FGF21 Can Be Mimicked In Vitro and In Vivo by a Novel Anti-FGFR1c/β-Klotho Bispecific Protein

• DOI: 10.1371/journal.pone.0061432
• Publication Date: 2013-04-23T03:07:35Z
• Authors: Richard Smith; Amy Duguay; Alice Bakker; Peng Li; Jennifer Weiszmann; Melissa R. Thomas; Benjamin M. Alba; Xinle Wu; Jamila Gupte; Li Yang; Jennitte Stevens; Agnes Hamburger; Stephen Smith; Jiyun Chen; Renee Komorowski; Kevin W. Moore; Murielle M. Véniant; Yang Li
• Keywords: Male; Science; Molecular Sequence Data; Drug Evaluation, Preclinical; Binding, Competitive; Cell Line; Mice; 03 medical and health sciences; Animals; Insulin; Amino Acid Sequence; Obesity; Klotho Proteins; 2. Zero hunger; 0303 health sciences; Binding Sites; Q; Body Weight; Molecular Mimicry; R; Membrane Proteins; 3. Good health; Fibroblast Growth Factors; Macaca fascicularis; Medicine; Anti-Obesity Agents; Peptides; Research Article; Protein Binding

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.