Liver and pancreatic-targeted interleukin-22 as a therapeutic for metabolic dysfunction-associated steatohepatitis

Haressh Sajiir, Sahar Keshvari, Kuan Yau Wong, Danielle J. Borg, Frederik J. Steyn, Christian Fercher, Karin Taylor, Breten Taylor, Ross T. Barnard, Alexandra Müller, Md Moniruzzaman, Gregory Miller, Ran Wang, Amelia Fotheringham, Veronika Schreiber, Yong Hua Sheng, Janelle Louise Hancock, Dorothy Loo, Lucy Burr, Tony Huynh, Jack Lockett, Grant A. Ramm, Graeme A. Macdonald, Johannes B. Prins, Michael A. McGuckin and Sumaira Z. Hasnain ()
Additional contact information
Haressh Sajiir: Mater Research Institute-The University of Queensland, Translational Research Institute
Sahar Keshvari: Mater Research Institute-The University of Queensland, Translational Research Institute
Kuan Yau Wong: Mater Research Institute-The University of Queensland, Translational Research Institute
Danielle J. Borg: Mater Research Institute-The University of Queensland, Translational Research Institute
Frederik J. Steyn: The University of Queensland
Christian Fercher: The University of Queensland
Karin Taylor: The University of Queensland
Breten Taylor: The University of Queensland
Ross T. Barnard: The University of Queensland
Alexandra Müller: Mater Research Institute-The University of Queensland, Translational Research Institute
Md Moniruzzaman: Mater Research Institute-The University of Queensland, Translational Research Institute
Gregory Miller: The University of Queensland
Ran Wang: Mater Research Institute-The University of Queensland, Translational Research Institute
Amelia Fotheringham: Mater Research Institute-The University of Queensland, Translational Research Institute
Veronika Schreiber: Mater Research Institute-The University of Queensland, Translational Research Institute
Yong Hua Sheng: Mater Research Institute-The University of Queensland, Translational Research Institute
Janelle Louise Hancock: Translational Research Institute
Dorothy Loo: Translational Research Institute
Lucy Burr: Mater Research Institute-The University of Queensland, Translational Research Institute
Tony Huynh: Queensland Children’s Hospital
Jack Lockett: Mater Research Institute-The University of Queensland, Translational Research Institute
Grant A. Ramm: The University of Queensland
Graeme A. Macdonald: The University of Queensland
Johannes B. Prins: Royal Brisbane and Women’s Hospital
Michael A. McGuckin: University of Melbourne
Sumaira Z. Hasnain: Mater Research Institute-The University of Queensland, Translational Research Institute

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Metabolic dysfunction-associated steatohepatitis (MASH) is the most prevalent cause of liver disease worldwide, with a single approved therapeutic. Previous research has shown that interleukin-22 (IL-22) can suppress β-cell stress, reduce local islet inflammation, restore appropriate insulin production, reverse hyperglycemia, and ameliorate insulin resistance in preclinical models of diabetes. In clinical trials long-acting forms of IL-22 have led to increased proliferation in the skin and intestine, where the IL-22RA1 receptor is highly expressed. To maximise beneficial effects whilst reducing the risk of epithelial proliferation and cancer, we designed short-acting IL-22-bispecific biologic drugs that successfully targeted the liver and pancreas. Here we show 10-fold lower doses of these bispecific biologics exceed the beneficial effects of native IL-22 in multiple preclinical models of MASH, without off-target effects. Treatment restores glycemic control, markedly reduces hepatic steatosis, inflammation, and fibrogenesis. These short-acting IL-22-bispecific targeted biologics are a promising new therapeutic approach for MASH.

Date: 2024
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DOI: 10.1038/s41467-024-48317-x

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