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 Issa; Christopher A. Hunter; Mark S. Anderson; Jeffrey A. Bluestone; Giorgio Raimondi; Jamie B. Spangler

doi:10.1016/j.celrep.2022.111478

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 journal › Article › peer-review

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.

Original language	English (US)
Article number	111478
Journal	Cell Reports
Volume	41
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2022.111478
State	Published - Oct 18 2022

Keywords

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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10.1016/j.celrep.2022.111478

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VanDyke, D., Iglesias, M., Tomala, J., Young, A., Smith, J., Perry, J. A., Gebara, E., Cross, A. R., Cheung, L. S., Dykema, A. G., Orcutt-Jahns, B. T., Henclová, T., Golias, J., Balolong, J., Tomasovic, L. M., Funda, D., Meyer, A. S., Pardoll, D. M., Hester, J., ... Spangler, J. B. (2022). Engineered human cytokine/antibody fusion proteins expand regulatory T cells and confer autoimmune disease protection. Cell Reports, 41(3), Article 111478. https://doi.org/10.1016/j.celrep.2022.111478

VanDyke, D, Iglesias, M, Tomala, J, Young, A, Smith, J, Perry, JA, Gebara, E, Cross, AR, Cheung, LS, Dykema, AG, Orcutt-Jahns, BT, Henclová, T, Golias, J, Balolong, J, Tomasovic, LM, Funda, D, Meyer, AS, Pardoll, DM, Hester, J, Issa, F, Hunter, CA, Anderson, MS, Bluestone, JA, Raimondi, G & Spangler, JB 2022, 'Engineered human cytokine/antibody fusion proteins expand regulatory T cells and confer autoimmune disease protection', Cell Reports, vol. 41, no. 3, 111478. https://doi.org/10.1016/j.celrep.2022.111478

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

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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doi = "10.1016/j.celrep.2022.111478",

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AU - VanDyke, Derek

AU - Iglesias, Marcos

AU - Tomala, Jakub

AU - Young, Arabella

AU - Smith, Jennifer

AU - Perry, Joseph A.

AU - Gebara, Edward

AU - Cross, Amy R.

AU - Cheung, Laurene S.

AU - Dykema, Arbor G.

AU - Orcutt-Jahns, Brian T.

AU - Henclová, Tereza

AU - Golias, Jaroslav

AU - Balolong, Jared

AU - Tomasovic, Luke M.

AU - Funda, David

AU - Meyer, Aaron S.

AU - Pardoll, Drew M.

AU - Hester, Joanna

AU - Issa, Fadi

AU - Hunter, Christopher A.

AU - Anderson, Mark S.

AU - Bluestone, Jeffrey A.

AU - Raimondi, Giorgio

AU - Spangler, Jamie B.

PY - 2022/10/18

Y1 - 2022/10/18

N2 - 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.

AB - 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.

KW - CP: Immunology

KW - antibody

KW - autoimmune disease

KW - cytokine

KW - immunocytokine

KW - interleukin-2

KW - molecular therapeutics

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ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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