Treating Diabetes and Obesity with an FGF21-Mimetic Antibody Activating the βKlotho/FGFR1c Receptor Complex
Treating Diabetes and Obesity with an FGF21-Mimetic Antibody Activating the βKlotho/FGFR1c Receptor Complex
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DOI：
10.1126/scitranslmed.3004690
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发表时间：
2012-11-28
影响因子：
17.1
通讯作者：
Li, Yang
中科院分区：
文献类型：
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作者：
Foltz, Ian N.;Hu, Sylvia;Li, Yang
成纤维细胞生长因子21(FGF21)是成纤维细胞生长因子家族中一个独特的成员，对血脂、体重和糖代谢有很大的益处，作为一种潜在的治疗糖尿病和肥胖症的药物引起了人们的极大兴趣。作为天然FGF21的替代，我们开发了一种单抗MimAb1，它与βKlotho高亲和力结合，并特异性地激活来自Beta Klotho/FGFR1c(成纤维细胞生长因子受体1c)受体复合体的信号。在肥胖的食蟹猴中，注射miAb1导致了类似FGF21的代谢效应，包括在耐力测试期间体重、血浆胰岛素、甘油三酯和葡萄糖的减少。具有脂肪选择性FGFR1基因敲除的小鼠对FGF21诱导的糖代谢和体重的改善无效。在肥胖猴子(MimAb1)和FGFR1基因敲除小鼠(FGF21)上的这些结果证明了FGFR1c在FGF21功能中的重要作用，并表明脂肪是细胞因子和抗体的关键靶组织。由于MimAb1依赖bKlotho来激活FGFR1c，因此预计它不会单独激活FGFR1c而引起副作用。一种抗体可以通过细胞表面受体激活FGF21样信号，这一出人意料的发现为糖尿病和肥胖症的创新治疗方法提供了临床前验证。
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 beta Klotho with high affinity and specifically activates signaling from the beta Klotho/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.