Targeting activated lymphocytes with an entirely human immunotoxin analogue: Human pancreatic RNase1-human IL-12 fusion

Kyriakos Psarras, Masakazu Ueda, Minoru Tanabe, Masaki Kitajima, Sadakazu Aiso, Setsuko Komatsu, Masaharu Seno

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

A hybrid human protein was produced in E. coli by fusing the genes encoding human pancreatic RNase1 (hpRNase1) and human IL-2 (hIL-2). The recombinant hpRNase1-hIL-2 inhibited protein synthesis in HTLV-1-infected, malignant T cells, which hyperproduce high affinity IL-2 receptors, with an IC50 of 2 x 10-8 M, whereas no inhibition was detectable in control cells with lower affinity receptors. HpRNase1 alone had an IC50 of almost 10-3 M. A molar excess of hIL-2 blocked the protein synthesis inhibition dose-dependently. In a human mixed lymphocyte culture, hpRNase1-hIL-2 inhibited the proliferation of responder cells with potency comparable to that of cyclosporine, while non-effective doses of FK506 importantly improved its potency. Despite its short half-life in animals, hpRNase1-hIL-2 rapidly enters cells in a few minutes and arrests the protein translation in less than 10 h. Thus, hpRNase1-hIL-2 may be useful to selectively eliminate activated lymphocytes hyperproducing high affinity IL-2 receptors, as in allograft rejection, gaft-versus-host disease, autoimmune disorders, adult T cell leukaemia and other lymphoproliferative or retroviral malignancies including HIV infection, without inducing general immunosuppression. As an entirely human 'immunotoxin analogue' it may alleviate the dose limiting toxicity and immunogenicity of conventional immunotoxins. (C) 2000 Academic Press.

Original languageEnglish
Pages (from-to)786-790
Number of pages5
JournalCytokine
Volume12
Issue number6
DOIs
Publication statusPublished - 2000 Jun
Externally publishedYes

Keywords

  • Activated lymphocytes
  • Adult T cell leukaemia
  • Allograft rejection
  • Engineered human proteins
  • IL-2 receptor targeted therapy

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Biochemistry
  • Hematology
  • Molecular Biology

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