TY - JOUR
T1 - Treating diabetes and obesity with an FGF21-mimetic antibody activating the βKlotho/FGFR1c receptor complex
AU - Foltz, Ian N.
AU - Hu, Sylvia
AU - King, Chadwick
AU - Wu, Xinle
AU - Yang, Chaofeng
AU - Wang, Wei
AU - Weiszmann, Jennifer
AU - Stevens, Jennitte
AU - Chen, Jiyun Sunny
AU - Nuanmanee, Noi
AU - Gupte, Jamila
AU - Komorowski, Renee
AU - Sekirov, Laura
AU - Hager, Todd
AU - Arora, Taruna
AU - Ge, Hongfei
AU - Baribault, Helene
AU - Wang, Fen
AU - Sheng, Jackie
AU - Karow, Margaret
AU - Wang, Minghan
AU - Luo, Yongde
AU - McKeehan, Wallace
AU - Wang, Zhulun
AU - Véniant, Murielle M.
AU - Li, Yang
PY - 2012/11/28
Y1 - 2012/11/28
N2 - 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 bKlotho 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 bKlotho 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.
AB - 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 bKlotho 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 bKlotho 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.
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U2 - 10.1126/scitranslmed.3004690
DO - 10.1126/scitranslmed.3004690
M3 - Article
C2 - 23197570
AN - SCOPUS:84870359606
SN - 1946-6234
VL - 4
JO - Science translational medicine
JF - Science translational medicine
IS - 162
M1 - 162ra153
ER -