title: Treg depletion in non-human primates using a novel diphtheria toxin-based anti-human CCR4 immunotoxin.
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.
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Shannon G
authors.initials: SG
authors.lastname: Pratts
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Spencer
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Ruichao
authors.initials: R
authors.lastname: Yu
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Makoto
authors.initials: M
authors.lastname: Tonsho
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Jigesh A
authors.initials: JA
authors.lastname: Shah
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Tatsu
authors.initials: T
authors.lastname: Tanabe
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Harrison R
authors.initials: HR
authors.lastname: Powell
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Christene A
authors.initials: CA
authors.lastname: Huang
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Division of Cardiac Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Joren C
authors.initials: JC
authors.lastname: Madsen
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; TBRC Laboratories, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Sachs
authors.affiliation: Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: zwang7@mgh.harvard.edu.
authors.forename: Zhirui
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000818:Animals; D004167:Diphtheria Toxin / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D000922:Immunotoxins / Q000276:immunology / Q000494:pharmacology*; D008212:Lymphocyte Depletion / Q000379:methods*; D008252:Macaca fascicularis; D008297:Male; D054398:Receptors, CCR4 / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C515354:CCR4 protein, human; D004167:Diphtheria Toxin; D000922:Immunotoxins; D054398:Receptors, CCR4
keywords: CCR4; Diphtheria toxin; Immunotoxin; NHP Treg