In:
Journal for ImmunoTherapy of Cancer, BMJ, Vol. 10, No. 7 ( 2022-07), p. e004991-
Abstract:
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-2Rβ/γ + natural killer (NK) cells and CD8 + , CD4 + and gamma delta (γδ) T cells. However, IL-2 also potently activates immunosuppressive IL-2Rα + regulatory T cells (Tregs) and IL-2Rα + 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-2Rα + cells and suboptimal pharmacokinetics with high C max and short half-life. Methods TransCon IL-2 β/γ was designed to optimally address these drawbacks. To abolish IL-2Rα binding yet retain strong IL-2Rβ/γ activity, IL-2 β/γ was created by permanently attaching a small methoxy polyethylene glycol (mPEG) moiety in the IL-2Rα binding site. To improve pharmacokinetics, IL-2 β/γ was transiently attached to a 40 kDa mPEG carrier via a TransCon (transient conjugation) linker creating a prodrug, TransCon IL-2 β/γ, with sustained release of IL-2 β/γ. IL-2 β/γ was characterized in binding and primary cell assays while TransCon IL-2 β/γ was studied in tumor-bearing mice and cynomolgus monkeys. Results IL-2 β/γ demonstrated selective and potent human IL-2Rβ/γ binding and activation without IL-2Rα interactions. TransCon IL-2 β/γ showed slow-release pharmacokinetics with a low C max and a long ( 〉 30 hours) effective half-life for IL-2 β/γ in monkeys. In mouse tumor models, TransCon IL-2 β/γ promoted CD8 + T cell and NK cell activation and antitumor activity. In monkeys, TransCon IL-2 β/γ induced robust activation and expansion of CD8 + T cells, NK cells and γδ T cells, relative to CD4 + T cells, Tregs and eosinophils, with no evidence of cytokine storm or VLS. Similarly, IL-2 β/γ enhanced proliferation and cytotoxicity of primary human CD8 + T cells, NK cells and γδ T cells. Summary TransCon IL-2 β/γ is a novel long-acting prodrug with sustained release of an IL-2Rβ/γ-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 β/γ is currently being evaluated in a Phase 1/2 clinical trial ( NCT05081609 ).
Type of Medium:
Online Resource
ISSN:
2051-1426
DOI:
10.1136/jitc-2022-004991
Language:
English
Publisher:
BMJ
Publication Date:
2022
detail.hit.zdb_id:
2719863-7
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