1. Treatment of type 2 diabetes with the designer cytokine IC7Fc.
- Author
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Findeisen M, Allen TL, Henstridge DC, Kammoun H, Brandon AE, Baggio LL, Watt KI, Pal M, Cron L, Estevez E, Yang C, Kowalski GM, O'Reilly L, Egan C, Sun E, Thai LM, Krippner G, Adams TE, Lee RS, Grötzinger J, Garbers C, Risis S, Kraakman MJ, Mellet NA, Sligar J, Kimber ET, Young RL, Cowley MA, Bruce CR, Meikle PJ, Baldock PA, Gregorevic P, Biden TJ, Cooney GJ, Keating DJ, Drucker DJ, Rose-John S, and Febbraio MA
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Animals, Binding, Competitive, Cytokines chemistry, Diabetes Mellitus, Type 2 metabolism, Drug Design, Fatty Liver prevention & control, Glucose Tolerance Test, Humans, Hyperglycemia drug therapy, Hyperglycemia metabolism, Incretins metabolism, Interleukin-6 antagonists & inhibitors, Interleukin-6 metabolism, Male, Mice, Muscle, Skeletal drug effects, Obesity metabolism, Pancreas metabolism, Phosphoproteins metabolism, Protein Engineering, Receptors, Interleukin-6 metabolism, Signal Transduction, Transcription Factors, Weight Gain drug effects, YAP-Signaling Proteins, Cytokine Receptor gp130 metabolism, Cytokines chemical synthesis, Cytokines therapeutic use, Diabetes Mellitus, Type 2 drug therapy, Immunoglobulin G therapeutic use, Recombinant Fusion Proteins therapeutic use
- Abstract
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.
- Published
- 2019
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