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 Issa, Christopher A Hunter, Mark S Anderson, Jeffrey A Bluestone, Giorgio Raimondi, Jamie B Spangler
Cell reports 2022 Oct 18Low-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. Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
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 Issa, Christopher A Hunter, Mark S Anderson, Jeffrey A Bluestone, Giorgio Raimondi, Jamie B Spangler. Engineered human cytokine/antibody fusion proteins expand regulatory T cells and confer autoimmune disease protection. Cell reports. 2022 Oct 18;41(3):111478
PMID: 36261022
View Full Text