Regulatory T cells (Treg) play a critical role in immune homeostasis and are dysfunctional in many autoimmune diseases. Interleukin 2 (IL-2) via the heterotrimeric IL-2 receptor drives the proliferation and function of Treg and IL-2Ra/CD25 loss-of-function in mice is associated with Treg deficiency and widespread autoimmunity. Low dose IL-2 expands Treg and is being evaluated as a therapy for patients with autoimmune diseases. However, IL-2 can also activate other immune cells including conventional T cells and Natural Killer (NK) cells which express IL-2Rb/CD122 and IL-2g/CD132. To enhance IL-2 selectivity for Treg, mutations can be introduced that increase the affinity for CD25and decrease affinity for CD122/CD132. IL-2 Muteins with these properties are able to selectively activate and expand Tregs. Here we describe the activity of PT101, an IL-2 mutein cytokine Fc fusion protein that selectively induces STAT5 phosphorylation downstream of the IL-2R in human and cynomolgus monkey Tregs in vitro. In humanized NOD-scid IL2Rg-null (NSG) mice, PT101 expands Treg without significant effects on other immune cell types and without inducing pro-inflammatory cytokines. Treg from PT101-dosed humanized mice have increased expression of FOXP3 and CD25, suggesting enhanced function and stability. In cynomolgus monkeys, single dose administration of PT101 dose-dependently and selectively expands Treg.
Erik Sampson– Principal Scientist, Pandion Therapeutics
Jyothsna Visweswaraiah– Scientist Therapeutic Protein Technologies, Pandion Therapeutics
Nathan Higginson-Scott– Director Therapeutics Protein Technologies, Pandion Therapeutics
Joanne Viney– Chief Scientific Officer, Pandion Therapeutics
Kevin Otipoby– Director Immunology, Pandion Therapeutics