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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.
Type 2 diabetes (T2D) is highly prevalent, with an estimated 370 million affected individuals worldwide, and this is predicted to double by 20301,2. Despite the presence of several well-established drug classes for treating T2D, there is still a considerable unmet need for a drug that halts or reverses disease progression. The gp130 receptor cytokines IL-6 and CNTF modify food intake and body weight and improve insulin resistance in mice and humans3-6. Axokine, the human variant of CNTF, underwent human clinical trials for the treatment of amyotrophic lateral sclerosis, but the drug was repurposed to treat obesity and T2D7-9. After showing promise, the clinical development of Axokine was discontinued when some treated patients developed antibodies9, because of the fear that this could interfere with the neuroprotective action of endogenous CNTF. Although IL-6 protects against obesity and insulin resistance10, it is also pro-inflammatory owing-in part-to its 'trans-signalling' effects11,12, which limits its therapeutic utility.
The gp130 cytokines signal by binding to the cytokine a-receptors, which are the IL-6 receptor (IL-6R) and CNTF receptor (CNTFR) for IL-6 and CNTF, respectively. Binding initiates the recruitment and dimerization of two transmembrane ß-receptors: the IL-6-IL-6R complex binds two gp130 receptors as a homodimer, whereas the CNTF-CNTFR complex binds gp130 receptor and the LIF receptor (LIFR) as a heterodimer13. By transferring the LIFR-binding module from CNTF to IL-6, we engineered the chimeric protein IC714, which predominantly consists of IL-6 residues, rendering...