A Novel Fusion of IL-10 Engineered to Traffic across Intestinal Epithelium to Treat Colitis

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.

Treatment of Inflammatory Bowel Disease: A Comprehensive Review

“…However, the longer efficacy and safety of Mongerson for IBD treatment still need further investigation. IL-10 is a kind of proinflammatory cytokine that can decrease a number of proinflammatory signals associated with IBD (233). However, the application of IL-10 has been limited by some side effects (e.g., anemia and thrombocytopenia) and gut-restricted distribution.…”

“…AMT-101 is a chimera produced by genetically fusing non-toxic fragment of cholix to human IL-10 (233). AMT-101 can efficiently cross the epithelial barrier and selectively activate human IL-10 receptors in the intestinal lamina propria (233), which allows IL-10 to play a targeted anti-inflammatory role without causing systemic side effects. Further clinical studies are needed to evaluate the efficacy and safety of AMT-101 for IBD treatment.…”

The Anti-Inflammatory Effect and Mucosal Barrier Protection of Clostridium butyricum RH2 in Ceftriaxone-Induced Intestinal Dysbacteriosis

“…Cyclooxygenase-2 (COX-2), an inducible enzyme, drives inflammation and has been found to be highly expressed in patients with IBD ( Nair et al., 2011 ). Interleukin-10 (IL-10), a potent anti-inflammatory cytokine, is capable of suppressing a number of proinflammatory signals associated with intestinal inflammatory diseases, such as ulcerative colitis and Crohn’s disease ( Fay et al., 2020 ). Previous studies have reported that CB administration reduced inflammatory cytokines, including IL-1β, IL-6, COX-2, and TNF-α, while increased IL-10 expression levels in colon tissue ( Hagihara et al., 2020 ; Liu et al., 2020a ).…”

Preclinical development of a bispecific TNFα/IL-23 neutralising domain antibody as a novel oral treatment for inflammatory bowel disease

“…Biologic therapies aiming to treat IBD via the oral route have been reported at various stages of development [53][54][55][56][57][58] . However, V56B2 is unique in that it is the first orally delivered intestinal protease resistant bispecific antibody to provide dual inhibition of two key, clinically validated, IBD pathways without systemic immunosuppression.…”