title: Improved cancer immunotherapy by a CD25-mimobody conferring selectivity to human interleukin-2.
abstract: 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+Tregsand 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.
authors.affiliation: Department of Immunology, University Hospital Zurich, University of Zurich, CH-8091 Zurich, Switzerland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Arenas-Ramirez
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
authors.forename: Chao
authors.initials: C
authors.lastname: Zou
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
authors.forename: Simone
authors.initials: S
authors.lastname: Popp
authors.affiliation: Stem Cell Biology, Institute of Anatomy, University of Zurich, CH-8057 Zurich, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Zingg
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Brannetti
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Wirth
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Calzascia
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
authors.forename: Jiri
authors.initials: J
authors.lastname: Kovarik
authors.affiliation: Stem Cell Biology, Institute of Anatomy, University of Zurich, CH-8057 Zurich, Switzerland.
authors.forename: Lukas
authors.initials: L
authors.lastname: Sommer
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Zenke
authors.affiliation: Department of Immunology, University Hospital Zurich, University of Zurich, CH-8091 Zurich, Switzerland.
authors.forename: Janine
authors.initials: J
authors.lastname: Woytschak
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Regnier
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Katopodis
authors.affiliation: Department of Immunology, University Hospital Zurich, University of Zurich, CH-8091 Zurich, Switzerland. onur.boyman@uzh.ch.
authors.forename: Onur
authors.initials: O
authors.lastname: Boyman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D001665:Binding Sites; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D049109:Cell Proliferation; D000939:Epitopes / Q000737:chemistry; D020868:Gene Silencing; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D011487:Protein Conformation; D011995:Recombination, Genetic; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; C508594:IL2 protein, human; C508017:IL2RA protein, human; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit