Improved cancer immunotherapy by a CD25-mimobody conferring selectivity to human interleukin-2.
Journal article

Improved cancer immunotherapy by a CD25-mimobody conferring selectivity to human interleukin-2.

  • Arenas-Ramirez N Department of Immunology, University Hospital Zurich, University of Zurich, CH-8091 Zurich, Switzerland.
  • Zou C Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
  • Popp S Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
  • Zingg D Stem Cell Biology, Institute of Anatomy, University of Zurich, CH-8057 Zurich, Switzerland.
  • Brannetti B Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
  • Wirth E Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
  • Calzascia T Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
  • Kovarik J Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
  • Sommer L Stem Cell Biology, Institute of Anatomy, University of Zurich, CH-8057 Zurich, Switzerland.
  • Zenke G Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
  • Woytschak J Department of Immunology, University Hospital Zurich, University of Zurich, CH-8091 Zurich, Switzerland.
  • Regnier CH Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
  • Katopodis A Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
  • Boyman O Department of Immunology, University Hospital Zurich, University of Zurich, CH-8091 Zurich, Switzerland. onur.boyman@uzh.ch.
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  • 2016-12-02
Published in:
  • Science translational medicine. - 2016
English Interleukin-2 (IL-2) immunotherapy is an attractive approach in treating advanced cancer. However, by binding to its IL-2 receptor α (CD25) subunit, IL-2 exerts unwanted effects, including stimulation of immunosuppressive regulatory T cells (Tregs) and contribution to vascular leak syndrome. We used a rational approach to develop a monoclonal antibody to human IL-2, termed NARA1, which acts as a high-affinity CD25 mimic, thereby minimizing association of IL-2 with CD25. The structure of the IL-2-NARA1 complex revealed that NARA1 occupies the CD25 epitope of IL-2 and precisely overlaps with CD25. Association of NARA1 with IL-2 occurs with 10-fold higher affinity compared to CD25 and forms IL-2/NARA1 complexes, which, in vivo, preferentially stimulate CD8+ T cells while disfavoring CD25+ Tregs and improving the benefit-to-adverse effect ratio of IL-2. In two transplantable and one spontaneous metastatic melanoma model, IL-2/NARA1 complex immunotherapy resulted in efficient expansion of tumor-specific and polyclonal CD8+ T cells. These CD8+ T cells showed robust interferon-γ production and expressed low levels of exhaustion markers programmed cell death protein-1, lymphocyte activation gene-3, and T cell immunoglobulin and mucin domain-3. These effects resulted in potent anticancer immune responses and prolonged survival in the tumor models. Collectively, our data demonstrate that NARA1 acts as a CD25-mimobody that confers selectivity and increased potency to IL-2 and warrant further assessment of NARA1 as a therapeutic.
Language
  • English
Open access status
closed
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Persistent URL
https://sonar.ch/global/documents/21459
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