5LQB

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


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.291 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.194 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

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

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.

(2016) Sci Transl Med 8: 367ra166-367ra166

  • DOI: https://doi.org/10.1126/scitranslmed.aag3187
  • Primary Citation of Related Structures:  
    5LQB

  • 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 regs ) 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 regs 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.


  • Organizational Affiliation

    Department of Immunology, University Hospital Zurich, University of Zurich, CH-8091 Zurich, Switzerland.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Interleukin-2132Homo sapiensMutation(s): 1 
UniProt & NIH Common Fund Data Resources
Find proteins for P60568 (Homo sapiens)
Explore P60568 
Go to UniProtKB:  P60568
PHAROS:  P60568
GTEx:  ENSG00000109471 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP60568
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
anti-hIL2 FAB fragment heavy chainB [auth H]224Mus musculusMutation(s): 0 
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Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
anti-hIL2 FAB fragment light chainC [auth L]218Mus musculusMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.291 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.194 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 201.757α = 90
b = 36.233β = 102.93
c = 88.707γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-12-14
    Type: Initial release
  • Version 1.1: 2024-01-10
    Changes: Data collection, Database references, Refinement description