Abstract 4279: Isolation of a high affinity, specific human monoclonal antibody that binds to FGFR-2 IIIc

Fibroblast Growth Factor Receptor-2 (FGFR-2) expression and activation have been increasingly implicated in a number of human cancers, including prostate, ovarian, breast, gastric, bladder, pancreatic, endometrial and lung malignancies. Mechanisms include stimulation of angiogenesis, direct stimulation of tumor growth and promotion of tumor metastasis. Similar to other FGFRs, FGFR-2 binds a subset of FGF ligands with high affinity and consists of an extracellular region comprised of two or three immunoglobulin-like (Ig) domains, a single transmembrane region and an intracellular kinase domain. Variable splicing in the second half of the third Ig-like domain generates two isoforms, IIIb or IIIc, with different ligand binding specificity and expression patterns. An isoform switch from epithelial cell-expressed FGFR-2IIIb to mesenchymal cell-expressed FGFR2-IIIc has been shown to associate with an epithelial to mesenchymal transition (EMT), which increases cell migration and invasion and facilitates metastasis of epithelial carcinomas, such as prostate and bladder cancer. Several groups are developing antibodies to block FGFR-2 as therapeutics. Small molecule drugs that block FGFR-2 signaling are currently being evaluated in clinical trials. Recently, there have been reports of FGFR-2 IIIb-specific antibodies. In the same studies, monoclonal antibodies that bind both isoforms IIIb and IIIc were described, but, to date, no detailed studies describing the isolation of an FGFR-2 IIIc-specific antibody have been reported. The high degree of sequence conservation between the IIIb and IIIc exons is presumably the major reason why this has been technically challenging. In this study, we report the isolation of a high affinity, human monoclonal antibody, ATTO-1, and a murine mAb, 5H11, that bind to human and mouse FGFR-2 IIIc, but not FGFR2-IIIb, respectively. ATTO-1 binds to established mesenchymal tumor cell lines, such as AT3 and BT459 (FGFR-2 IIIc+), but not to MCF-7 or DT (FGFR-2 IIIb+). These antibodies may be valuable research tools for studying and developing novel therapies for blocking tumor invasion and metastasis. Citation Format: Ullrich S. Schwertschlag, Katherine J. Turner, Central Lab Naval Hospital Bejing. Isolation of a high affinity, specific human monoclonal antibody that binds to FGFR-2 IIIc. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): A