Fig. 2: Overview of IL-2 pharmacology and therapeutic hypothesis of pegylated IL-2 with “not alpha” receptor specificity.
From: An engineered IL-2 reprogrammed for anti-tumor therapy using a semi-synthetic organism
a Schematic depicting IL-2 receptor biology, highlighting the desired and undesired effects of IL-2 therapy. To stimulate anti-tumor responses, high IL-2 (purple chain) concentrations are required to agonize the IL-2Rβγ complex (cyan and green chains) on CD8+ T and NK cells, driving activation and proliferation needed for tumor destruction. However, immune cell types with undesired biological activities also express the IL-2Rα chain, allowing their response to lower IL-2 concentrations. This results in Treg-mediated suppression of effector T cell populations, or stimulation of ILC-2 cells (not shown), which release IL-5 to drive VLS indirectly via eosinophil activation9. Therefore, the high rhIL-2 concentrations required to drive efficacy also result in Treg activation and toxicity in an IL-2Rα dependent manner. Blocking engagement of IL-2Rα may provide an improved therapy with reduced undesired target activation. b Concept of a site-specific PEG-modified “not alpha” IL-2, in which PEG attachment at the IL-2Rα interface blocks IL-2Rα engagement. The resulting compound allows normal IL-2Rβγ signaling and extends half-life via increased molecular size (not shown). Schematic of IL-2 (left) and THOR-707 (right) binding to the IL-2 receptor complex. Human IL-2 (purple chain) forms a heterotrimeric complex with the IL-2 receptor β (cyan), γ (green) and α (blue) subunits. Site-specific PEG modification (orange polymer) of THOR-707 at the IL-2 Rα receptor interface allows targeted reduction of the IL-2 Rα engagement without specific reduction in the engagement of the IL-2 Rβγ complex.
