Treatment of type 2 diabetes with the designer cytokine IC7Fc

• Published in: Nature (London) Vol. 574; no. 7776; pp. 63 - 68
• Main Authors: Findeisen, Maria, Allen, Tamara L., Henstridge, Darren C., Kammoun, Helene, Brandon, Amanda E., Baggio, Laurie L., Watt, Kevin I., Pal, Martin, Cron, Lena, Estevez, Emma, Yang, Christine, Kowalski, Greg M., O’Reilly, Liam, Egan, Casey, Sun, Emily, Thai, Le May, Krippner, Guy, Adams, Timothy E., Lee, Robert S., Grötzinger, Joachim, Garbers, Christoph, Risis, Steve, Kraakman, Michael J., Mellet, Natalie A., Sligar, James, Kimber, Erica T., Young, Richard L., Cowley, Michael A., Bruce, Clinton R., Meikle, Peter J., Baldock, Paul A., Gregorevic, Paul, Biden, Trevor J., Cooney, Gregory J., Keating, Damien J., Drucker, Daniel J., Rose-John, Stefan, Febbraio, Mark A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2019; Nature Publishing Group
• Subjects: 631/154/51/2313; 631/443/319/1642/2037; Adaptor Proteins, Signal Transducing - metabolism; Animals; Atrophy; Binding sites; Binding, Competitive; Biological weapons; Care and treatment; Cytokine Receptor gp130 - metabolism; Cytokines; Cytokines - chemical synthesis; Cytokines - chemistry; Cytokines - therapeutic use; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diabetes therapy; Drug Design; Fatty liver; Fatty Liver - prevention & control; Glucose; Glucose tolerance; Glucose Tolerance Test; Glycoprotein gp130; Health aspects; Homeostasis; Humanities and Social Sciences; Humans; Hyperglycemia; Hyperglycemia - drug therapy; Hyperglycemia - metabolism; Immunogenicity; Immunoglobulin G; Immunoglobulin G - therapeutic use; Incretins - metabolism; Insulin resistance; Interleukin 6; Interleukin-6 - antagonists & inhibitors; Interleukin-6 - metabolism; Kinases; Ligands; Liver; Male; Metabolism; Mice; multidisciplinary; Muscle, Skeletal - drug effects; Muscles; Musculoskeletal system; Obesity; Obesity - metabolism; Pancreas - metabolism; Pandemics; Patient outcomes; Peptides; Phosphoproteins - metabolism; Phosphorylation; Polyethylene glycol; Primates; Protein Engineering; Proteins; Receptors, Interleukin-6 - metabolism; Recombinant Fusion Proteins - therapeutic use; Science; Science (multidisciplinary); Signal Transduction; Skeletal muscle; Steatosis; Transcription activation; Transcription Factors; Type 2 diabetes; Weight Gain - drug effects; Yes-associated protein; Australia
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-019-1601-9

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. The chimeric cytokine IC7Fc combines the beneficial effects of the cytokines IL-6 and CNTF on weight loss and metabolism in mice, with no obvious side effects in mice and non-human primates.