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; Mark A. Febbraio

doi:10.1038/s41586-019-1601-9

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 GrötzingerChristoph 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, Mark A. Febbraio

College of Medicine and Public Health

Research output: Contribution to journal › Article › peer-review

38 Citations (Scopus)

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.

Original language	English
Pages (from-to)	63-68
Number of pages	6
Journal	Nature
Volume	574
Issue number	7776
DOIs	https://doi.org/10.1038/s41586-019-1601-9
Publication status	Published - 3 Oct 2019

Keywords

gp130 ligand IC7Fc
gp130
metabolic homeostasis
type 2 diabetes
muscle atrophy

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Findeisen, M., Allen, T. L., Henstridge, D. C., Kammoun, H., Brandon, A. E., Baggio, L. L., Watt, K. I., Pal, M., Cron, L., Estevez, E., Yang, C., Kowalski, G. M., O’Reilly, L., Egan, C., Sun, E., Thai, L. M., Krippner, G., Adams, T. E., Lee, R. S., ... Febbraio, M. A. (2019). Treatment of type 2 diabetes with the designer cytokine IC7Fc. Nature, 574(7776), 63-68. https://doi.org/10.1038/s41586-019-1601-9

@article{2ebd531108ad45f195927fc2dd31f268,

title = "Treatment of type 2 diabetes with the designer cytokine IC7Fc",

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.",

keywords = "gp130 ligand IC7Fc, gp130, metabolic homeostasis, type 2 diabetes, muscle atrophy",

author = "Maria Findeisen and Allen, {Tamara L.} and Henstridge, {Darren C.} and Helene Kammoun and Brandon, {Amanda E.} and Baggio, {Laurie L.} and Watt, {Kevin I.} and Martin Pal and Lena Cron and Emma Estevez and Christine Yang and Kowalski, {Greg M.} and Liam O{\textquoteright}Reilly and Casey Egan and Emily Sun and Thai, {Le May} and Guy Krippner and Adams, {Timothy E.} and Lee, {Robert S.} and Joachim Gr{\"o}tzinger and Christoph Garbers and Steve Risis and Kraakman, {Michael J.} and Mellet, {Natalie A.} and James Sligar and Kimber, {Erica T.} and Young, {Richard L.} and Cowley, {Michael A.} and Bruce, {Clinton R.} and Meikle, {Peter J.} and Baldock, {Paul A.} and Paul Gregorevic and Biden, {Trevor J.} and Cooney, {Gregory J.} and Keating, {Damien J.} and Drucker, {Daniel J.} and Stefan Rose-John and Febbraio, {Mark A.}",

year = "2019",

month = oct,

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doi = "10.1038/s41586-019-1601-9",

language = "English",

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journal = "Nature",

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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 & Febbraio, MA 2019, 'Treatment of type 2 diabetes with the designer cytokine IC7Fc', Nature, vol. 574, no. 7776, pp. 63-68. https://doi.org/10.1038/s41586-019-1601-9

TY - JOUR

T1 - Treatment of type 2 diabetes with the designer cytokine IC7Fc

AU - Findeisen, Maria

AU - Allen, Tamara L.

AU - Henstridge, Darren C.

AU - Kammoun, Helene

AU - Brandon, Amanda E.

AU - Baggio, Laurie L.

AU - Watt, Kevin I.

AU - Pal, Martin

AU - Cron, Lena

AU - Estevez, Emma

AU - Yang, Christine

AU - Kowalski, Greg M.

AU - O’Reilly, Liam

AU - Egan, Casey

AU - Sun, Emily

AU - Thai, Le May

AU - Krippner, Guy

AU - Adams, Timothy E.

AU - Lee, Robert S.

AU - Grötzinger, Joachim

AU - Garbers, Christoph

AU - Risis, Steve

AU - Kraakman, Michael J.

AU - Mellet, Natalie A.

AU - Sligar, James

AU - Kimber, Erica T.

AU - Young, Richard L.

AU - Cowley, Michael A.

AU - Bruce, Clinton R.

AU - Meikle, Peter J.

AU - Baldock, Paul A.

AU - Gregorevic, Paul

AU - Biden, Trevor J.

AU - Cooney, Gregory J.

AU - Keating, Damien J.

AU - Drucker, Daniel J.

AU - Rose-John, Stefan

AU - Febbraio, Mark A.

PY - 2019/10/3

Y1 - 2019/10/3

N2 - 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.

AB - 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.

KW - gp130 ligand IC7Fc

KW - gp130

KW - metabolic homeostasis

KW - type 2 diabetes

KW - muscle atrophy

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U2 - 10.1038/s41586-019-1601-9

DO - 10.1038/s41586-019-1601-9

M3 - Article

C2 - 31554967

AN - SCOPUS:85072943462

VL - 574

SP - 63

EP - 68

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7776

ER -

Treatment of type 2 diabetes with the designer cytokine IC7Fc

Abstract

Keywords

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