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 ß-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 st...

Authors	Sajiir, H; Keshvari, S; Wong, KY; Borg, DJ; Steyn, FJ; Fercher, C; Taylor, K; Taylor, B; Barnard, RT; Müller, A; Moniruzzaman, M; Miller, G; Wang, R; Fotheringham, A; Schreiber, V; Sheng, YH; Hancock, JL; Loo, D; Burr, L; Huynh, T; Lockett, J; Ramm, GA; Macdonald, GA; Prins, JB; McGuckin, MA; Hasnain, SZ
Journal	Nature Communications
Pages	4528
Volume	15
Date	29/06/2024
Grant ID	Ideas Grant | Department of Health | National Health and Medical Research Council (NHMRC); Development Grant | Department of Health | National Health and Medical Research Council (NHMRC); Clinical Collaborative Grant | Gastroenterological Society of Australia (GESA)
Funding Body
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1038/s41467-024-48317-x