Researchers from the University of Bath in the United Kingdom and Applied Molecular Transport in San Francisco, California, have developed and characterized a novel therapeutic, based on the anti-inflammatory signalling molecule interleukin-10 (IL-10) and a component of a molecule secreted by the bacteria that causes Cholera, that could be used to control damaging inflammation associated with inflammatory bowel diseases.
Some patients with Inflammatory bowel diseases (IBD) such as Crohn’s disease and Ulcerative colitis have reduced levels of interleukin-10, which is known to be important for regulating the activity of the immune system in the gastrointestinal tract, where the clinical manifestations of IBD occur.
The administration of exogenous IL-10 to counter this deficiency and treat IBD has been attempted and shown promise in animal studies, but to a lesser extent in human clinical trials in large part due to side effects such as anemia and reduced platelet levels that result from the systemic administration of the drug, which may require especially high doses to achieve clinical effects.
If the systemic administration of IL-10 could be avoided, and the drug delivered directly to the intestinal mucosa, it is possible that IL-10 could be used effectively to treat IBD without causing toxicities.
Thus, the scientists sought to develop a novel approach to deliver IL-10 to the intestinal mucosa while avoiding intravenous administration. Their solution: a component of cholera toxin, a protein produced by Vibrio Cholerae, the bacteria that causes the deadly illness Cholera.
Their research was published in The Journal of Immunology under the title, “A Novel Fusion of IL-10 Engineered to Traffic across Intestinal Epithelium to Treat Colitis.”
The scientists used genetic engineering to fuse a fragment of cholix, an exotoxin produced by Vibrio Cholera, to human IL-10 to produce AMT-101, their novel treatment for IBD.
Under normal circumstances, the fragment of cholix, known as the transcytosis domain, would enable Vibrio Cholera’s damaging toxins to enter and harm intestinal epithelial cells. In this case, however, the protein instead supports the uptake of IL-10.
AMT-101 was shown by the researchers to “efficiently” cross the intestinal epithelium, activate receptors for IL-10, and induce anti-inflammatory changes in macrophages, a subset of white blood cell, during in vitro experiments.
Studies in mice and nonhuman primates showed that the drug increased the levels of an anti-inflammatory molecule known as IL-1Ra in the blood, indicating the ability of the drug to regulate the immune system even after their unusual administration approach.
Oral administration of the drug to mice with “induced colitis” prevented the occurrence of “associated pathological events and plasma cytokine changes.”
The researchers concluded that AMT-101 “can efficiently overcome the epithelial barrier to focus biologically active IL-10 to the intestinal lamina propria” and that oral administration of the drug could target the intestinal mucosa “to suppress inflammation without systemic PK.”
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Fay NC, Muthusamy BP, Nyugen LP, et al. (2020) A Novel Fusion of IL-10 Engineered to Traffic across Intestinal Epithelium to Treat Colitis. The Journal of Immunology, 205(11): 3191-3204.