A Human anti-IL-2 Antibody That Potentiates Regulatory T Cells by a Structure-Based Mechanism

Nat Med. 2018 Jul;24(7):1005-1014. doi: 10.1038/s41591-018-0070-2. Epub 2018 Jun 25.

Abstract

Interleukin-2 (IL-2) has been shown to suppress immune pathologies by preferentially expanding regulatory T cells (Tregs). However, this therapy has been limited by off-target complications due to pathogenic cell expansion. Recent efforts have been focused on developing a more selective IL-2. It is well documented that certain anti-mouse IL-2 antibodies induce conformational changes that result in selective targeting of Tregs. We report the generation of a fully human anti-IL-2 antibody, F5111.2, that stabilizes IL-2 in a conformation that results in the preferential STAT5 phosphorylation of Tregs in vitro and selective expansion of Tregs in vivo. When complexed with human IL-2, F5111.2 induced remission of type 1 diabetes in the NOD mouse model, reduced disease severity in a model of experimental autoimmune encephalomyelitis and protected mice against xenogeneic graft-versus-host disease. These results suggest that IL-2-F5111.2 may provide an immunotherapy to treat autoimmune diseases and graft-versus-host disease.

MeSH terms

  • Animals
  • Antibodies / chemistry*
  • Antibodies / pharmacology*
  • Antibodies / therapeutic use
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Proliferation / drug effects
  • Diabetes Mellitus, Type 1 / drug therapy
  • Diabetes Mellitus, Type 1 / immunology
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Graft vs Host Disease / drug therapy
  • Graft vs Host Disease / immunology
  • Humans
  • Immunoglobulin Fab Fragments / metabolism
  • Immunotherapy
  • Interleukin-2 / immunology*
  • Kinetics
  • Mice, Inbred C57BL
  • Models, Molecular
  • Muromegalovirus / drug effects
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • STAT5 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Structure-Activity Relationship
  • T-Lymphocytes, Regulatory / drug effects*
  • Up-Regulation / drug effects

Substances

  • Antibodies
  • Immunoglobulin Fab Fragments
  • Interleukin-2
  • STAT5 Transcription Factor