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Treatment of type 2 diabetes with the designer cytokine IC7Fc

Version 2 2024-06-04, 14:50
Version 1 2019-10-17, 11:21
journal contribution
posted on 2024-06-04, 14:50 authored by M Findeisen, TL Allen, DC Henstridge, H Kammoun, AE Brandon, LL Baggio, KI Watt, M Pal, L Cron, E Estevez, C Yang, Greg KowalskiGreg Kowalski, L O’Reilly, C Egan, E Sun, LM Thai, G Krippner, TE Adams, RS Lee, J Grötzinger, C Garbers, S Risis, MJ Kraakman, NA Mellet, J Sligar, ET Kimber, RL Young, MA Cowley, Clinton BruceClinton Bruce, PJ Meikle, PA Baldock, P Gregorevic, TJ Biden, GJ Cooney, DJ Keating, DJ Drucker, S Rose-John, MA Febbraio
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.

History

Journal

Nature

Volume

574

Pagination

63-68

Location

England

ISSN

0028-0836

eISSN

1476-4687

Language

English

Publication classification

C1 Refereed article in a scholarly journal

Copyright notice

2019, The Author(s), under exclusive licence to Springer Nature Limited.

Issue

7776

Publisher

NATURE PORTFOLIO