Treatment of type 2 diabetes with the designer cytokine IC7Fc

Maria Findeisen, Tamara L. Allen, Darren C. Henstridge, Helene Kammoun, Amanda E. Brandon, Laurie L. Baggio, Kevin I. Watt, Martin Pal, Lena Cron, Emma Estevez, Christine Yang, Greg M. Kowalski, Liam O’Reilly, Casey Egan, Emily Sun, Le May Thai, Guy Krippner, Timothy E. Adams, Robert S. Lee, Joachim Grötzinger, Christoph Garbers, Steve Risis, Michael J. Kraakman, Natalie A. Mellet, James Sligar, Erica T. Kimber, Richard L. Young, Michael A. Cowley, Clinton R. Bruce, Peter J. Meikle, Paul A. Baldock, Paul Gregorevic, Trevor J. Biden, Gregory J. Cooney, Damien J. Keating, Daniel J. Drucker, Stefan Rose-John and Mark A. Febbraio ()
Additional contact information
Maria Findeisen: The Garvan Institute of Medical Research
Tamara L. Allen: Baker Heart & Diabetes Institute
Darren C. Henstridge: Baker Heart & Diabetes Institute
Helene Kammoun: Baker Heart & Diabetes Institute
Amanda E. Brandon: The Garvan Institute of Medical Research
Laurie L. Baggio: University of Toronto
Kevin I. Watt: The University of Melbourne
Martin Pal: The Garvan Institute of Medical Research
Lena Cron: The Garvan Institute of Medical Research
Emma Estevez: The Garvan Institute of Medical Research
Christine Yang: Baker Heart & Diabetes Institute
Greg M. Kowalski: Baker Heart & Diabetes Institute
Liam O’Reilly: The Garvan Institute of Medical Research
Casey Egan: Monash University
Emily Sun: Flinders University
Le May Thai: The Garvan Institute of Medical Research
Guy Krippner: Baker Heart & Diabetes Institute
Timothy E. Adams: CSIRO Manufacturing
Robert S. Lee: Baker Heart & Diabetes Institute
Joachim Grötzinger: Christian-Albrechts-Universität zu Kiel
Christoph Garbers: Otto von Guericke University
Steve Risis: Baker Heart & Diabetes Institute
Michael J. Kraakman: Baker Heart & Diabetes Institute
Natalie A. Mellet: Baker Heart & Diabetes Institute
James Sligar: The Garvan Institute of Medical Research
Erica T. Kimber: The Garvan Institute of Medical Research
Richard L. Young: University of Adelaide
Michael A. Cowley: Monash University
Clinton R. Bruce: Baker Heart & Diabetes Institute
Peter J. Meikle: Baker Heart & Diabetes Institute
Paul A. Baldock: The Garvan Institute of Medical Research
Paul Gregorevic: The University of Melbourne
Trevor J. Biden: The Garvan Institute of Medical Research
Gregory J. Cooney: The Garvan Institute of Medical Research
Damien J. Keating: Flinders University
Daniel J. Drucker: University of Toronto
Stefan Rose-John: Christian-Albrechts-Universität zu Kiel
Mark A. Febbraio: The Garvan Institute of Medical Research

Nature, 2019, vol. 574, issue 7776, 63-68

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1601-9

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