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An IL-2-grafted antibody immunotherapy with potent efficacy against metastatic cancer

Author

Listed:
  • Dilara Sahin

    (University Hospital Zurich)

  • Natalia Arenas-Ramirez

    (University Hospital Zurich)

  • Matthias Rath

    (University Hospital Zurich)

  • Ufuk Karakus

    (University Hospital Zurich)

  • Monika Hümbelin

    (University Hospital Zurich)

  • Merel Gogh

    (University of Zurich)

  • Lubor Borsig

    (University of Zurich)

  • Onur Boyman

    (University Hospital Zurich
    University of Zurich)

Abstract

Modified interleukin-2 (IL-2) formulations are being tested in cancer patients. However, IL-2 immunotherapy damages IL-2 receptor (IL-2R)-positive endothelial cells and stimulates IL-2Rα (CD25)-expressing lymphocytes that curtail anti-tumor responses. A first generation of IL-2Rβ (CD122)-biased IL-2s addressed some of these drawbacks. Here, we present a second-generation CD122-biased IL-2, developed by splitting and permanently grafting unmutated human IL-2 (hIL-2) to its antigen-binding groove on the anti-hIL-2 monoclonal antibody NARA1, thereby generating NARA1leukin. In comparison to hIL-2/NARA1 complexes, NARA1leukin shows a longer in vivo half-life, completely avoids association with CD25, and more potently stimulates CD8+ T and natural killer cells. These effects result in strong anti-tumor responses in various pre-clinical cancer models, whereby NARA1leukin consistently surpasses the efficacy of hIL-2/NARA1 complexes in controlling metastatic disease. Collectively, NARA1leukin is a CD122-biased single-molecule construct based on unmutated hIL-2 with potent efficacy against advanced malignancies.

Suggested Citation

  • Dilara Sahin & Natalia Arenas-Ramirez & Matthias Rath & Ufuk Karakus & Monika Hümbelin & Merel Gogh & Lubor Borsig & Onur Boyman, 2020. "An IL-2-grafted antibody immunotherapy with potent efficacy against metastatic cancer," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-20220-1
    DOI: 10.1038/s41467-020-20220-1
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    Cited by:

    1. Kateryna Onyshchenko & Ren Luo & Elena Guffart & Simone Gaedicke & Anca-Ligia Grosu & Elke Firat & Gabriele Niedermann, 2023. "Expansion of circulating stem-like CD8+ T cells by adding CD122-directed IL-2 complexes to radiation and anti-PD1 therapies in mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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