FGF21 N‐ and C‐termini play different roles in receptor interaction and activation

Yie, Junming; Hecht, Randy; Patel, Jennifer; Stevens, Jennitte; Wang, Wei; Hawkins, Nessa; Steavenson, Shirley; Smith, Steve; Winters, Dwight; Fisher, Seth; Cai, Ling; Belouski, Ed; Chen, Ching; Michaels, Mark L.; Li, Yuesheng; Lindberg, Richard A.; Wang, Minghan; Véniant, Murielle M.; Xu, Jing

doi:10.1016/j.febslet.2008.11.023

Cited by 137 publications

(179 citation statements)

References 22 publications

Supporting

Mentioning

161

Contrasting

Order By: Relevance

“…Both the N and C terminus of FGF21 are important for its in vitro activity (Micanovic et al, 2009;Yie et al, 2009), and we found that certain CovX-Bodies were superior to the C terminally linked CovX-Body in that they maintained in vitro potency similar to the WT FGF21 protein. Some of the midlinked FGF21 CovX-Bodies had more prolonged half-lives than the terminally linked or other midlinked molecules.…”

Section: Antidiabetic Effect Of Long-acting Fgf21 Mimeticmentioning

confidence: 79%

“…Although it is not clear which FGFR subtypes mediate FGF21 action in vivo, FGFR1c, 3c, and 4 have been shown to be involved in FGF21 signaling in vitro Suzuki et al, 2008). Both the N and C termini of FGF21 have been shown to be important for its biologic activity, with the N terminus required for FGFR activation, and the C terminus shown to directly bind bKlotho (Micanovic et al, 2009;Yie et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…Although genetic fusion can improve the pharmacokinetic property of a protein, this involves the N or C terminus of the protein. In the case of FGF21, however, N or C terminal genetic fusion may impair the bioactivity of the protein, as the termini have been shown to be important for biologic function (Micanovic et al, 2009;Yie et al, 2009). Polyethylene glycol (PEG)ylation has also been used to improve the pharmacokinetic property of proteins and peptides, although PEGylated FGF21 exhibits lower intrinsic potency compared with the wild-type (WT) protein (Mu et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Development of a Novel Long-Acting Antidiabetic FGF21 Mimetic by Targeted Conjugation to a Scaffold Antibody

Huang

Ishino

Chen

et al. 2013

J Pharmacol Exp Ther

108

123

View full text Add to dashboard Cite

Fibroblast growth factor (FGF)21 improves insulin sensitivity, reduces body weight, and reverses hepatic steatosis in preclinical species. We generated long-acting FGF21 mimetics by site-specific conjugation of the protein to a scaffold antibody. Linking FGF21 through the C terminus decreased bioactivity, whereas bioactivity was maintained by linkage to selected internal positions. In mice, these CovX-Bodies retain efficacy while increasing half-life up to 70-fold compared with wild-type FGF21. A preferred midlinked CovX-Body, CVX-343, demonstrated enhanced in vivo stability in preclinical species, and a single injection improved glucose tolerance for 6 days in ob/ob mice. In diet-induced obese mice, weekly doses of CVX-343 reduced body weight, blood glucose, and lipids levels. In db/db mice, CVX-343 increased glucose tolerance, pancreatic b-cell mass, and proliferation. CVX-343, created by linkage of the CovX scaffold antibody to the engineered residue A129C of FGF21 protein, demonstrated superior preclinical pharmacodynamics by extending serum half-life of FGF21 while preserving full therapeutic functionality.

show abstract

Section: Antidiabetic Effect Of Long-acting Fgf21 Mimeticmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Development of a Novel Long-Acting Antidiabetic FGF21 Mimetic by Targeted Conjugation to a Scaffold Antibody

Huang

Ishino

Chen

et al. 2013

J Pharmacol Exp Ther

108

123

View full text Add to dashboard Cite

show abstract

“…The FGF21 ligand is produced from several organs such as the liver and adipose tissue (Ito et al 2000), skeletal muscle (Joki et al 2015), and the heart (Nishimura et al 2000, Kharitonenkov 2009, Planavila et al 2013, Patel et al 2014. To activate FGF21 signaling, FGF21 binds to FGFR1c with its C-terminus, and also with b-Klotho as its co-receptor with its N-terminus, to form the FGFR/ b-Klotho complex (Kharitonenkov 2008, Suzuki et al 2008, Yie et al 2009, Ding et al 2012, Hale et al 2012.…”

