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

Zhaohui Wang, Shannon G. Pratts, Huiping Zhang, Philip J. Spencer, Ruichao Yu, Makoto Tonsho, Jigesh A. Shah, Tatsu Tanabe, Harrison R. Powell, Christene A. Huang, Joren C. Madsen, David H. Sachs, Zhirui Wang

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)553-565
Number of pages13
JournalMolecular oncology
Volume10
Issue number4
DOIs
StatePublished - Apr 1 2016
Externally publishedYes

Keywords

  • CCR4
  • Diphtheria toxin
  • Immunotoxin
  • NHP Treg

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Oncology
  • Cancer Research

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