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

作者：Huang Jie; Ishino Tetsuya; Chen Gang; Rolzin Paul; Osothprarop Trina F; Retting Kelsey; Li Lingna; Jin Ping; Matin Marla J; Huyghe Bernard; Talukdar Saswata^*; Bradshaw Curt W; Palanki Moorthy; Violand Bernard N; Woodnutt Gary; Lappe Rodney W; Ogilvie Kathleen; Levin Nancy

来源：Journal of Pharmacology and Experimental Therapeutics, 2013, 346(2): 270-280.

DOI：10.1124/jpet.113.204420

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 beta-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.

• 出版日期2013-8