A Novel Approach to Improve the Function of FGF21

作者：Smith Richard^*; Duguay Amy; Weiszmann Jennifer; Stanislaus Shanaka; Belouski Ed; Cai Ling; Yie Junming; Xu Jing; Gupte Jamila; Wu Xinle; Li Yang

来源：BioDrugs, 2013, 27(2): 159-166.

DOI：10.1007/s40259-013-0013-x

Background and Objective 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 beta Klotho interaction domain.
Methods We first identified Avimer proteins that are capable of binding beta Klotho. Then we explored replacing the C-terminal beta Klotho interaction domain of FGF21 with a beta Klotho-binding Avimer protein.
Results Such a beta Klotho-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.
Conclusion 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.

• 出版日期2013-4