GP369, an FGFR2-IIIb–Specific Antibody, Exhibits Potent Antitumor Activity against Human Cancers Driven by Activated FGFR2 Signaling

Abstract

Dysregulated fibroblast growth factor (FGF) signaling has been implicated in the pathogenesis of human cancers. Aberrant activation of FGF receptor 2 (FGFR2) signaling, through overexpression of FGFR2 and/or its ligands, mutations, and receptor amplification, has been found in a variety of human tumors. We generated monoclonal antibodies against the extracellular ligand-binding domain of FGFR2 to address the role of FGFR2 in tumorigenesis and to explore the potential of FGFR2 as a novel therapeutic target. We surveyed a broad panel of human cancer cell lines for the dysregulation of FGFR2 signaling and discovered that breast and gastric cancer cell lines harboring FGFR2 amplification predominantly express the IIIb isoform of the receptor. Therefore, we used an FGFR2-IIIb-specific antibody, GP369, to investigate the importance of FGFR2 signaling in vitro and in vivo. GP369 specifically and potently suppressed ligand-induced phosphorylation of FGFR2-IIIb and downstream signaling, as well as FGFR2-driven proliferation in vitro. The administration of GP369 in mice significantly inhibited the growth of human cancer xenografts harboring activated FGFR2 signaling. Our findings support the hypothesis that dysregulated FGFR2 signaling is one of the critical oncogenic pathways involved in the initiation and/or maintenance of tumors. Cancer patients with aberrantly activated/amplified FGFR2 signaling could potentially benefit from therapeutic intervention with FGFR2-targeting antibodies.

FGFR a promising druggable target in cancer: Molecular biology and new drugs

“…Several different mAb have been developed to target components of the FGF-FGFR axis: GP369 (Bai et al, 2010), GAL-FR21 (Zhao et al, 2010), GAL-FR22 (Inokuchi et al, 2015), GAL-F2 , MFGR1877S (Fauvel and Yasri, 2014), hLD1.vb (Bumbaca et al, 2011), FP-1039(Marshall et al, 2011, R3Mab (French et al, 2012), PRO-001 (French et al, 2012), 1A6 (Pai et al, 2008) and LD1 (French et al, 2012). Two main mechanisms of action have been considered; either blocking ligand binding (trap-ligand) or preventing receptor dimerization.…”

The heparan sulfate sulfotransferase 3-OST3A (HS3ST3A) is a novel tumor regulator and a prognostic marker in breast cancer

“…Alteration of the FGF-7-FGFR2IIIb signaling axis contributes to the oncogenic process by activating intracellular kinase cascades including ERKdependent proliferation and AKT-mediated cell survival in breast cancer cells 37 , and antiFGFR2IIIb antibodies offer a new therapeutic option. 38 Since FGF-7 is one of the most structurally specific FGFs with respect to its requirement for a 3-O-sulfated motif to coordinate ligand-receptor complex assembly 39,40 , we investigated whether 3-OST3A expression may regulate its signaling pathway to trigger the tumor-suppressive effect observed in the lumA-MCF-7 cells. Supporting this assumption, our data show that reinstating 3-OST3A expression in these cells: i) impaired interactions between FGF-7 and HS chains, ii) inhibited proliferative signals via ERK dephosphorylation, and iii) boosted apoptotic signals via AKT dephosphorylation and p38 phosphorylation.…”

Fibroblast Growth Factors and their Emerging Cancer-Related Aspects

“…Besides tyrosine kinase inhibitors, other forms of therapies have evolved in the recent years to hinder the activity of FGFRs. These types include monoclonal antibodies directed towards FGFRs [236,237] and FGFligand traps. The novel strategy for blocking FGF/FGFR interaction is the ligand trap.…”