IL-2/CD25: A long-acting fusion protein that promotes immune tolerance by selectively targeting the IL-2 receptor on regulatory t cells

Natasha C. Ward, Aixin Yu, Alejandro Moro, Yuguang Ban, Xi Chen, Sunnie Hsiung, James Keegan, Jaren M. Arbanas, Martine Loubeau, Anil Thankappan, Aaron P. Yamniuk, Jonathan H. Davis, Mary Struthers, Thomas Malek

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Low-dose IL-2 represents an immunotherapy to selectively expand regulatory T cells (Tregs) to promote tolerance in patients with autoimmunity. In this article, we show that a fusion protein (FP) of mouse IL-2 and mouse IL-2Ra (CD25), joined by a noncleavable linker, has greater in vivo efficacy than rIL-2 at Treg expansion and control of autoimmunity. Biochemical and functional studies support a model in which IL-2 interacts with CD25 in the context of this FP in trans to form inactive head-to-tail dimers that slowly dissociate into an active monomer. In vitro, IL-2/CD25 has low sp. act. However, in vivo IL-2/CD25 is long lived to persistently and selectively stimulate Tregs. In female NOD mice, IL-2/CD25 administration increased Tregs within the pancreas and reduced the instance of spontaneous diabetes. Thus, IL-2/CD25 represents a distinct class of IL-2 FPs with the potential for clinical development for use in autoimmunity or other disorders of an overactive immune response.

Original languageEnglish (US)
Pages (from-to)2579-2592
Number of pages14
JournalJournal of Immunology
Volume201
Issue number9
DOIs
StatePublished - Nov 1 2018

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Ward, N. C., Yu, A., Moro, A., Ban, Y., Chen, X., Hsiung, S., Keegan, J., Arbanas, J. M., Loubeau, M., Thankappan, A., Yamniuk, A. P., Davis, J. H., Struthers, M., & Malek, T. (2018). IL-2/CD25: A long-acting fusion protein that promotes immune tolerance by selectively targeting the IL-2 receptor on regulatory t cells. Journal of Immunology, 201(9), 2579-2592. https://doi.org/10.4049/jimmunol.1800907