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

Interleukin-22 Interleukins / metabolism Animals Liver / metabolism Pancreas / pathology Humans Mice Fatty Liver / drug therapy Male Mice, Inbred C57BL Disease Models, Animal Insulin Resistance Receptors, Interleukin / metabolism

Journal

Nature communications

ISSN: 2041-1723

Titre abrégé: Nat Commun

Pays: England

ID NLM: 101528555

Informations de publication

Date de publication:
29 May 2024

Historique:

received: 25 09 2023

accepted: 26 04 2024

medline: 30 5 2024

pubmed: 30 5 2024

entrez: 29 5 2024

Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-024-48317-x PMID: 38811532

pubmed: 38811532

doi: 10.1038/s41467-024-48317-x

pii: 10.1038/s41467-024-48317-x

doi:

Substances chimiques

Interleukin-22 0

Interleukins 0

interleukin-22 receptor 0

Receptors, Interleukin 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

4528

Subventions

Organisme : Department of Health | National Health and Medical Research Council (NHMRC)

ID : Ideas Grant

Organisme : Department of Health | National Health and Medical Research Council (NHMRC)

ID : Development Grant

Organisme : Gastroenterological Society of Australia (GESA)

ID : Clinical Collaborative Grant

Informations de copyright

Références

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