Arenas-Amirez, Natalia, Zou, Chao, Popp, Simone, Zingg, Daniel, Brannetti, Barbara, Wirth, Emmanuelle, Calzascia, Thomas, Kovarik, Jiri, Sommer , Lukas, Zenke, Gerhard, Woytschak, Janine, Regnier, Catherine, Katopodis, Andreas and Boyman, Onur (2016) Improved cancer immunotherapy by a CD25-mimobody conferring selectivity to human interleukin-2. Science Translational Medicine, 8 (367). ISSN 1946-62341946-6242

Abstract

Interleukin-2 (IL-2) immunotherapy is an attractive approach to treating advanced cancer. However, via binding to its IL-2 receptor alpha (CD25) subunit, IL-2 exerts unwanted effects including stimulation of immunosuppressive regulatory T (Treg) cells and contribution to endothelial cell toxicity. Using a rational approach we here developed a monoclonal antibody to human IL-2, termed NARA1, acting as a high-affinity CD25-mimic, thereby minimizing association of IL-2 with CD25. The structure of the IL-2–NARA1 complex reveals that NARA1 occupies IL-2's CD25 epitope 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+ Treg cells and improving IL-2's benefit-to-adverse-effect ratio. In two transplantable and a spontaneous metastatic melanoma model, IL-2/NARA1 complex immunotherapy leads to efficient expansion of tumor-specific and polyclonal CD8+ T cells. These CD8+ T cells express low levels of exhaustion markers programmed cell death protein-1, lymphocyte activation gene-3 and T cell immunoglobulin and mucin domain-3 when isolated from tumors and show robust interferon-gamma production. These effects result in potent anti-cancer immune responses and prolonged survival in the tumor models. Collectively, our data demonstrate that NARA1 acts as a CD25-mimobody conferring selectivity and increased potency to IL-2 and warrant further assessment of NARA1 as a therapeutic.

Item Type:	Article
Date Deposited:	18 Jan 2017 00:45
Last Modified:	18 Jan 2017 00:45
URI:	https://oak.novartis.com/id/eprint/30775