title: Antibody-mediated inhibition of fibroblast growth factor 19 results in increased bile acids synthesis and ileal malabsorption of bile acids in cynomolgus monkeys.
abstract: Fibroblast growth factor 19 (FGF19) represses cholesterol 7α-hydroxylase (Cyp7α1) and inhibits bile acid synthesis in vitro and in vivo. Previous studies have shown that anti-FGF19 antibody treatment reduces growth of colon tumor xenografts and prevents hepatocellular carcinomas in FGF19 transgenic mice and thus may be a useful cancer target. In a repeat dose safety study in cynomolgus monkeys, anti-FGF19 treatment (3-100 mg/kg) demonstrated dose-related liver toxicity accompanied by severe diarrhea and low food consumption. The mechanism of anti-FGF19 toxicity was investigated using in vitro and in vivo approaches. Our results show that anti-FGF19 antibody had no direct cytotoxic effect on monkey hepatocytes. Anti-FGF19 increased Cyp7α1, as expected, but also increased bile acid efflux transporter gene (bile salt export pump, multidrug resistant protein 2 [MRP2], and MRP3) expression and reduced sodium taurocholate cotransporting polypeptide and organic anion transporter 2 expression in liver tissues from treated monkeys and in primary hepatocytes. In addition, anti-FGF19 treatment increased solute transporter gene (ileal bile acid-binding protein, organic solute transporter α [OST-α], and OST-β) expression in ileal tissues from treated monkeys but not in Caco-2 cells. However, deoxycholic acid (a secondary bile acid) increased expression of FGF19 and these solute transporter genes in Caco-2 cells. Gas chromatography-mass spectrometry analysis of monkey feces showed an increase in total bile acids and cholic acid derivatives. These findings suggest that high doses of anti-FGF19 increase Cyp7α1 expression and bile acid synthesis and alter the expression of bile transporters in the liver resulting in enhanced bile acid efflux and reduced uptake. Increased bile acids alter expression of solute transporters in the ileum causing diarrhea and the enhanced enterohepatic recirculation of bile acids leading to liver toxicity.
authors.affiliation: Department of Safety Assessment, Genentech Incorporated, South San Francisco, California 94080, USA. rpai@gene.com
authors.forename: Rama
authors.initials: R
authors.lastname: Pai
authors.forename: Dorothy
authors.initials: D
authors.lastname: French
authors.forename: Ning
authors.initials: N
authors.lastname: Ma
authors.forename: Kathy
authors.initials: K
authors.lastname: Hotzel
authors.forename: Emile
authors.initials: E
authors.lastname: Plise
authors.forename: Laurent
authors.initials: L
authors.lastname: Salphati
authors.forename: Kenneth D R
authors.initials: KD
authors.lastname: Setchell
authors.forename: Joseph
authors.initials: J
authors.lastname: Ware
authors.forename: Veronique
authors.initials: V
authors.lastname: Lauriault
authors.forename: Leah
authors.initials: L
authors.lastname: Schutt
authors.forename: Dylan
authors.initials: D
authors.lastname: Hartley
authors.forename: Donna
authors.initials: D
authors.lastname: Dambach
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology*; D001647:Bile Acids and Salts / Q000096:biosynthesis* / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors* / Q000276:immunology; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D007082:Ileum / Q000378:metabolism*; D007408:Intestinal Absorption; D008252:Macaca fascicularis
chemical_list: D000906:Antibodies; D001647:Bile Acids and Salts; D005346:Fibroblast Growth Factors