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

Cell Rep. 2022 Oct 18;41(3):111478. doi: 10.1016/j.celrep.2022.111478.

Authors

Derek VanDyke¹, Marcos Iglesias², Jakub Tomala³, Arabella Young⁴, Jennifer Smith⁵, Joseph A Perry⁶, Edward Gebara⁷, Amy R Cross⁸, Laurene S Cheung⁹, Arbor G Dykema⁹, Brian T Orcutt-Jahns¹⁰, Tereza Henclová³, Jaroslav Golias¹¹, Jared Balolong⁵, Luke M Tomasovic¹, David Funda¹¹, Aaron S Meyer¹⁰, Drew M Pardoll⁹, Joanna Hester⁸, Fadi Issa⁸, Christopher A Hunter⁶, Mark S Anderson⁵, Jeffrey A Bluestone¹², Giorgio Raimondi², Jamie B Spangler¹³

Affiliations

¹ Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
² Vascularized Composite Allotransplantation Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Institute of Biotechnology of the Academy of Sciences of the Czech Republic, Vestec 252 50, Czech Republic.
⁴ Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA; Sean N. Parker Autoimmune Research Laboratory, University of California San Francisco, San Francisco, CA 94143, USA; Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA; Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
⁵ Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA.
⁶ Department of Pathobiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷ Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
⁸ Translational Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 9DU, UK.
⁹ Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD 21231, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA.
¹⁰ Department of Bioengineering, Jonsson Comprehensive Cancer Center, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹¹ Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague 142 20, Czech Republic.
¹² Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA; Sean N. Parker Autoimmune Research Laboratory, University of California San Francisco, San Francisco, CA 94143, USA; Sonoma Biotherapeutics, South San Francisco, CA 94080, USA.
¹³ Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD 21231, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address: jamie.spangler@jhu.edu.

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.

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

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antibodies / metabolism
Autoimmune Diseases*
Cytokines / metabolism
Humans
Interleukin-2*
Mice
T-Lymphocytes, Regulatory

Substances

Interleukin-2
Antibodies
Cytokines

Abstract

Publication types

MeSH terms

Substances

Grants and funding