FGFR3-targeted mAb therapy for bladder cancer and multiple myeloma

Gain-of-function mutations in FGF receptor 3 (FGFR3) have been implicated in severe skeletal dysplasias and in a variety of cancers. In their study in this issue of the JCI, Qing et al. used specific shRNA probes to demonstrate that FGFR3 functions as an important driver of bladder carcinoma cell proliferation (see the related article beginning on page 1216). A unique anti-FGFR3 mAb was shown to exhibit antitumor activity in human bladder carcinoma cells in vitro and in mouse bladder cancer or multiple myeloma xenograft tumor models bearing either wild-type or mutant FGFR3. These results suggest that clinical development of anti-FGFR3 mAbs should be considered for targeted therapy of cancer and other diseases. FGFs are members of a large family of growth factors that play an important role in the control of diverse cellular processes (e.g., cell proliferation, differentiation, survival, and migration) during embryonic development and in the maintenance of cellular homeostasis in virtually all organs and tissues (1, 2). FGFs act in concert with heparan sulfate proteoglycans (HSPGs) to activate a family of four receptor tyrosine kinases (RTKs) designated FGF receptors 1–4 (FGFR1–4). Each FGFR consists of an extracellular region composed of three Ig-like domains designated D1, D2, and D3; a short stretch of amino acids in the D1–D2 linker region, designated the acid box; and a single transmembrane domain followed by an intracellular tyrosine kinase domain with additional regulatory sequences (1). Diversity in ligand-binding specificity and tissue expression patterns of FGFR1–3 are further enhanced by alternative RNA splicing in the C-terminal half of D3 to generate either the IIIb or the IIIc splice isoform. It was previously shown that the IIIb isoform is expressed in epithelial cells and the IIIc isoform is expressed in mesenchymal cells (1). Interestingly, FGFs that activate the epithelial IIIb FGFR isoforms are expressed in mesenchymal cells, whereas FGFs that activate the mesenchymal IIIc FGFR isoforms are produced in epithelial cells (1). A variety of human skeletal dysplasias associated with severe impairment in cranial, digital, and skeletal development have been shown to be driven by gain-of-function mutations in FGFR1–3 (1). Gain-of-function mutations in FGFRs have also been identified in a variety of human cancers, including myeloproliferative syndromes, lymphomas, glioblastoma, as well as prostate, bladder, and mammary carcinomas (1). Importantly, the t(4;14)(p16.3;q32) chromosomal translocation that results in FGFR3 overexpression in 20% of multiple myeloma patients is correlated with poor clinical response and patient survival (3). FGFR3 overexpression has also been identified in bladder carcinoma (4). Moreover, somatic gain-of-function mutations in FGFR3 have been identified in 65% of papillary and in 20% of muscle-invasive bladder carcinomas (4). These studies suggest that FGFR3 could be considered a candidate for targeted therapies for the treatment of cancers and skeletal dysplasias driven by gain-of-function FGFR3 mutations. Several small molecule inhibitors of the tyrosine kinase activity of FGFR3 and other members of the FGFRs have been described, some of which are currently in clinical development (5, 6). However, potent small molecule inhibitors that specifically interfere with the tyrosine kinase activity of FGFR3 are difficult to develop because of the close structural similarity of the FGFR3 tyrosine kinase domain to that of other members of the FGFR family and other RTKs. An alternative approach for developing a selective inhibitor of FGFR3 that does not interfere with the activity of other FGFRs and RTKs is to raise inhibitory mAbs that selectively bind to the extracellular domain of FGFR3.