title: A novel approach to improve the function of FGF21.
abstract: 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 βKlotho interaction domain.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, USA. rsmith04@amgen.com
authors: Richard
authors: R
authors: Smith
authors: Amy
authors: A
authors: Duguay
authors: Jennifer
authors: J
authors: Weiszmann
authors: Shanaka
authors: S
authors: Stanislaus
authors: Ed
authors: E
authors: Belouski
authors: Ling
authors: L
authors: Cai
authors: Junming
authors: J
authors: Yie
authors: Jing
authors: J
authors: Xu
authors: Jamila
authors: J
authors: Gupte
authors: Xinle
authors: X
authors: Wu
authors: Yang
authors: Y
authors: Li
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019440:Anti-Obesity Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001786:Blood Glucose / Q000032:analysis; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000494:pharmacology* / Q000592:standards / Q000627:therapeutic use; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009765:Obesity / Q000097:blood / Q000188:drug therapy; D015202:Protein Engineering / Q000379:methods*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology* / Q000592:standards / Q000627:therapeutic use
chemical_list: D019440:Anti-Obesity Agents; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D011993:Recombinant Fusion Proteins; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors