Treg depletion in non-human primates using a novel diphtheria toxin-based anti-human CCR4 immunotoxin

Mol Oncol. 2016 Apr;10(4):553-65. doi: 10.1016/j.molonc.2015.11.008. Epub 2015 Nov 19.

Abstract

Regulatory T cells (Treg) play an important role in modulating the immune response and has attracted increasing attention in diverse fields such as cancer treatment, transplantation and autoimmune diseases. CC chemokine receptor 4 (CCR4) is expressed on the majority of Tregs, especially on effector Tregs. Recently we have developed a diphtheria-toxin based anti-human CCR4 immunotoxin for depleting CCR4(+) cells in vivo. In this study, we demonstrated that the anti-human CCR4 immunotoxin bound and depleted monkey CCR4(+) cells in vitro. We also demonstrated that the immunotoxin bound to the CCR4(+)Foxp3(+) monkey Tregs in vitro. In vivo studies performed in two naive cynomolgus monkeys revealed 78-89% CCR4(+)Foxp3(+) Treg depletion in peripheral blood lasting approximately 10 days. In lymph nodes, 89-96% CCR4(+)Foxp3(+) Tregs were depleted. No effect was observed in other cell populations including CD8(+) T cells, other CD4(+) T cells, B cells and NK cells. To our knowledge, this is the first agent that effectively depleted non-human primate (NHP) Tregs. This immunotoxin has potential to deplete effector Tregs for combined cancer treatment.

Keywords: CCR4; Diphtheria toxin; Immunotoxin; NHP Treg.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Diphtheria Toxin / immunology
  • Diphtheria Toxin / pharmacology*
  • Humans
  • Immunotoxins / immunology
  • Immunotoxins / pharmacology*
  • Lymphocyte Depletion / methods*
  • Macaca fascicularis
  • Male
  • Receptors, CCR4 / immunology*
  • T-Lymphocytes, Regulatory / immunology*

Substances

  • CCR4 protein, human
  • Diphtheria Toxin
  • Immunotoxins
  • Receptors, CCR4