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: Ian N Foltz, Sylvia Hu, Chadwick King, Xinle Wu, Chaofeng Yang, Wei Wang, Jennifer Weiszmann, Jennitte Stevens, Jiyun Sunny Chen, Noi Nuanmanee, Jamila Gupte, Renee Komorowski, Laura Sekirov, Todd Hager, Taruna Arora, Hongfei Ge, Helene Baribault, Fen Wang, Jackie Sheng, Margaret Karow, Minghan Wang, Yongde Luo, Wallace McKeehan, Zhulun Wang, Murielle M Véniant, Yang Li
• Journal: Science translational medicine (Sci Transl Med) Vol. 4 Issue 162 Pg. 162ra153 (Nov 28 2012) ISSN: 1946-6242 [Electronic] United States
• PMID: 23197570 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Epitopes
• Phosphates
• Triglycerides
• fibroblast growth factor 21
• Fibroblast Growth Factors
• Receptor, Fibroblast Growth Factor, Type 1
• Glucuronidase
• Klotho Proteins
• Glucose

Topics

• Adipose Tissue (drug effects, metabolism, pathology)
• Animals
• Antibodies, Monoclonal (pharmacology, therapeutic use)
• Body Weight (genetics)
• Diabetes Mellitus (blood, drug therapy)
• Epitopes (chemistry)
• Fibroblast Growth Factors (immunology)
• Glucose (metabolism)
• Glucuronidase (immunology, metabolism)
• Humans
• Klotho Proteins
• Macaca fascicularis
• Mice
• Obesity (blood, complications, drug therapy)
• Phosphates (blood)
• Receptor, Fibroblast Growth Factor, Type 1 (agonists, metabolism)
• Signal Transduction (drug effects)
• Triglycerides (blood)