Pandion Therapeutics announced positive top-line data from its Phase 1a single-dose, healthy volunteer clinical trial, demonstrating proof of mechanism of PT101, an engineered IL-2 mutein fused to a protein backbone, in development for ulcerative colitis (UC), systemic lupus erythematosus (SLE), and other autoimmune diseases. In the Phase 1a clinical trial, PT101 was observed to be well-tolerated and there were no serious adverse events. PT101 selectively expanded total regulatory T cells (Tregs), with a mean maximal increase up to of 3.6-fold over baseline. A subset of activated Tregs with high CD25 expression, known as CD25 bright Tregs, expanded, with a mean maximal increase of up to 72.5-fold over baseline. There was no evidence of expansion of natural killer T (NK) cells and pro-inflammatory conventional T (Tconv) at any dose studied. In third-party clinical trials using low-dose native IL-2, a two-fold increase in total Tregs was associated with clinical benefit across multiple autoimmune diseases. The Phase 1a randomized, blinded clinical trial enrolled 56 healthy volunteers across seven cohorts who each received a single subcutaneous fixed dose of PT101 ranging from 1 mg to 10 mg, or placebo. Subjects were followed for 28 days after dosing and evaluated for safety and tolerability as well as pharmacokinetic and pharmacodynamic measures. These measures were selected to assess the potency and selectivity of PT101 in order to establish proof of mechanism. All adverse events observed in the trial were low grade (Grade 1 or 2) and self-limited. The most common adverse events were skin reactions of itching, redness or pain near or around the site of injection of PT101. In laboratory tests, some subjects showed transient elevations of eosinophils, a type of white blood cell, that were self-limited in nature and did not require medical treatment. The Company believes the eosinophil elevation may be related to the IL-2 mechanism of PT101. Expansion of both total Tregs and the CD25 bright Treg subset was observed throughout the dose range, as depicted in the table below. Peak expansion of Tregs was observed between days 8 and 10. At doses of 3.5 mg and above, PT101 induced a two-fold or greater expansion of total Tregs in more than 80% of subjects. Tregs returned to baseline or near-baseline over the 28-day follow-up period, supporting the Company’s plan to utilize a dosing regimen of every four weeks in future clinical trials. Full data from the trial are expected to be presented at upcoming medical meetings. Tregs act as a control node within the immune system and can inhibit the activity of several different pro-inflammatory immune cell types. Tregs are critical for self-tolerance, or the ability of the immune system to recognize a hosts’ cells and not produce an immune attack against them. Defects in Tregs result in multi-organ inflammation and their dysfunction is associated with many autoimmune diseases. Multiple third-party clinical trials suggest that expansion of Tregs by low-dose IL-2 can benefit patients with autoimmune diseases. CD25 bright Tregs are a subset of Tregs with high expression of CD25 (also known as the IL-2 receptor alpha subunit). It has been reported that CD25 bright Tregs may be a more active subset of Tregs with enhanced immune regulatory function. PT101 is an engineered IL-2 mutein fused to a protein backbone designed to selectively activate and expand regulatory T cells for the treatment of autoimmune diseases. In autoimmune diseases, the immune system inappropriately attacks a host’s cells, and targeting regulatory T cells could allow the immune system to regain control and return to homeostasis. PT101 has completed a Phase 1a clinical trial, which met its primary endpoint of safety and tolerability. In the trial, PT101 demonstrated proof of mechanism by selectively expanding Tregs in healthy volunteers.