W67 - Novel Therapy with Neddylation Inhibitor Delays the Progression of Disease in Pre-Diabetic Non-Obese Diabetic Mice by Restoring Endogenous Treg Function

Abstract Text: Autoimmune diseases, including type 1 diabetes, can result from a defect in peripheral regulatory T cells (Tregs). We found that the Tregs of autoimmunity patients exhibit a defect where IL-2R signaling is turned off too soon. Normally, IL-2R signaling is maintained by inhibition of IL-2R desensitization. This is accomplished by blocking degradation of pJAK1 (associated with IL-2Rb) via inhibition of neddylation at the SOCS3/Cul5 cullin ring ligase (CRL) that normally ubiquitinates and degrades pJAK1. We showed that Treg function can be restored using a neddylation activating enzyme inhibitor (NAEi) that blocks neddylation at Cul5 CRL. Here, we demonstrate that the NAEi, MLN4924, can be used in combination with low dose IL-2 to treat 12 week old late-stage pre-diabetic NOD mice when administered at a relatively high dose, daily for 3 weeks. Disease was reduced to 24% vs. 56% in MLN/IL-2-treated mice vs. mice treated with IL-2 alone. The onset of disease, however, was only delayed by 2 weeks, to 15 weeks of age, and systemic administration of the NAEi had toxic effects. To obviate this, we generated an IL-2 protein-drug conjugate (PDC) for targeted delivery of MLN4924, allowing lower amounts of drug to be utilized. The IL-2 activity of the PDC was comparable to IL-2, and 5 daily treatments of PDC was sufficient to delay disease onset until 23 weeks of age, with biweekly or monthly single maintenance doses delaying disease further to 27 weeks of age. Together, these data support the potential use of NAEi-containing drugs for immune therapy.