The Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia.
Nature. 2019 Oct;574(7776):63-68. doi: 10.1038/s41586-019-1601-9. Epub 2019 Sep 25.
The gp130 receptor cytokines IL-6 and CNTF improve metabolic homeostasis but have limited therapeutic use for the treatment of type 2 diabetes. Accordingly, we engineered the gp130 ligand IC7Fc, in which one gp130-binding site is removed from IL-6 and replaced with the LIF-receptor-binding site from CNTF, fused with the Fc domain of immunoglobulin G, creating a cytokine with CNTF-like, but IL-6-receptor-dependent, signalling. Here we show that IC7Fc improves glucose tolerance and hyperglycaemia and prevents weight gain and liver steatosis in mice. In addition, IC7Fc either increases, or prevents the loss of, skeletal muscle mass by activation of the transcriptional regulator YAP1. In human-cell-based assays, and in non-human primates, IC7Fc treatment results in no signs of inflammation or immunogenicity. Thus, IC7Fc is a realistic next-generation biological agent for the treatment of type 2 diabetes and muscle atrophy, disorders that are currently pandemic.
gp130 受体细胞因子 IL-6 和 CNTF 可改善代谢稳态，但在治疗 2 型糖尿病方面的治疗用途有限。因此，我们设计了 gp130 配体 IC7Fc，它从 IL-6 中去除了一个 gp130 结合位点，并被 CNTF 的 LIF 受体结合位点取代，与免疫球蛋白 G 的 Fc 结构域融合，从而产生了一种具有 CNTF 样但依赖于 IL-6 受体的信号转导的细胞因子。在这里，我们表明 IC7Fc 可改善葡萄糖耐量和高血糖，并预防小鼠体重增加和肝脏脂肪变性。此外，IC7Fc 通过激活转录调节剂 YAP1 增加或防止骨骼肌质量的损失。在基于人类细胞的测定和非人类灵长类动物中，IC7Fc 治疗没有炎症或免疫原性的迹象。因此，IC7Fc 是治疗 2 型糖尿病和肌肉萎缩症的一种现实的下一代生物制剂，这两种疾病目前都很流行。
