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.
Show more…
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
-
-
Open access status
-
closed
-
Identifiers
-
-
Persistent URL
-
https://sonar.ch/global/documents/21459
Statistics
Document views: 17
File downloads: