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. Issue 7 (11th July 2022)

• Record Type: Journal Article
• Authors: 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; Hehn, Yvonne; Killian, Steffen; Viet, Laura; Runz, Josefine; Faltinger, Frank; Tabrizi, Mohammad; Abel, Kristin Laura; Breinholt, Vibeke Miller; Singel, Stina M; Sprogøe, Kennett; Punnonen, Juha;
• Is Part Of: Journal for immunotherapy of cancer. Volume 10:Issue 7(2022)
• Publication Date: 2022-07-11
• Subjects: Immunotherapy -- Cytokines -- Lymphocyte Activation -- Killer Cells, Natural -- T-Lymphocytes; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2022-004991
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : 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 ).