We have previously shown that the gp130 cytokines interleukin-6 (IL-6) and ciliary neurotrophic factor (CNTF) can improve obesity and insulin resistance in both mice and humans 1,2. However, due to the known inflammatory effects of IL6 and the antigenic response in some patients to the clinically used form of CNTF (Axokine), both proteins have no therapeutic utility. In an attempt to overcome this issue, we have designed a chimeric gp130 ligand, termed IC7, where one gp130 binding site has been removed from IL6 and replaced with the LIFR binding site from CNTF. This ‘module swap’ creates a new cytokine with CNTF-like, but IL-6R dependent activity. In a series of experiments, we have shown that IC7 has similar positive metabolic effects as CNTF, but may overcome the negative effects experienced by Axokine. Specifically, IC7 significantly improved glucose tolerance and hyperglycemia and prevents weight gain and liver steatosis in obese mice. In addition, we have shown efficacy and safety in a study in non-human primates (Macaca fascicularis). In addition, in comprehensive human cell based assays, we have demonstrated that IC7, unlike Axokine, results in no signs of immunogenicity. Thus IC7 is a realistic and viable next generation biological for the treatment of obesity and T2D, disorders that are currently pandemic.
Supported by the NHMRC Australia