TransCon IL-2 β/γ：一种新型长效前药，可持续释放药代动力学改善且能强效激活细胞毒性免疫细胞的 IL-2Rβ/γ 选择性 IL-2 变体，用于治疗癌症

Recombinant interleukin-2 (IL-2, aldesleukin) is an approved cancer immunotherapy but causes severe toxicities including cytokine storm and vascular leak syndrome (VLS). IL-2 promotes antitumor function of IL-2R / + natural killer (NK) cells and CD8 + , CD4 + and gamma delta ( ) T cells. However, IL-2 also potently activates immunosuppressive IL-2R + regulatory T cells (Tregs) and IL-2R + eosinophils and endothelial cells, which may promote VLS. Aldesleukin is rapidly cleared requiring frequent dosing, resulting in high C max likely potentiating toxicity. Thus, IL-2 cancer immunotherapy has two critical drawbacks: potent activation of undesired IL-2R + cells and suboptimal pharmacokinetics with high C max and short half-life.

TransCon IL-2 / was designed to optimally address these drawbacks. To abolish IL-2R binding yet retain strong IL-2R / activity, IL-2 / was created by permanently attaching a small methoxy polyethylene glycol (mPEG) moiety in the IL-2R binding site. To improve pharmacokinetics, IL-2 / was transiently attached to a 40 kDa mPEG carrier via a TransCon (transient conjugation) linker creating a prodrug, TransCon IL-2 / , with sustained release of IL-2 / . IL-2 / was characterized in binding and primary cell assays while TransCon IL-2 / was studied in tumor-bearing mice and cynomolgus monkeys.

IL-2 / demonstrated selective and potent human IL-2R / binding and activation without IL-2R interactions. TransCon IL-2 / showed slow-release pharmacokinetics with a low C max and a long (>30 hours) effective half-life for IL-2 / in monkeys. In mouse tumor models, TransCon IL-2 / promoted CD8 + T cell and NK cell activation and antitumor activity. In monkeys, TransCon IL-2 / induced robust activation and expansion of CD8 + T cells, NK cells and T cells, relative to CD4 + T cells, Tregs and eosinophils, with no evidence of cytokine storm or VLS. Similarly, IL-2 / enhanced proliferation and cytotoxicity of primary human CD8 + T cells, NK cells and T cells. SUMMARY: TransCon IL-2 / is a novel long-acting prodrug with sustained release of an IL-2R / -selective IL-2. It has remarkable and durable pharmacodynamic effects in monkeys and potential for improved clinical efficacy and tolerability compared with aldesleukin. TransCon IL-2 / is currently being evaluated in a Phase 1/2 clinical trial (NCT05081609).