5LQB

Complex structure of human IL2 mutant, Proleukin, with Fab fragment of NARA1 antibody

Summary for 5LQB

• Entry DOI: 10.2210/pdb5lqb/pdb
• Descriptor: Interleukin-2, anti-hIL2 FAB fragment heavy chain, anti-hIL2 FAB fragment light chain, ... (4 entities in total)
• Functional Keywords: il2, proleukin, nara1, anti-il2, cytokine
• Biological source: Homo sapiens (Human); More
• Cellular location: Secreted: P60568
• Total number of polymer chains: 3
• Total formula weight: 63049.49

Authors

Zou, C.,Wirth, E. (deposition date: 2016-08-16, release date: 2016-12-14, Last modification date: 2024-10-16)

Primary citation

Arenas-Ramirez, N.,Zou, C.,Popp, S.,Zingg, D.,Brannetti, B.,Wirth, E.,Calzascia, T.,Kovarik, J.,Sommer, L.,Zenke, G.,Woytschak, J.,Regnier, C.H.,Katopodis, A.,Boyman, O.
Improved cancer immunotherapy by a CD25-mimobody conferring selectivity to human interleukin-2.
Sci Transl Med, 8:367ra166-367ra166, 2016

PubMed 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 (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.

PubMed: 27903862
DOI: 10.1126/scitranslmed.aag3187

Experimental method

X-RAY DIFFRACTION (1.95 Å)