Alleviating FGF19's tumorigenic risk by suppressing its FGF Receptor dimerization ability

Administration of FGF19 - a physiological regulator of bile acid homeostasis - to diabetic and diet-induced-obese mice can suppress plasma glucose concentration and improve insulin sensitivity. Repurposing FGF19 as a therapeutic agent for treating type 2 diabetes and cholestatic liver disease is therefore of significant interest. However, the tumorigenic risk associated with prolonged FGF19 administration is a major hurdle in realizing its full clinical potential. Here we show that non-mitogenic FGF19 variants that retain full beneficial glucose-lowering activity of wild-type FGF19 (FGF19WT) can be engineered by diminishing FGF19's ability to induce dimerization of its cognate FGF receptors (FGFR). As proof-of-principle, we generated three such mutants, each with a partial defect in binding affinity to FGFR (FGF19?FGFR), and its co-receptors ?klotho (FGF19?KLB) or heparan sulfate (FGF19?HBS). Pharmacological assays in healthy and db/db mice confirmed that these variants incur a dramatic loss in mitogenic activity, yet are indistinguishable from FGF19WT in eliciting glycemic control. Our approach provides a simple framework for the development of safer and efficacious FGF19 analogs. Overall design: Lver tissues of db/db mice treated with PBS, FGF19WT, or FGF19?KLB for 12 weeks were collected. Total RNA was extracted using the TRIzol reagent (Invitrogen) and analyzed using a Bio-analyzer 2100 and an RNA 6000 Nano Lab Chip Kit