Development of a therapeutic monoclonal antibody that targets secreted fatty acid-binding protein aP2 to treat type 2 diabetes
Development of a therapeutic monoclonal antibody that targets secreted fatty acid-binding protein aP2 to treat type 2 diabetes
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DOI：
10.1126/scitranslmed.aac6336
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发表时间：
2015-12-23
影响因子：
17.1
通讯作者：
Hotamisligil, Goekhan S.
中科院分区：
文献类型：
--
作者：
Burak, M. Furkan;Inouye, Karen E.;Hotamisligil, Goekhan S.
脂质伴侣aP 2/FABP 4已经涉及许多免疫代谢疾病的病理学，包括人类的糖尿病，但是aP 2尚未被靶向用于治疗应用。aP 2不仅是一种细胞内蛋白质，而且是一种活性脂肪因子，通过促进肝脏新生和干扰外周胰岛素作用而导致高血糖。血清aP 2水平在小鼠和人类肥胖中显著升高，并且与代谢并发症强烈相关。这些观察结果提高了通过用针对aP 2的单克隆抗体（mAb）靶向血清aP 2来治疗代谢疾病的新策略的可能性。我们评估了针对aP 2的mAb，并确定了一种CA 33，其在肥胖小鼠模型中降低空腹血糖，改善全身葡萄糖代谢，增加全身胰岛素敏感性，并减少脂肪量和肝脏脂肪变性。我们检查了aP 2-CA 33复合物的结构，并通过晶体学研究与另一种缺乏体内功效的mAb相比解析了靶表位。在高胰岛素-正葡萄糖钳夹研究中，我们发现CA 33的抗糖尿病作用主要与肝脏葡萄糖输出和外周葡萄糖利用的调节有关。该抗体在aP 2缺陷小鼠中没有作用，证明了其靶特异性。我们的结论是aP 2单克隆抗体介导的治疗构成了一个可行的方法治疗糖尿病。
The lipid chaperone aP2/FABP4 has been implicated in the pathology of many immunometabolic diseases, including diabetes in humans, but aP2 has not yet been targeted for therapeutic applications. aP2 is not only an intracellular protein but also an active adipokine that contributes to hyperglycemia by promoting hepatic gluconeogenesis and interfering with peripheral insulin action. Serum aP2 levels are markedly elevated in mouse and human obesity and strongly correlate with metabolic complications. These observations raise the possibility of a new strategy to treat metabolic disease by targeting serum aP2 with a monoclonal antibody (mAb) to aP2. We evaluated mAbs to aP2 and identified one, CA33, that lowered fasting blood glucose, improved systemic glucose metabolism, increased systemic insulin sensitivity, and reduced fat mass and liver steatosis in obese mouse models. We examined the structure of the aP2-CA33 complex and resolved the target epitope by crystallographic studies in comparison to another mAb that lacked efficacy in vivo. In hyperinsulinemic-euglycemic clamp studies, we found that the antidiabetic effect of CA33 was predominantly linked to the regulation of hepatic glucose output and peripheral glucose utilization. The antibody had no effect in aP2-deficient mice, demonstrating its target specificity. We conclude that an aP2 mAb-mediated therapeutic constitutes a feasible approach for the treatment of diabetes.