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.
MeSH terms
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Amino Acid Sequence
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Animals
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Anti-Obesity Agents / pharmacokinetics
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Anti-Obesity Agents / pharmacology*
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Binding Sites
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Binding, Competitive
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Body Weight / drug effects
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Cell Line
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Drug Evaluation, Preclinical
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Fibroblast Growth Factors / chemistry
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Fibroblast Growth Factors / physiology*
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Insulin / blood
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Klotho Proteins
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Macaca fascicularis
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Male
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Membrane Proteins / antagonists & inhibitors*
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Membrane Proteins / biosynthesis
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Mice
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Molecular Mimicry
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Molecular Sequence Data
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Obesity / blood
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Obesity / drug therapy*
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Peptides / pharmacokinetics
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Peptides / pharmacology*
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Protein Binding
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Rats
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Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors*
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Receptor, Fibroblast Growth Factor, Type 4 / chemistry
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Recombinant Fusion Proteins / antagonists & inhibitors
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Recombinant Fusion Proteins / biosynthesis
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Serum Albumin / pharmacokinetics
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Serum Albumin / pharmacology
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Signal Transduction
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Triglycerides / blood
Substances
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Anti-Obesity Agents
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C3201 peptide
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Insulin
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KLB protein, human
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Membrane Proteins
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Peptides
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Recombinant Fusion Proteins
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Serum Albumin
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Triglycerides
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fibroblast growth factor 21
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Fibroblast Growth Factors
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FGFR4 protein, human
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Receptor, Fibroblast Growth Factor, Type 1
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Receptor, Fibroblast Growth Factor, Type 4
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Klotho Proteins
Grants and funding
These authors have no support or funding to report.