title: FGF21 can be mimicked in vitro and in vivo by a novel anti-FGFR1c/β-Klotho bispecific protein.
abstract: The endocrine hormone FGF21 has attracted considerable interest as a potential therapeutic for treating diabetes and obesity. As an alternative to the native cytokine, we generated bispecific Avimer polypeptides that bind with high affinity and specificity to one of the receptor and coreceptor pairs used by FGF21, FGFR1c and β-Klotho. These Avimers exhibit FGF21-like activity in in vitro assays with potency greater than FGF21. In a study conducted in obese male cynomolgus monkeys, animals treated with an FGFR1c/β-Klotho bispecific Avimer showed improved metabolic parameters and reduced body weight comparable to the effects seen with FGF21. These results not only demonstrate the essential roles of FGFR1c and β-Klotho in mediating the metabolic effects of FGF21, they also describe a first bispecific activator of this unique receptor complex and provide validation for a novel therapeutic approach to target this potentially important pathway for treating diabetes and obesity.
authors: Therapeutic Discovery, Amgen Inc., South San Francisco, California, United States of America.
authors: Richard
authors: R
authors: Smith
authors: Amy
authors: A
authors: Duguay
authors: Alice
authors: A
authors: Bakker
authors: Peng
authors: P
authors: Li
authors: Jennifer
authors: J
authors: Weiszmann
authors: Melissa R
authors: MR
authors: Thomas
authors: Benjamin M
authors: BM
authors: Alba
authors: Xinle
authors: X
authors: Wu
authors: Jamila
authors: J
authors: Gupte
authors: Li
authors: L
authors: Yang
authors: Jennitte
authors: J
authors: Stevens
authors: Agnes
authors: A
authors: Hamburger
authors: Stephen
authors: S
authors: Smith
authors: Jiyun
authors: J
authors: Chen
authors: Renee
authors: R
authors: Komorowski
authors: Kevin W
authors: KW
authors: Moore
authors: Murielle M
authors: MM
authors: Véniant
authors: Yang
authors: Y
authors: Li
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019440:Anti-Obesity Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001665:Binding Sites; D001667:Binding, Competitive; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D005346:Fibroblast Growth Factors / Q000737:chemistry / Q000502:physiology*; D007328:Insulin / Q000097:blood; D000090265:Klotho Proteins; D008252:Macaca fascicularis; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D051379:Mice; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009765:Obesity / Q000097:blood / Q000188:drug therapy*; D010455:Peptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors*; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000737:chemistry; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D012709:Serum Albumin / Q000493:pharmacokinetics / Q000494:pharmacology; D015398:Signal Transduction; D014280:Triglycerides / Q000097:blood
chemical_list: D019440:Anti-Obesity Agents; C584285:C3201 peptide; D007328:Insulin; C538995:KLB protein, human; D008565:Membrane Proteins; D010455:Peptides; D011993:Recombinant Fusion Proteins; D012709:Serum Albumin; D014280:Triglycerides; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; C496371:FGFR4 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051499:Receptor, Fibroblast Growth Factor, Type 4; D000090265:Klotho Proteins
references: Sci Transl Med. 2012 Nov 28;4(162):162ra153
references: 23197570
references: Endocrinology. 2012 Sep;153(9):4192-203
references: 22798348
references: Curr Opin Investig Drugs. 2009 Apr;10(4):359-64
references: 19337957
references: J Biol Chem. 2007 Apr 27;282(17):12650-60
references: 17347147
references: Proc Natl Acad Sci U S A. 2007 May 1;104(18):7432-7
references: 17452648
references: BioDrugs. 2008;22(1):37-44
references: 18215089
references: Biochem Biophys Res Commun. 2010 Jun 11;396(4):793-9
references: 20447380
references: Biosci Biotechnol Biochem. 2009 Mar 23;73(3):688-94
references: 19270384
references: PLoS One. 2011;6(6):e20669
references: 21673953
references: Dev Biol (Basel). 2003;112:135-9
references: 12762512
references: J Biol Chem. 2010 Feb 19;285(8):5165-70
references: 20018895
references: J Biol Chem. 2007 Sep 14;282(37):26687-26695
references: 17623664
references: Endocrinology. 2007 Feb;148(2):774-81
references: 17068132
references: BioDrugs. 2009;23(2):93-109
references: 19489651
references: Mol Endocrinol. 2010 Oct;24(10):2050-64
references: 20667984
references: Chem Biol Drug Des. 2012 Apr;79(4):398-410
references: 22248288
references: Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14379-84
references: 19706524
references: J Cell Physiol. 2009 May;219(2):227-34
references: 19117008
references: PLoS One. 2012;7(11):e49977
references: 23209629
references: Physiol Res. 2009;58(1):1-7
references: 19331512
references: Endocrinology. 2009 Sep;150(9):4084-93
references: 19470704
references: Diabetes. 2012 Feb;61(2):505-12
references: 22210323
references: Biotechnol J. 2008 Jan;3(1):90-7
references: 18041103
references: Cell Metab. 2007 Jun;5(6):415-25
references: 17550777
references: Am J Physiol Endocrinol Metab. 2009 Nov;297(5):E1105-14
references: 19706786
references: J Mol Biol. 2011 May 6;408(3):491-502
references: 21392510
references: FEBS Lett. 2009 Jan 5;583(1):19-24
references: 19059246
references: Cytokine. 1999 Oct;11(10):729-35
references: 10525310
references: Curr Diabetes Rev. 2009 Nov;5(4):216-20
references: 19531026
references: Nat Biotechnol. 2005 Dec;23(12):1556-61
references: 16299519
references: Endocrinology. 2008 Dec;149(12):6018-27
references: 18687777
references: Sci Transl Med. 2011 Dec 14;3(113):113ra126
references: 22174314
references: Toxicol Sci. 1998 Apr;42(2):152-7
references: 9579027
references: Diabetes. 2009 Jan;58(1):250-9
references: 18840786
references: J Interferon Cytokine Res. 2003 Jan;23(1):25-36
references: 12639296
references: J Mol Biol. 2004 Jun 11;339(4):821-34
references: 15165853
references: PLoS One. 2012;7(3):e33603
references: 22457778
references: J Clin Invest. 2005 Jun;115(6):1627-35
references: 15902306
references: Endocrinology. 2009 Nov;150(11):4931-40
references: 19819944
references: Endocr J. 2008 Mar;55(1):23-31
references: 17878606
references: Cell Metab. 2012 Sep 5;16(3):387-93
references: 22958921
references: Metabolism. 2011 Feb;60(2):306-11
references: 20362303
references: Cell. 2000 May 12;101(4):413-24
references: 10830168