Abstract
Abstract Regulatory T cells (Treg) are vital for immune homeostasis and are dysfunctional in autoimmunity. Interleukin 2 (IL-2) drives the proliferation and function of Tregs via its heterotrimeric receptor (CD25/CD122/CD132). Low dose IL-2 is being evaluated for treatment of autoimmune diseases and has been shown to expand Tregs, yet it has a small selectivity window over conventional T cells (Tconv) and natural killer (NK) cells. To enhance IL-2 selectivity, mutations can be introduced to reduce its CD122/CD132 affinity thus creating a CD25 dependency for signaling through CD122/CD132 upon IL-2 facilitated CD25/CD122/CD132 trimer formation. Using structure guided approach, we introduced mutations in IL-2 that significantly decreased CD122 affinity in addition to mutations that increased CD25 affinity. Finally, we explored other mutations, orientation, and linkers to generate a potent, selective molecule with drug-like manufacturability. These structure activity relationship efforts culminated in the generation of PT101, a mutant IL-2 Fc fusion that was selective in activating and expanding Tregs. PT101 selectively induced STAT5 phosphorylation in human and non-human primate (NHP) Tregs in vitro. In humanized mice and NHPs, administration of PT101 dose-dependently and selectively expanded Treg without significant effects on other immune cell types, nor eliciting proinflammatory cytokine production. In a Phase 1a clinical trial, PT101 was well-tolerated and selectively expanded total Tregs by up to a mean maximum of 3.6-fold. There was no evidence of expansion of NK cells nor pro-inflammatory Tconv at any dose studied. Clinical trials in patients with ulcerative colitis and systemic lupus erythematosus are planned with PT101.
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