Engineering a Single-Agent Cytokine/Antibody Fusion That Selectively Expands Regulatory T Cells for Autoimmune Disease Therapy

J Immunol. 2018 Oct 1;201(7):2094-2106. doi: 10.4049/jimmunol.1800578. Epub 2018 Aug 13.


IL-2 has been used to treat diseases ranging from cancer to autoimmune disorders, but its concurrent immunostimulatory and immunosuppressive effects hinder efficacy. IL-2 orchestrates immune cell function through activation of a high-affinity heterotrimeric receptor (composed of IL-2Rα, IL-2Rβ, and common γ [γc]). IL-2Rα, which is highly expressed on regulatory T (TReg) cells, regulates IL-2 sensitivity. Previous studies have shown that complexation of IL-2 with the JES6-1 Ab preferentially biases cytokine activity toward TReg cells through a unique mechanism whereby IL-2 is exchanged from the Ab to IL-2Rα. However, clinical adoption of a mixed Ab/cytokine complex regimen is limited by stoichiometry and stability concerns. In this study, through structure-guided design, we engineered a single agent fusion of the IL-2 cytokine and JES6-1 Ab that, despite being covalently linked, preserves IL-2 exchange, selectively stimulating TReg expansion and exhibiting superior disease control to the mixed IL-2/JES6-1 complex in a mouse colitis model. These studies provide an engineering blueprint for resolving a major barrier to the implementation of functionally similar IL-2/Ab complexes for treatment of human disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antibodies / genetics
  • Antibodies / metabolism*
  • Autoimmune Diseases / immunology*
  • Autoimmune Diseases / therapy
  • Cell Proliferation
  • Cells, Cultured
  • Colitis / immunology*
  • Colitis / therapy
  • Cytokines / genetics
  • Cytokines / immunology
  • Cytokines / metabolism*
  • Disease Models, Animal
  • Humans
  • Immunotherapy / methods*
  • Lymphocyte Activation
  • Mice
  • Protein Engineering
  • Receptors, Interleukin-2 / immunology*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism*
  • T-Lymphocytes, Regulatory / immunology*


  • Antibodies
  • Cytokines
  • Receptors, Interleukin-2
  • Recombinant Fusion Proteins