A Novel Approach to Improve the Function of FGF21

Autor: Amy N. Duguay, Yang Li, Richard Smith, Ed Belouski, Junming Yie, Shanaka Stanislaus, Jing Xu, Ling Cai, Xinle Wu, Jamila Gupte, Jennifer Weiszmann
Rok vydání: 2013
Předmět:
Zdroj: BioDrugs. 27:159-166
ISSN: 1179-190X
1173-8804
Popis: Fibroblast growth factor 21 (FGF21) has potent effects on normalizing glucose, lipid, and energy homeostasis, and represents an attractive novel therapy for type 2 diabetes mellitus and obesity. Approaches to improve the pharmacokinetic properties of FGF21, such as conjugation with polyethylene glycol, have been explored for therapeutic development. However, not only is there room for further pharmacokinetic improvements, additional re-engineering approaches to improve the potency and stability of FGF21 have not been reported. Here, we describe a novel approach to modify and improve the function of FGF21 by altering its C-terminal βKlotho interaction domain. We first identified Avimer proteins that are capable of binding βKlotho. Then we explored replacing the C-terminal βKlotho interaction domain of FGF21 with a βKlotho-binding Avimer protein. Such a βKlotho-binding Avimer protein was able to fully complement the C-terminal domain function of FGF21. The resulting FGF21-Avimer fusion is functionally indistinguishable from wild type FGF21, and more tolerant of C-terminal modification. These results demonstrate a viable strategy to modulate the affinity, potency, and engineering of FGF21, paving the way for further improvements of FGF21 as a therapeutic.
Databáze: OpenAIRE