TransCon IL-2 β/γ: a novel long-acting prodrug with sustained release of an IL-2Rβ/γ-selective IL-2 variant with improved pharmacokinetics and potent activation of cytotoxic immune cells for the treatment of cancer
| Autor: | Anne Månsson Kvarnhammar, Juha Punnonen, Enping Hong, Diana Reich, Karan Uppal, Kathy Bang, David B Rosen, Burkhardt Laufer, Thomas Knappe, Jens Jakob Karlsson, Yu-Chi Lee, Dhruv Thakar, Luis Alejandro Zúñiga, Simran Singh Sabharwal, Janne Damm Olling, Kristian Kjaergaard, Thomas Kurpiers, Meike Schnabel, Philipp Glock, Joachim Zettler, Mathias Krusch, Ana Bernhard, Stefan Heinig, Valentino Konjik, Thomas Wegge, Yvonne Hehn, Steffen Killian, Laura Viet, Josefine Runz, Frank Faltinger, Mohammad Tabrizi, Kristin Laura Abel, Vibeke Miller Breinholt, Stina M Singel, Kennett Sprogøe |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Journal for ImmunoTherapy of Cancer, Vol 10, Iss 7 (2022) |
| Druh dokumentu: | article |
| ISSN: | 2022-0049 2051-1426 |
| DOI: | 10.1136/jitc-2022-004991 |
| Popis: | Background 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 Cmax likely potentiating toxicity. Thus, IL-2 cancer immunotherapy has two critical drawbacks: potent activation of undesired IL-2Rα+ cells and suboptimal pharmacokinetics with high Cmax 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 Cmax 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). |
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