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

Abstract

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.

Metabolic syndrome and nonalcoholic fatty liver disease: Is insulin resistance the link?

“…Together, these studies show that dietary interventions stimulate the growth of beneficial gut bacteria, which may in part contribute to reverse NAFLD and hepatic insulin resistance. Could be considered as a treatment for NAFLD, but requires further investigations in humans Gaich et al, 2013, Huang et al, 2013 Low-fat or low-carbohydrate lowcalorie diet…”

“…This may be due to the short duration of the trial (28 days), but may also reflect FGF21 resistance . Importantly, other FGF21 mimetic molecules are in development (Foltz et al, 2012;Huang et al, 2013;Veniant et al, 2012;Wu et al, 2011a). It would be of interest to investigate whether FGF21 analogs are able to reverse or stop the development of NAFLD in humans as they do in animals.…”

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

“…Engineered site-specific linkage sites remote from the NT and CT of FGF21 preserved in vitro potency while increasing serum persistence of FGF21 30-to 90-fold (Huang et al, 2013).…”

“…1) (Huang et al, 2013). PF-05231023 demonstrated comparable in vitro potency, enhanced pharmacokinetics (PK), and prolonged in vivo pharmacodynamics relative to rFGF21.…”

“…PF-05231023 demonstrated comparable in vitro potency, enhanced pharmacokinetics (PK), and prolonged in vivo pharmacodynamics relative to rFGF21. The PK of PF-05231023 in rodents and nonhuman primates was previously characterized using a sandwich enzyme-linked immunosorbent assay with specificity for the mid-region of FGF21 (Huang et al, 2013). However, this assay lacked specificity for measuring the bioactive NT and CT of FGF21.…”