IL-2 as a Therapeutic Target

IL-2 is a growth factor that is critical for all T cells. At low concentrations, it activates and expands regulatory T cells (Tregs), which in turn can regulate immune responses and attenuate autoimmunity. At high concentrations, IL-2 can also activate pro-inflammatory immune cells, such as conventional T cells (Tconv) and NK cells.

Selectivity for Tregs for IL-2

Treg’s higher sensitivity for IL-2 compared to Tconv and NK cells’ sensitivity to IL-2 is influenced by the format of the IL-2 receptor on these different immune cells. Tregs constitutively express an IL-2 receptor trimer of alpha, beta and gamma IL-2R subunits. Tconv and NK cells express an IL-2 receptor dimer of beta and gamma subunits.

IL-2 Muteins for Treg Selectivity

Pandion engineered IL-2 to selectively bind the alpha-containing IL-2R trimer, creating an IL-2 mutein that preferentially expands and activates Tregs. Tregs have been shown to play a key role in autoimmunity and their expansion and activation is a promising treatment approach for many autoimmune diseases. In clinical trials using low-dose native IL-2 as a means to activate Tregs, a two-fold increase in total Tregs was associated with clinical benefit across multiple autoimmune diseases.

PT101

Our lead product candidate, PT101, contains our engineered IL-2 mutein effector module fused to an Fc protein backbone. PT101 showed a high degree of selectivity for Treg cells over proinflammatory Tconv and NK cells in vitro, in vivo and in a Phase 1a clinical trial.

In the Phase 1a trial, PT101 was shown to be well-tolerated, which was the primary objective of the trial. There were no serious adverse events. In the trial, PT101 selectively expanded total Tregs with a mean maximal increase of up to 3.6-fold over baseline and, in addition, expanded a subset of activated Tregs, called CD25 bright Tregs, with a mean maximal increase of up to 72.5-fold over baseline. There was no evidence of expansion of Tconv or NK cells at any dose studied.

We are developing PT101 for subcutaneous administration for the treatment of a variety of autoimmune and inflammatory diseases, with an initial focus on patients with ulcerative colitis (UC) and patients with systemic lupus erythematosus (SLE). We expect to initiate a Phase 1b/2a clinical trial in UC in mid-2021 and a Phase 2 clinical trial in SLE in the second half of 2021.

PT101 structure

PT002

PT002 is a bifunctional molecule, consisting of our engineered IL-2 mutein with a MAdCAM tether. MAdCAM is constitutively expressed in the gastrointestinal tract and is a critical receptor for the trafficking of immune cells into gut tissue. Pandion’s MAdCAM tether is a proprietary antibody designed to localize the IL-2 mutein to the gut, but not interfere with MAdCAM’s function. PT002 has the potential to increase concentration and effect of an IL-2 mutein to the gut as an approach to treat gut-restricted autoimmune diseases. PT002 is currently in preclinical studies.

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