Neutralizing antibody against FGFR3 shows anti-tumor effects in multiple tumor models in vivo

2080 Dysregulation of FGFR3 signaling has been observed in certain cancers: in Urothelial Cell Carcinoma (UCC) FGFR3 expression is higher in tumor cells compared to normal tissue; in Multiple Myeloma (MM) t(4;14)(p16;q32)-translocation leads to FGFR3 over-expression. Activating mutations of the receptor are common in both cancer types and some of these mutations are capable of transforming normal cells. We have shown that a neutralizing antibody against FGFR3, IMC-D11, inhibits FGFR3 signaling in vitro. Here we tested the anti-tumor activity of IMC-D11 in mouse xenograft models. A range of tumor cell lines, including UCC and MM, were screened for FGFR3 expression by flow cytometry and RT-PCR. High FGFR3 expression was confirmed in RT-112, RT-4, OPM-2 (harboring an activating K650E point mutation in FGFR3), GEO, and Fadu. Treating the tumor cells with FGF1 and/or FGF9 led to up-regulation of phospho-Erk1/2, phospho-Akt, and/or phospho-p38; suggesting FGFR3 signaling may play a role in tumor growth and survival. IMC-D11 significantly inhibited growth of these tumor cells in mouse xenografts. When combined with cytoxic agents, the antibody produced enhanced anti-tumor effects in RT-112, RT-4 and Fadu xenografts. In contrast, the antibody showed no effect on FGFR3-null PC-3 tumors in an orthotopic xenograft model. Our study suggests that IMC-D11 inhibits xenograft tumor growth by specifically down-modulating FGFR3 mediated mitogenic and/or survival signaling in tumor cells and that FGFR3 may be a viable therapeutic target for not only UCC and MM, but also other tumors that express high levels of the receptor.