Section: Introductionmentioning

confidence: 99%

Effects of fibroblast growth factor 21 on the heart

Tanajak¹,

Chattipakorn²

2015

Journal of Endocrinology

View full text Add to dashboard Cite

Fibroblast growth factor 21 (FGF21) is a novel polypeptide ligand that has been shown to be involved in several physiological and pathological processes including regulation of glucose and lipids as well as reduction of arteriosclerotic plaque formation in the great vessels. It has also been shown to exert cardioprotective effects in myocardial infarction, cardiac ischemiareperfusion injury, cardiac hypertrophy and diabetic cardiomyopathy. Moreover, FGF21 protects the myocardium and great arteries by attenuating remodeling, inflammation, oxidative stress and also promoting the energy supply to the heart through fatty acid b-oxidation. This growing evidence emphasizes the important roles of FGF21 in cardioprotection. This review comprehensively summarizes and discusses the consistent and inconsistent findings regarding the beneficial effects of FGF21 on the heart available from both basic research and clinical reports. The details of the signaling, biological and pharmacological effects of FGF21 with regard to its protection of the heart are also presented and discussed in this review.

show abstract

“…The N terminus of FGF21 displays affinity for several fibroblast growth factor receptors (FGFRs), including FGFR1c, FGFR3c, and FGFR4, whereas the C terminus binds to the membrane-associated cofactor b-klotho. Truncation of N termini (NT) by six or more residues, or C termini (CT) by two or more residues, decreased in vitro potency more than 10-fold, suggesting that potent functional activity was derived from both termini of FGF21 (Micanovic et al, 2009;Yie et al, 2009). In diabetic animal models and patients with type 2 diabetes, recombinant fibroblast growth factor 21 (rFGF21) and its analogs demonstrated dose-dependent reductions in low-density lipoprotein cholesterol, apolipoproteins, fasting triglycerides, fasting insulin, and body weight, as well as dose-dependent elevations of high-density lipoprotein cholesterol and adiponectin (Adams et al, 2013;Gaich et al, 2013;Kharitonenkov et al, 2013;Smith et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Investigation of the Preclinical Pharmacokinetics and Interspecies Scaling of PF-05231023, a Fibroblast Growth Factor 21–Antibody Protein Conjugate

Giragossian

Vage

et al. 2015

Drug Metab Dispos

View full text Add to dashboard Cite

PF-05231023, a long-acting fibroblast growth factor 21 (FGF21) analog, was generated by covalently conjugating two engineered [des-His1, Ala129Cys]FGF21 molecules to a nontargeting human IgG 1k scaffold. The pharmacokinetics (PK) of PF-05231023 after i.v. and s.c. administration was evaluated in rats and monkeys using two enzyme-linked immunosorbent assays with high specificity for biologically relevant intact N termini (NT) and C termini (CT) of FGF21. Intact CT of FGF21 displayed approximately 5-fold faster systemic plasma clearance (CL), an approximately 2-fold lower steady-state volume of distribution, and at least 5-fold lower bioavailability compared with NT. In vitro serum stability studies in monkeys and humans suggested that the principal CL mechanism for PF-05231023 was degradation by serum proteases. Direct scaling of in vitro serum degradation rates for intact CT of FGF21 underestimated in vivo CL 5-fold, 1.4-fold, and 2-fold in rats, monkeys, and humans, respectively. The reduced steady-state volume of distribution and the bioavailability for intact CT relative to NT in rats and monkeys were compatible with proteolytic degradation occurring outside the plasma compartment via an unidentified mechanism. Human CL and PK profiles for intact NT and CT of FGF21 were well predicted using monkey single-species allometric and Dedrick scaling. Physiologically based pharmacokinetic models incorporating serum stability data and an extravascular extraction term based on differential bioavailability of intact NT and CT of FGF21 in monkeys improved accuracy of human PK predictions relative to Dedrick scaling. Mechanistic physiologically based pharmacokinetic models of this nature may be highly valuable for predicting human PK of fusion proteins, synthetically conjugated proteins, and other complex biologics.

show abstract

FGF21 N‐ and C‐termini play different roles in receptor interaction and activation

Cited by 137 publications

References 22 publications

Development of a Novel Long-Acting Antidiabetic FGF21 Mimetic by Targeted Conjugation to a Scaffold Antibody

Development of a Novel Long-Acting Antidiabetic FGF21 Mimetic by Targeted Conjugation to a Scaffold Antibody

Effects of fibroblast growth factor 21 on the heart

Mechanistic Investigation of the Preclinical Pharmacokinetics and Interspecies Scaling of PF-05231023, a Fibroblast Growth Factor 21–Antibody Protein Conjugate

Contact Info

Product

Resources

About