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Rosen, David B; Kvarnhammar, Anne Månsson; Laufer, Burkhardt; Knappe, Thomas; Karlsson, Jens Jakob; Hong, Enping; Lee, Yu-Chi; Thakar, Dhruv; Zúñiga, Luis Alejandro; Bang, Kathy; Sabharwal, Simran Singh; Uppal, Karan; Olling, Janne Damm; Kjaergaard, Kristian; Kurpiers, Thomas; Schnabel, Meike; Reich, Diana; Glock, Philipp; Zettler, Joachim; Krusch, Mathias; Bernhard, Ana; Heinig, Stefan; Konjik, Valentino; Wegge, Thomas; [...]

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

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  • Medientyp: E-Artikel
  • Titel: 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
  • Beteiligte: Rosen, David B; Kvarnhammar, Anne Månsson; Laufer, Burkhardt; Knappe, Thomas; Karlsson, Jens Jakob; Hong, Enping; Lee, Yu-Chi; Thakar, Dhruv; Zúñiga, Luis Alejandro; Bang, Kathy; Sabharwal, Simran Singh; Uppal, Karan; Olling, Janne Damm; Kjaergaard, Kristian; Kurpiers, Thomas; Schnabel, Meike; Reich, Diana; Glock, Philipp; Zettler, Joachim; Krusch, Mathias; Bernhard, Ana; Heinig, Stefan; Konjik, Valentino; Wegge, Thomas; [...]
  • Erschienen: BMJ, 2022
  • Erschienen in: Journal for ImmunoTherapy of Cancer
  • Sprache: Englisch
  • DOI: 10.1136/jitc-2022-004991
  • ISSN: 2051-1426
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:sec><jats:title>Background</jats:title><jats:p>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<jats:sup>+</jats:sup>natural killer (NK) cells and CD8<jats:sup>+</jats:sup>, CD4<jats:sup>+</jats:sup>and gamma delta (γδ) T cells. However, IL-2 also potently activates immunosuppressive IL-2Rα<jats:sup>+</jats:sup>regulatory T cells (Tregs) and IL-2Rα<jats:sup>+</jats:sup>eosinophils and endothelial cells, which may promote VLS. Aldesleukin is rapidly cleared requiring frequent dosing, resulting in high C<jats:sub>max</jats:sub>likely potentiating toxicity. Thus, IL-2 cancer immunotherapy has two critical drawbacks: potent activation of undesired IL-2Rα<jats:sup>+</jats:sup>cells and suboptimal pharmacokinetics with high C<jats:sub>max</jats:sub>and short half-life.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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<jats:sub>max</jats:sub>and a long (&gt;30 hours) effective half-life for IL-2 β/γ in monkeys. In mouse tumor models, TransCon IL-2 β/γ promoted CD8<jats:sup>+</jats:sup>T cell and NK cell activation and antitumor activity. In monkeys, TransCon IL-2 β/γ induced robust activation and expansion of CD8<jats:sup>+</jats:sup>T cells, NK cells and γδ T cells, relative to CD4<jats:sup>+</jats:sup>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<jats:sup>+</jats:sup>T cells, NK cells and γδ T cells.</jats:p></jats:sec><jats:sec><jats:title>Summary</jats:title><jats:p>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 (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT05081609">NCT05081609</jats:ext-link>).</jats:p></jats:sec>
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