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第六届胶原蛋白行业论坛第一轮通知

以糖尿病为标靶的抗体开发成功

2011/12/19 来源:中国生物技术信息网
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导读
在这项研究中,研究人员研发出了可以在小鼠体内对抗高血糖的抗体。这些蛋白质可能被用来研发治疗II型糖尿病的新药。

Science  Translational  Medicine杂志刊登了一项最新研究成果"Amelioration  of  Type  2  Diabetes  by  Antibody-Mediated  Activation  of  Fibroblast  Growth  Factor  Receptor  1",在这项研究中,研究人员研发出了可以在小鼠体内对抗高血糖的抗体。这些蛋白质可能被用来研发治疗II型糖尿病的新药。

II型糖尿病是最常见形式的糖尿病,它是在当胰脏停止制造胰岛素的时候或是当身体停止对胰岛素做出反应时(称作胰岛素抵抗)出现的。在没有足够胰岛素供应的情况下,身体无法将血糖从血液中运送到那些用糖作为能源的细胞内。相反,糖会在血液中积聚,并大肆破坏心脏、血管、神经、眼睛甚或皮肤。在分子水平,II型糖尿病与一族成纤维细胞生长因子或FGF蛋白及它们的受体有关联。  这些生长因子中的某一些显示出有望逆转肥胖和其它与糖尿病有关的疾病。  

例如,在先前的研究中,身体超重并有糖尿病的小鼠在得到一种叫做FGF21的生长因子蛋白治疗后重新恢复了正常的代谢并减轻了体重(无需在跑步机上花多个小时运动)。然而,在人身上尝试用这种燃烧脂肪的蛋白质却失败了。在一周之内,与那些接受某种非特异性的对照抗体的糖尿病小鼠相比,那些接受了抗体注射的糖尿病小鼠的血糖缩减至接近正常的水平(且没有任何有害的副作用)。  

该治疗还帮助糖尿病小鼠减轻了体重,表明FGFR1在糖尿病和肥胖症中都起着某种作用。重要的是,这些抗体的生产容易并可长时间地在体内保持活性,使得它们在将来的对受到II型糖尿病折磨的病人的临床试验中有望成为候选药物。

 

Amelioration of Type 2 Diabetes by Antibody-Mediated Activation of Fibroblast Growth Factor Receptor 1

Ai-Luen Wu, Ganesh Kolumam, Scott Stawicki, Yongmei Chen, Jun Li, Jose Zavala-Solorio


Clinical use of recombinant fibroblast growth factor 21 (FGF21) for the treatment of type 2 diabetes and other disorders linked to obesity has been proposed; however, its clinical development has been challenging owing to its poor pharmacokinetics. Here, we describe an alternative antidiabetic strategy using agonistic anti-FGFR1 (FGF receptor 1) antibodies (R1MAbs) that mimic the metabolic effects of FGF21. A single injection of R1MAb into obese diabetic mice induced acute and sustained amelioration of hyperglycemia, along with marked improvement in hyperinsulinemia, hyperlipidemia, and hepatosteatosis. R1MAb activated the mitogen-activated protein kinase pathway in adipose tissues, but not in liver, and neither FGF21 nor R1MAb improved glucose clearance in lipoatrophic mice, which suggests that adipose tissues played a central role in the observed metabolic effects. In brown adipose tissues, both FGF21 and R1MAb induced phosphorylation of CREB (cyclic adenosine 5′-monophosphate response element–binding protein), and mRNA expression of PGC-1α (peroxisome proliferator–activated receptor-γ coactivator 1α) and the downstream genes associated with oxidative metabolism. Collectively, we propose FGFR1 in adipose tissues as a major functional receptor for FGF21, as an upstream regulator of PGC-1α, and as a compelling target for antibody-based therapy for type 2 diabetes and other obesity-associated disorders.

文献链接:http://stm.sciencemag.org/content/3/113/113ra126

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