title: 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 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.
authors.affiliation: CovX Research, Pfizer Worldwide Research and Development, San Diego, California, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ishino
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Paul
authors.initials: P
authors.lastname: Rolzin
authors.forename: Trina F
authors.initials: TF
authors.lastname: Osothprarop
authors.forename: Kelsey
authors.initials: K
authors.lastname: Retting
authors.forename: Lingna
authors.initials: L
authors.lastname: Li
authors.forename: Ping
authors.initials: P
authors.lastname: Jin
authors.forename: Marla J
authors.initials: MJ
authors.lastname: Matin
authors.forename: Bernard
authors.initials: B
authors.lastname: Huyghe
authors.forename: Saswata
authors.initials: S
authors.lastname: Talukdar
authors.forename: Curt W
authors.initials: CW
authors.lastname: Bradshaw
authors.forename: Moorthy
authors.initials: M
authors.lastname: Palanki
authors.forename: Bernard N
authors.initials: BN
authors.lastname: Violand
authors.forename: Gary
authors.initials: G
authors.lastname: Woodnutt
authors.forename: Rodney W
authors.initials: RW
authors.lastname: Lappe
authors.forename: Kathleen
authors.initials: K
authors.lastname: Ogilvie
authors.forename: Nancy
authors.initials: N
authors.lastname: Levin
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D000906:Antibodies / Q000737:chemistry*; D001835:Body Weight / Q000187:drug effects; D003545:Cysteine / Q000737:chemistry; D003692:Delayed-Action Preparations; D003920:Diabetes Mellitus / Q000097:blood / Q000188:drug therapy; D004734:Energy Metabolism / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000737:chemistry*; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000473:pathology; D008239:Lysine / Q000737:chemistry; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008820:Mice, Obese; D018716:Molecular Mimicry; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D000906:Antibodies; D003692:Delayed-Action Preparations; D007004:Hypoglycemic Agents; D007140:Immunoglobulin Fab Fragments; D011994:Recombinant Proteins; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D008239:Lysine; D003545:Cysteine