Engineered human cytokine/antibody fusion proteins expand regulatory T cells and confer autoimmune disease protection

Derek VanDyke, Marcos Iglesias, Jakub Tomala, Arabella Young, Jennifer Smith, Joseph A. Perry, Edward Gebara, Amy R. Cross, Laurene S. Cheung, Arbor G. Dykema, Brian T. Orcutt-Jahns, Tereza Henclová, Jaroslav Golias, Jared Balolong, Luke M. Tomasovic, David Funda, Aaron S. Meyer, Drew M. Pardoll, Joanna Hester, Fadi IssaChristopher A. Hunter, Mark S. Anderson, Jeffrey A. Bluestone, Giorgio Raimondi, Jamie B. Spangler

Research output: Contribution to journalArticlepeer-review


Low-dose human interleukin-2 (hIL-2) treatment is used clinically to treat autoimmune disorders due to the cytokine's preferential expansion of immunosuppressive regulatory T cells (Tregs). However, off-target immune cell activation and short serum half-life limit the clinical potential of IL-2 treatment. Recent work showed that complexes comprising hIL-2 and the anti-hIL-2 antibody F5111 overcome these limitations by preferentially stimulating Tregs over immune effector cells. Although promising, therapeutic translation of this approach is complicated by the need to optimize dosing ratios and by the instability of the cytokine/antibody complex. We leverage structural insights to engineer a single-chain hIL-2/F5111 antibody fusion protein, termed F5111 immunocytokine (IC), which potently and selectively activates and expands Tregs. F5111 IC confers protection in mouse models of colitis and checkpoint inhibitor-induced diabetes mellitus. These results provide a roadmap for IC design and establish a Treg-biased immunotherapy that could be clinically translated for autoimmune disease treatment.

Original languageEnglish (US)
Article number111478
JournalCell Reports
Issue number3
StatePublished - Oct 18 2022


  • CP: Immunology
  • antibody
  • autoimmune disease
  • cytokine
  • immunocytokine
  • interleukin-2
  • molecular therapeutics
  • regulatory T cell

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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