Background/Purpose: CD4+ regulatory T cells (Tregs) play a crucial role in maintaining immune homeostasis. Treg dysfunction is associated with multi-organ autoimmune (AI) and inflammatory-related diseases. Treg-mediated down-modulation of the immune effector function (Teffs and T helpers) that prevents antigen recall may reset immune tolerance in select AI disorders.

A current focus for therapeutic intervention of autoimmune disorders includes cytokine therapies such as IL-2.  Administered at low dose, IL-2 induces limited expansion of CD4+ regulatory T cells (Tregs) and showed therapeutic benefit in chronic graft-versus-host disease (cGVHD) and HCV-induced vasculitis and is currently in clinical investigation for treatment of diverse Tcell-mediated autoimmune disorders. However, the sub-optimal pharmacological properties of IL-2 complicate administration and may limit the efficacy of low dose IL-2 therapy. Multiple IL-2 muteins, most of them consisting of fusions to IgG or its Fc domain, are in pre-clinical and clinical development, to address the pharmacokinetic and pharmacodynamic liabilities of low dose IL-2.

Methods: To engineer an improved IL-2 for autoimmune therapy, we applied our recombinant platform technology that expands the genetic code by adding a new DNA base pair. This allows for optimization of proteins through incorporation of novel amino acids encoded by our new DNA base pair, enabling site-specific modifications that enhance the pharmacological properties of these therapeutics.  Here we report on the discovery of a site-specific, covalently-pegylated IL-2 that has substantially improved pharmacologic properties over native IL-2 for expansion of Tregs.

Results: Screening of distinct site-specific PEG-IL-2 conjugates in vitro and in mouse identified THOR-809, which showed significantly improved half-life and sustained exposure. In mouse, THOR-809 preferentially stimulated proliferation of peripheral Tregs relative to Teffs (no expansion) and NK cells (minimal expansion). Expanded Treg populations demonstrated significant upregulation of markers that correlate with Treg suppressive function, including FoxP3, CD25, ICOS and Helios.  In Cynomolgus monkey, subcutaneous dosing of THOR-809 demonstrated dose-dependent proliferation and activation of peripheral Tregs with no detectable proliferation of Teffs or NK cells up to 200 mcg/kg. We also show that PEG length and shape influences the half-life and pharmacodynamic response for expansion of Tregs in vivo.

Conclusion: Overall, our results indicate that THOR-809 is an IL-2 tuned for biased activation and expansion of Treg cells, with no activation and expansion of Teff or NK cells. These findings support the development of THOR-809 as a treatment for AI disorders.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/thor-809-an-il-2-engineered-from-an-expanded-genetic-alphabet-for-the-potential-treatment-of-autoimmune-disorders/