Circulating PEG-indoleamine 2,3-dioxygenase ameliorates diverse inflammatory diseases without toxicity or compromising immunocompetence.

Abstract

Indoleamine 2,3-dioxygenase (IDO), the enzyme responsible for tryptophan catabolism, is protective in many autoimmune and inflammatory diseases. We previously developed a localized immunomodulation approach through the fusion of IDO to a carbohydrate binding protein [E. Bracho-Sanchez <i>et al.</i>, <i>Nat. Biomed. Eng.</i> <b>7</b>, 1156-1169 (2023)]. Here we further develop IDO as a protein therapeutic for inflammation, investigating systemic delivery via conjugation of poly(ethylene glycol) (PEG) to IDO. PEGylation extended circulation time and treatment PEG-IDO demonstrated therapeutic efficacy in five autoimmune and inflammatory models. Treatment with a single dose of PEG-IDO resulted in reversal of hind limb paralysis in experimental autoimmune encephalomyelitis as model of multiple sclerosis; protected against hepatic damage in liver ischemia-reperfusion injury; prevention of abdominal aortic aneurysm; and decreased severity of imiquimod-induced psoriasis. Treatment with two doses of PEG-IDO provided maintenance of body weight and colon length in acute ulcerative colitis. PEG-IDO treatment increased regulatory T cell populations and reduced pathogenic Th17 cell populations and inflammatory cytokine production. Systemic delivery of PEG-IDO had little-to-no off-target effects. Mice maintained immunocompetency, clearing the <i>Listeria</i> monocytogenes infection, and had no observed toxicity. Additionally, PEG-IDO increased serum kynurenine, consistent with a kynurenine-mediated mechanism of action. These findings demonstrate systemic immunomodulation via circulating PEG-IDO ameliorates a breadth of disparate autoinflammatory diseases, protecting against inflammation-driven tissue destruction in spinal cord, liver, abdominal aorta, skin, and colon, while presenting a positive safety profile, and expanding the scope of potential applications for this therapeutic approach.