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

Derek VanDyke(Johns Hopkins University), Marcos Iglesias(Johns Hopkins University), Jakub Tomala(Czech Academy of Sciences), Arabella Young(University of California, San Francisco), Jennifer Smith(University of California, San Francisco), Joseph A. Perry(University of Pennsylvania), Edward Gebara(Johns Hopkins University), Amy Cross(University of Oxford), Laurene S. Cheung(Bloomberg (United States)), Arbor G. Dykema(Bloomberg (United States)), Brian Orcutt-Jahns(University of California, Los Angeles), Tereza Henclová(Czech Academy of Sciences), Jaroslav Goliáš(Czech Academy of Sciences), Jared Balolong(University of California, San Francisco), Luke M. Tomasovic(Johns Hopkins University), David P. Funda(Czech Academy of Sciences), Aaron S. Meyer(University of California, Los Angeles), Drew M. Pardoll(Bloomberg (United States)), Joanna Hester(University of Oxford), Fadi Issa(University of Oxford), Christopher A. Hunter(University of Pennsylvania), Mark S. Anderson(University of California, San Francisco), Jeffrey A. Bluestone(University of California, San Francisco), Giorgio Raimondi(Johns Hopkins University), Jamie B. Spangler(Bloomberg (United States))
Cell Reports
October 1, 2022
10.1016/j.celrep.2022.111478
Cited by 43Open Access
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Abstract

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.

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