A Novel Fc-FGF21 With Improved Resistance to Proteolysis, Increased Affinity Toward β-Klotho, and Enhanced Efficacy in Mice and Cynomolgus Monkeys
| Autor: | Dwight Winters, Todd Hager, Michael Hall, Shanaka Stanislaus, Murielle M. Véniant, Randy Ira Hecht, Chris Spahr, Lei Zhou, Jing Xu, Wei Wang, Yang Li, Junming Yie, Yue-Sheng Li, Liying Deng, Jennifer Weiszmann, Stephen Smith |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty FGF21 Recombinant Fusion Proteins 030209 endocrinology & metabolism Plasma protein binding Biology Protein Engineering medicine.disease_cause Fibroblast growth factor Diabetes Mellitus Experimental Mice 03 medical and health sciences 0302 clinical medicine Endocrinology Drug Stability In vivo 3T3-L1 Cells Internal medicine medicine Animals Humans Potency Obesity Klotho Proteins Mutation Immunogenicity Membrane Proteins In vitro Immunoglobulin Fc Fragments Fibroblast Growth Factors Mice Inbred C57BL Disease Models Animal Macaca fascicularis HEK293 Cells Treatment Outcome 030104 developmental biology Proteolysis Anti-Obesity Agents Half-Life Protein Binding |
| Zdroj: | Endocrinology. 158:1314-1327 |
| ISSN: | 1945-7170 0013-7227 |
| Popis: | 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 and reduce aggregation and in vivo degradation of FGF21. We now describe a new variant developed to reduce the extreme C-terminal degradation and improve the binding affinity to β-Klotho. We demonstrate, by introducing one additional mutation located at the C terminus of FGF21 (A180E), that the new molecule, Fc-FGF21(RGE), has gained many improved attributes. Compared with Fc-FGF21(RG), Fc-FGF21(RGE) has similar in vitro potency, preserves β-Klotho dependency, and maintains FGF receptor selectivity and cross-species reactivity. In vivo, Fc-FGF21(RGE) showed reduced susceptibility to extreme C-terminal degradation and increased plasma levels of the bioactive intact molecule. The circulating half-life of intact Fc-FGF21(RGE) increased twofold compared with that of Fc-FGF21(RG) in mice and cynomolgus monkeys. Additionally, Fc-FGF21(RGE) exhibited threefold to fivefold enhanced binding affinity to coreceptor β-Klotho across mouse, cynomolgus monkey, and human species. In obese and diabetic mouse and cynomolgus monkey models, Fc-FGF21(RGE) demonstrated greater efficacies to Fc-FGF21(RG), resulting in larger and more sustained improvements in multiple metabolic parameters. No increased immunogenicity was observed with Fc-FGF21(RGE). The superior biophysical, pharmacokinetic, and pharmacodynamic properties, as well as the positive metabolic effects across species, suggest that further clinical development of Fc-FGF21(RGE) as a metabolic therapy for diabetic and/or obese patients may be warranted. |
| Databáze: | OpenAIRE |
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