OP0023 GENERATION OF PT101, A HIGHLY SELECTIVE IL-2 MUTEIN FOR TREATMENT OF AUTOIMMUNE DISEASES

Background: Regulatory T cells (Tregs) play a critical role in immune homeostasis and are dysfunctional many autoimmune diseases. Interleukin 2 (IL-2) drives the proliferation function of Tregs. via heterotrimeric IL-2 receptor (CD25/CD122/CD132). As result, CD25 loss-of-function mice is associated with Treg deficiency widespread autoimmunity. Low dose being evaluated for treatment diseases has been shown to expand Tregs, however it narrow selectivity window before activating conventional natural killer cells. To enhance improve its therapeutic utility expanding mutations can be introduced that reduce CD122/CD132 affinity thus creating dependency on binding signaling through upon facilitated CD25/CD122/CD132 trimer formation. Objectives: generate highly selective mutein activates expands Tregs selectively used Methods: Using structure guided approach, we significantly decreased CD122 addition other increased affinity. Finally, explored additional mutations, format, orientation, linker lengths most potent, molecule drug-like manufacturability. These activity relationship efforts culminated generation PT101, mutant Fc fusion vitro vivo. Results: PT101 induced STAT5 phosphorylation human cynomolgus monkey vitro. In humanized NOD-scid IL-2Rg-null (NSG) monkeys, administration dose-dependently expanded without significant effects cell types, eliciting proinflammatory cytokine production. The from PT101-dosed have expression FOXP3 CD25, suggesting enhanced stability. Phase 1a single ascending clinical trial, was well-tolerated total mean maximal increase up 3.6-fold over baseline healthy volunteers. There no evidence expansion nor pro-inflammatory at any doses studied. Conclusion: activated stability as seen by these maintained 1 trial A 1b/2a patients ulcerative colitis systemic lupus erythematosus planned further evaluate PT101. Disclosure Interests: None declared