1. Engineered human cytokine/antibody fusion proteins expand regulatory T cells and confer autoimmune disease protection
- Author
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VanDyke, Derek, Iglesias, Marcos, Tomala, Jakub, Young, Arabella, Smith, Jennifer, Perry, Joseph A, Gebara, Edward, Cross, Amy R, Cheung, Laurene S, Dykema, Arbor G, Orcutt-Jahns, Brian T, Henclová, Tereza, Golias, Jaroslav, Balolong, Jared, Tomasovic, Luke M, Funda, David, Meyer, Aaron S, Pardoll, Drew M, Hester, Joanna, Issa, Fadi, Hunter, Christopher A, Anderson, Mark S, Bluestone, Jeffrey A, Raimondi, Giorgio, and Spangler, Jamie B
- Subjects
Biological Sciences ,Diabetes ,Biotechnology ,Vaccine Related ,Immunization ,Autoimmune Disease ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Inflammatory and immune system ,Mice ,Animals ,Humans ,Interleukin-2 ,T-Lymphocytes ,Regulatory ,Autoimmune Diseases ,Antibodies ,Cytokines ,CP: Immunology ,antibody ,autoimmune disease ,cytokine ,immunocytokine ,interleukin-2 ,molecular therapeutics ,regulatory T cell ,Biochemistry and Cell Biology ,Medical Physiology ,Biological sciences - 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.
- Published
- 2022