title: Treating diabetes and obesity with an FGF21-mimetic antibody activating the βKlotho/FGFR1c receptor complex.
abstract: Fibroblast growth factor 21 (FGF21) is a distinctive member of the FGF family with potent beneficial effects on lipid, body weight, and glucose metabolism and has attracted considerable interest as a potential therapeutic for treating diabetes and obesity. As an alternative to native FGF21, we have developed a monoclonal antibody, mimAb1, that binds to βKlotho with high affinity and specifically activates signaling from the βKlotho/FGFR1c (FGF receptor 1c) receptor complex. In obese cynomolgus monkeys, injection of mimAb1 led to FGF21-like metabolic effects, including decreases in body weight, plasma insulin, triglycerides, and glucose during tolerance testing. Mice with adipose-selective FGFR1 knockout were refractory to FGF21-induced improvements in glucose metabolism and body weight. These results in obese monkeys (with mimAb1) and in FGFR1 knockout mice (with FGF21) demonstrated the essential role of FGFR1c in FGF21 function and suggest fat as a critical target tissue for the cytokine and antibody. Because mimAb1 depends on βKlotho to activate FGFR1c, it is not expected to induce side effects caused by activating FGFR1c alone. The unexpected finding of an antibody that can activate FGF21-like signaling through cell surface receptors provided preclinical validation for an innovative therapeutic approach to diabetes and obesity.
authors.affiliation: Amgen British Columbia, 7990 Enterprise Street, Burnaby, British Columbia V5A1V7, Canada.
authors.forename: Ian N
authors.initials: IN
authors.lastname: Foltz
authors.forename: Sylvia
authors.initials: S
authors.lastname: Hu
authors.forename: Chadwick
authors.initials: C
authors.lastname: King
authors.forename: Xinle
authors.initials: X
authors.lastname: Wu
authors.forename: Chaofeng
authors.initials: C
authors.lastname: Yang
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Weiszmann
authors.forename: Jennitte
authors.initials: J
authors.lastname: Stevens
authors.forename: Jiyun Sunny
authors.initials: JS
authors.lastname: Chen
authors.forename: Noi
authors.initials: N
authors.lastname: Nuanmanee
authors.forename: Jamila
authors.initials: J
authors.lastname: Gupte
authors.forename: Renee
authors.initials: R
authors.lastname: Komorowski
authors.forename: Laura
authors.initials: L
authors.lastname: Sekirov
authors.forename: Todd
authors.initials: T
authors.lastname: Hager
authors.forename: Taruna
authors.initials: T
authors.lastname: Arora
authors.forename: Hongfei
authors.initials: H
authors.lastname: Ge
authors.forename: Helene
authors.initials: H
authors.lastname: Baribault
authors.forename: Fen
authors.initials: F
authors.lastname: Wang
authors.forename: Jackie
authors.initials: J
authors.lastname: Sheng
authors.forename: Margaret
authors.initials: M
authors.lastname: Karow
authors.forename: Minghan
authors.initials: M
authors.lastname: Wang
authors.forename: Yongde
authors.initials: Y
authors.lastname: Luo
authors.forename: Wallace
authors.initials: W
authors.lastname: McKeehan
authors.forename: Zhulun
authors.initials: Z
authors.lastname: Wang
authors.forename: Murielle M
authors.initials: MM
authors.lastname: Véniant
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D001835:Body Weight / Q000235:genetics; D003920:Diabetes Mellitus / Q000097:blood / Q000188:drug therapy*; D000939:Epitopes / Q000737:chemistry; D005346:Fibroblast Growth Factors / Q000276:immunology*; D005947:Glucose / Q000378:metabolism; D005966:Glucuronidase / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D000090265:Klotho Proteins; D008252:Macaca fascicularis; D051379:Mice; D009765:Obesity / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D010710:Phosphates / Q000097:blood; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014280:Triglycerides / Q000097:blood
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D010710:Phosphates; D014280:Triglycerides; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D051496:Receptor, Fibroblast Growth Factor, Type 1; D005966:Glucuronidase; D000090265:Klotho Proteins; D005947:Glucose