Introduction and Objective: Deficient IL-2 signaling impairs regulatory T cell (Treg) baseline levels, functional maturity, and lineage stability, enabling autoreactive effector T cell expansion and pancreatic islet destruction in Type 1 diabetes (T1D). Our goal was to develop PSB234, a novel antibody-targeted immuno-cytokine, that could selectively expand suppressive Tregs and delay hyperglycemia onset in spontaneous T1D mice. Methods: PSB234 incorporates an IL-2 mutein with 100-fold reduced IL-2 receptor affinity in its unconjugated form. Signaling is restored to wild-type levels only upon cell-specific antibody anchoring. Treg selectivity and activation was assessed in vivo in mice and in human cells. Efficacy was evaluated in spontaneous NOD T1D mice treated at 12 weeks with a PSB234 surrogate, with vehicle and anti-CD3 as controls. Hyperglycemia incidence and blood glucose were monitored through 30 weeks. Results: Antibody-targeted delivery of our IL-2 mutein drove robust, dose-dependent Treg expansion with significantly enriched expression of GITR, ICOS, and CD25 and minimal NK or CD8 T cell expansion in vivo. In NOD mice, treatment with targeted IL-2 mutein reduced hyperglycemia incidence, with only 20% of treated mice diabetic at the end of study compared to 46.7% of vehicle and anti-CD3 treated mice. Finally, PSB234 also drove robust 20-100 fold and selective expansion of Tregs in mice with human immune cells. Conclusion: Treatment with antibody-targeted IL-2 mutein selectively amplifies suppressive Tregs and provides potent, durable delay of hyperglycemia in spontaneous NOD T1D mice. Our lead candidate molecule for PSB234 also drives robust expansion of Tregs with little to no effector immune cell expansion in mice with human immune cells. These results support the therapeutic potential of PSB234 as a precise, Treg-targeted approach to restoring and maintaining long-term immune homeostasis in Type 1 diabetes. Disclosure J.M. Kinder: None.
JEREMY M. KINDER (Fri,) studied this question.