Building a designer cytokine to treat type 2 diabetes

Abstract

volume 18 | NovemBeR 2019 | 825 Although multiple drug classes have been developed to treat type 2 diabetes (T2D), there is still an unmet need for a drug that reverses disease progression. Febbraio and colleagues have now engineered a chimeric cytokine that prevents weight gain and liver steatosis in mouse models, with a safety profile that could allow progression to clinical trials. The gp130-dependent cytokines interleukin-6 (IL-6) and ciliary neurotrophic factor (CNTF) regulate food intake, body weight and insulin resistance in mice and humans. However, therapeutic application of these cytokines has been hampered by adverse effects: IL-6 also has proinflammatory effects, and a recombinant human CNTF drug candidate that entered clinical development for obesity and T2D failed owing to unwanted antidrug immune responses. Mechanistically, IL-6 binds to the IL-6 receptor (IL-6R), a complex that then engages gp130, while CNTF binds to the CNTF receptor (CNTFR), which together bind gp130 and the LIF receptor (LIFR). With the aim of circumventing potential side effects, Febbraio and colleagues fused the key LIFRbinding module of CNTF to IL-6 — coupled to the fragment crystallizable domain of IgG (Fc) — generating the chimeric protein IC7Fc. As this chimeric protein largely consists of IL-6 residues, it is less likely to induce an antidrug immune response compared with CNTF. In addition, because IC7Fc exhibits a unique sequence and structure, any neutralizing antibodies against it will be less likely to interfere with endogenous protein activity. Treating mice that had been fed a highfat diet (HFD) with IC7Fc (1 mg kg−1 for 7 days intraperitoneally (i.p.)) resulted in a decrease in body mass and fat mass, without any effect on lean mass. Fasting glucose levels were markedly reduced, with a corresponding improvement in glucose tolerance and a decrease in hepatosteatosis. Mechanistically, chronic IC7Fc treatment decreased body weight, fat mass and liver