Journal for ImmunoTherapy of Cancer (Jul 2022)

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

  • 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

DOI
https://doi.org/10.1136/jitc-2022-004991
Journal volume & issue
Vol. 10, no. 7

Abstract

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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).