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. 2023 Feb 16;1(4):286–303. doi: 10.1038/s44222-023-00030-y

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Fig. 2 — a, Bioengineering methods for improving the function and pharmacokinetic properties of IL-2 include directed evolution, rational PEGylation and de novo design signalling. Taking advantage of these engineering tools, three different cytokine-based drugs (MDNA11, THOR-707 and Neo-2/15) have been developed to enhance IL-2Rβγ-mediated signalling. MDNA11 is a variant of IL-2, developed using directed evolution, with 200-fold higher binding affinity for IL-2 receptor subunit-β (IL-2Rβ) compared to IL-2. To develop THOR-707, rational PEGylation is employed to block IL-2’s affinity for IL-2Rα to eliminate IL-2’s innate bias towards cells that express IL-2Rα. Neo-2/15 is produced by computationally modelling peptide motifs in IL-2Rβγ without interacting with IL-2Rα, resulting in a de novo protein that selectively mediates IL-2Rβγ signalling. b, High specificity of cytokine-based drugs increases effector T cell and natural killer (NK) cell activation and proliferation, but prevents signalling through the trimeric form (IL-2Rαβγ), thereby minimizing undesired activation of regulatory T cells. JAK, Janus kinase; PEG, polyethylene glycol.