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

• Published in: Science translational medicine 2016-11, Vol.8 (367), p.367ra166-367ra166
• Main Authors: Arenas-Ramirez, Natalia, Zou, Chao, Popp, Simone, Zingg, Daniel, Brannetti, Barbara, Wirth, Emmanuelle, Calzascia, Thomas, Kovarik, Jiri, Sommer, Lukas, Zenke, Gerhard, Woytschak, Janine, Regnier, Catherine H, Katopodis, Andreas, Boyman, Onur
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - chemistry; Binding Sites; CD8-Positive T-Lymphocytes - cytology; Cell Proliferation; Epitopes - chemistry; Gene Silencing; Humans; Immunotherapy - methods; Interleukin-2 - antagonists & inhibitors; Interleukin-2 Receptor alpha Subunit - immunology; Melanoma, Experimental - immunology; Melanoma, Experimental - therapy; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Neoplasms - immunology; Neoplasms - therapy; Protein Conformation; Recombination, Genetic; T-Lymphocytes, Cytotoxic - cytology; T-Lymphocytes, Regulatory - immunology
• ISSN: 1946-6234; 1946-6242
• DOI: 10.1126/scitranslmed.aag3187

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 (T ) 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 T 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.