A novel fusion of IL-10 engineered to traffic across intestinal epithelium to treat colitis

Nicole C. Fay, Baby Periyanayaki Muthusamy, Linh P. Nyugen, Radhika C. Desai, Alistair Taverner, Julia MacKay, Minji Seung, Tom Hunter, Keyi Liu, Apurva Chandalia, Michael P. Coyle, Hyojin L. Kim, Sally Postlethwaite, Khushdeep Mangat, Lisa Song, Elbert Seto, Aatif Alam, Charles V. Olson, Weijun Feng, Maziyar SaberiTahir A. Mahmood, Randall J. Mrsny

Research output: Contribution to journalArticlepeer-review

Abstract

IL-10 is a potent anti-inflammatory cytokine capable of suppressing a number of proinflammatory signals associated with intestinal inflammatory diseases, such as ulcerative colitis and Crohn's disease. Clinical use of human IL-10 (hIL-10) has been limited by anemia and thrombocytopenia following systemic injection, side effects that might be eliminated by a gut-restricted distribution. We have identified a transcytosis pathway used by cholix, an exotoxin secreted by nonpandemic forms of the intestinal pathogen Vibrio cholerae. A nontoxic fragment of the first 386 aa of cholix was genetically fused to hIL-10 to produce recombinant AMT-101. In vitro and in vivo characterization of AMT-101 showed it to efficiently cross healthy human intestinal epithelium (SMI-100) by a vesicular transcytosis process, activate hIL-10 receptors in an engineered U2OS osteosarcoma cell line, and increase cellular phospho-STAT3 levels in J774.2 mouse macrophage cells. AMT-101 was taken up by inflamed intestinal mucosa and activated pSTAT3 in the lamina propria with limited systemic distribution. AMT-101 administered to healthy mice by oral gavage or to cynomolgus monkeys (nonhuman primates) by colonic spray increased circulating levels of IL-1R antagonist (IL-1Ra). Oral gavage of AMT-101 in two mouse models of induced colitis prevented associated pathological events and plasma cytokine changes. Overall, these studies suggest that AMT-101 can efficiently overcome the epithelial barrier to focus biologically active IL-10 to the intestinal lamina propria.

Original languageEnglish
Pages (from-to)3191-3204
Number of pages14
JournalJournal of Immunology
Volume205
Issue number11
Early online date23 Nov 2020
DOIs
Publication statusPublished - 1 Dec 2020

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this