Circulating PEG-indoleamine 2,3-dioxygenase ameliorates diverse inflammatory diseases without toxicity or compromising immunocompetence
- Jennifer A. Simonovich
- Ryan A. Clark
- Alexander J. Kwiatkowski
- Madeline J. Fuchs
- Mariana E. Viso
- Chen Lu
- Sabrina L. Macias
- Isabella Pinto
- Abhishek P. Shrestha
- Tran B. Ngo
- Sergio Duarte
- Yong He
- Qiongyao Hu
- Guanyi Lu
- Joseph B. Hartman
- Gang Su
- Salvatore T. Scali
- Scott A. Berceli
- Ashish K. Sharma
- Gilbert R. Upchurch
- Shamima Islam
- Arun Wanchoo
- Gregory A. Hudalla
- Scott T. Robinson
- Ali Zarrinpar
- Dorina Avram
- Benjamin G. Keselowsky
2026-07-08
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 et al. , Nat. Biomed. Eng. 7 , 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 Listeria 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.