PT  - JOURNAL ARTICLE
AU  - Jie Huang
AU  - Tetsuya Ishino
AU  - Gang Chen
AU  - Paul Rolzin
AU  - Trina F. Osothprarop
AU  - Kelsey Retting
AU  - Lingna Li
AU  - Ping Jin
AU  - Marla J. Matin
AU  - Bernard Huyghe
AU  - Saswata Talukdar
AU  - Curt W. Bradshaw
AU  - Moorthy Palanki
AU  - Bernard N. Violand
AU  - Gary Woodnutt
AU  - Rodney W. Lappe
AU  - Kathleen Ogilvie
AU  - Nancy Levin
TI  - Development of a Novel Long-Acting Antidiabetic FGF21 Mimetic by Targeted Conjugation to a Scaffold Antibody
AID  - 10.1124/jpet.113.204420
DP  - 2013 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 270--280
VI  - 346
IP  - 2
4099  - http://jpet.aspetjournals.org/content/346/2/270.short
4100  - http://jpet.aspetjournals.org/content/346/2/270.full
SO  - J Pharmacol Exp Ther2013 Aug 01; 346
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.