RT Journal Article
SR Electronic
T1 Development of a Novel Long-Acting Antidiabetic FGF21 Mimetic by Targeted Conjugation to a Scaffold Antibody
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 270
OP 280
DO 10.1124/jpet.113.204420
VO 346
IS 2
A1 Jie Huang
A1 Tetsuya Ishino
A1 Gang Chen
A1 Paul Rolzin
A1 Trina F. Osothprarop
A1 Kelsey Retting
A1 Lingna Li
A1 Ping Jin
A1 Marla J. Matin
A1 Bernard Huyghe
A1 Saswata Talukdar
A1 Curt W. Bradshaw
A1 Moorthy Palanki
A1 Bernard N. Violand
A1 Gary Woodnutt
A1 Rodney W. Lappe
A1 Kathleen Ogilvie
A1 Nancy Levin
YR 2013
UL http://jpet.aspetjournals.org/content/346/2/270.abstract
AB 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 β-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.