Treatment of type 2 diabetes with the designer cytokine IC7Fc

Maria Findeisen^#¹, Tamara L Allen^#², Darren C Henstridge², Helene Kammoun², Amanda E Brandon^{1

3}, Laurie L Baggio⁴, Kevin I Watt⁵, Martin Pal^{1

6}, Lena Cron¹, Emma Estevez¹, Christine Yang², Greg M Kowalski^{2

7}, Liam O'Reilly¹, Casey Egan⁸, Emily Sun⁹, Le May Thai¹, Guy Krippner², Timothy E Adams¹⁰, Robert S Lee², Joachim Grötzinger¹¹, Christoph Garbers¹², Steve Risis², Michael J Kraakman², Natalie A Mellet², James Sligar¹, Erica T Kimber¹, Richard L Young¹³, Michael A Cowley¹⁴, Clinton R Bruce^{2

7}, Peter J Meikle², Paul A Baldock¹, Paul Gregorevic⁵, Trevor J Biden¹, Gregory J Cooney^{1

3}, Damien J Keating⁹, Daniel J Drucker⁴, Stefan Rose-John¹¹, Mark A Febbraio^{15

16

17}

Affiliations

¹ The Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
² Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia.
³ Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia.
⁴ Department of Medicine, Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
⁵ Centre of Muscle Research, Department of Physiology, The University of Melbourne, Melbourne, Victoria, Australia.
⁶ Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia.
⁷ Institute for Physical Activity and Nutrition, Deakin University, Melbourne, Victoria, Australia.
⁸ Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia.
⁹ Molecular & Cellular Physiology Laboratory, Flinders University, Adelaide, South Australia, Australia.
¹⁰ CSIRO Manufacturing, Melbourne, Victoria, Australia.
¹¹ Department of Biochemistry, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
¹² Institut Für Pathologie, Otto von Guericke University, Magdeburg, Germany.
¹³ Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.
¹⁴ Department of Physiology, Monash University, Melbourne, Victoria, Australia.
¹⁵ The Garvan Institute of Medical Research, Sydney, New South Wales, Australia. mark.febbraio@monash.edu.
¹⁶ Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia. mark.febbraio@monash.edu.
¹⁷ Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia. mark.febbraio@monash.edu.

^# Contributed equally.

PMID: 31554967
DOI: 10.1038/s41586-019-1601-9

Treatment of type 2 diabetes with the designer cytokine IC7Fc

Maria Findeisen et al. Nature. 2019 Oct.

. 2019 Oct;574(7776):63-68.

doi: 10.1038/s41586-019-1601-9. Epub 2019 Sep 25.

Authors

Affiliations

¹ The Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
² Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia.
³ Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia.
⁴ Department of Medicine, Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
⁵ Centre of Muscle Research, Department of Physiology, The University of Melbourne, Melbourne, Victoria, Australia.
⁶ Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia.
⁷ Institute for Physical Activity and Nutrition, Deakin University, Melbourne, Victoria, Australia.
⁸ Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia.
⁹ Molecular & Cellular Physiology Laboratory, Flinders University, Adelaide, South Australia, Australia.
¹⁰ CSIRO Manufacturing, Melbourne, Victoria, Australia.
¹¹ Department of Biochemistry, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
¹² Institut Für Pathologie, Otto von Guericke University, Magdeburg, Germany.
¹³ Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.
¹⁴ Department of Physiology, Monash University, Melbourne, Victoria, Australia.
¹⁵ The Garvan Institute of Medical Research, Sydney, New South Wales, Australia. mark.febbraio@monash.edu.
¹⁶ Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia. mark.febbraio@monash.edu.
¹⁷ Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia. mark.febbraio@monash.edu.

^# Contributed equally.

PMID: 31554967
DOI: 10.1038/s41586-019-1601-9

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.

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Comment in

Designing a new therapy for T2DM.
Greenhill C. Greenhill C. Nat Rev Endocrinol. 2019 Dec;15(12):684. doi: 10.1038/s41574-019-0272-9. Nat Rev Endocrinol. 2019. PMID: 31591504 No abstract available.
Building a designer cytokine to treat type 2 diabetes.
Paiva SL. Paiva SL. Nat Rev Drug Discov. 2019 Oct;18(11):825. doi: 10.1038/d41573-019-00168-8. Nat Rev Drug Discov. 2019. PMID: 31673130 No abstract available.

References

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Treatment of type 2 diabetes with the designer cytokine IC7Fc

Affiliations

Treatment of type 2 diabetes with the designer cytokine IC7Fc

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