IL-2 receptor-targeted cytolytic IL-2/Fc fusion protein treatment blocks diabetogenic autoimmunity in nonobese diabetic mice

Xin Xiao Zheng, Alan W. Steele, Wayne W. Hancock, Kensaku Kawamoto, Xian Chang Li, Peter W. Nickerson, Yongsheng Li, Yan Tian, Terry B. Strom

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

High affinity IL-2R5 is present on recently activated but not on resting or memory T cells. Selective targeting of T cells bearing high affinity IL-2R is an attractive therapy for many T cell-dependent cytopathic disease processes. A variety of rodent mAbs directed against the α-chain of the IL-2R, as well as IL-2 fusion toxins, have been used in animals and humans to achieve selective immunosuppression. Here we report on the development of a novel IL-2R targeting agent, a cytolytic chimeric IL-2/Fc fusion protein. This immunoligand binds specifically and with high affinity to IL-2R and is structurally capable of recruiting host Ab-dependent cell- mediated cytotoxicity and complement-dependent cytotoxicity activities. The Ig component ensures an extended circulating t(1/2) of 25 h following systemic administration. To subsequently explore the mechanisms of the antidiabetogenic effects of IL-2/Fc, we have mutated the FcR binding and complement C1q binding (Fc(-/-)) domains of the Fc fragment to render the Fc unable to direct Ab-dependent cell-mediated cytotoxicity and complement- dependent cytotoxicity activities. In a model of passive transfer of diabetes in nonobese diabetic mice, lytic IL-2/Fc, but not nonlytic IL-2/Fc(-/-), exhibited striking antidiabetogenic effects. Together with the negligible potential of IL-2/Fc for immunogenicity, this finding forecasts that cytolytic IL-2/Fc may offer a new therapeutic approach for selective targeting of auto and alloimmune T cells.

Original languageEnglish (US)
Pages (from-to)4041-4048
Number of pages8
JournalJournal of Immunology
Volume163
Issue number7
StatePublished - Oct 1 1999

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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