Liver and pancreatic-targeted interleukin-22 as a therapeutic for metabolic dysfunction-associated steatohepatitis
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2024-12-01
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Nature Communications
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NATURE PORTFOLIO
Melbourne Authors
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Minerva Elements
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Journal Article
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Sajiir, H., Keshvari, S., Wong, K. Y., Borg, D. J., Steyn, F. J., Fercher, C., Taylor, K., Taylor, B., Barnard, R. T., Müller, A., Moniruzzaman, M., Miller, G., Wang, R., Fotheringham, A., Schreiber, V., Sheng, Y. H., Hancock, J. L., Loo, D., Burr, L. ,... Hasnain, S. Z. (2024). Liver and pancreatic-targeted interleukin-22 as a therapeutic for metabolic dysfunction-associated steatohepatitis. Nature Communications, 15 (1), https://doi.org/10.1038/s41467-024-48317-x.
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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.