| Autor: |
Huang J; CovX Research, Pfizer Worldwide Research and Development, San Diego, California, USA., Ishino T, Chen G, Rolzin P, Osothprarop TF, Retting K, Li L, Jin P, Matin MJ, Huyghe B, Talukdar S, Bradshaw CW, Palanki M, Violand BN, Woodnutt G, Lappe RW, Ogilvie K, Levin N |
| Jazyk: |
angličtina |
| Zdroj: |
The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2013 Aug; Vol. 346 (2), pp. 270-80. Date of Electronic Publication: 2013 May 29. |
| DOI: |
10.1124/jpet.113.204420 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
