGF-family ligands in SMG development from E12 to E13. In mesenchyme-free, Matrigel-embedded cultures, EGF + lysophosphatidic acid (LPA) induced branching in E13 epithelium, whereas E12 epithelium remained spherical and no branching occurred under the same culture conditions; however, both E12 and E13 epithelia elongated in response to FGF10. Reverse transcriptase-polymerase chain reaction studies showed that the expression of ErbB1 among four EGF receptors and Lpa3 among three LPA receptors was lower in E12 than in E13 epithelia. Fgf10, Fgf7, and their major receptor Fgfr2b were highly and equally expressed in E12 and E13 rudiments. After 24 hr of mesenchyme-free culture with FGF10 or FGF7, E12 epithelium was primed to initiate branching morphogenesis in response to EGF + LPA coincident with ErbB1 and Lpa3 up-regulation. These results suggest that the EGF-family ligand-receptor system is undeveloped at E12 and that it becomes primed on E13 by the FGF ligand-receptor system to play an important role in the induction of branching morphogenesis. Developmental Dynamics 238:315-323, 2009. (c) 2008 Wiley-Liss, Inc.