A Novel Fc-FGF21 With Improved Resistance to Proteolysis, Increased Affinity Toward β-Klotho, and Enhanced Efficacy in Mice and Cynomolgus Monkeys.

摘要: Fibroblast growth factor (FGF) 21 is a natural hormone that modulates glucose, lipid, and energy metabolism. Previously, we engineered an Fc fusion FGF21 variant with two mutations, Fc-FGF21(RG), to extend the half-life reduce aggregation in vivo degradation of FGF21. We now describe new developed extreme C-terminal improve binding affinity β-Klotho. demonstrate, by introducing one additional mutation located at C terminus (A180E), molecule, Fc-FGF21(RGE), has gained many improved attributes. Compared Fc-FGF21(RGE) similar vitro potency, preserves β-Klotho dependency, maintains FGF receptor selectivity cross-species reactivity. In vivo, showed reduced susceptibility increased plasma levels bioactive intact molecule. The circulating twofold compared Fc-FGF21(RG) mice cynomolgus monkeys. Additionally, exhibited threefold fivefold enhanced coreceptor across mouse, monkey, human species. obese diabetic mouse monkey models, demonstrated greater efficacies resulting larger more sustained improvements multiple metabolic parameters. No immunogenicity was observed Fc-FGF21(RGE). superior biophysical, pharmacokinetic, pharmacodynamic properties, as well positive effects species, suggest further clinical development therapy for and/or patients may be warranted.