Engineered cytokine/antibody fusion proteins improve IL-2 delivery to pro-inflammatory cells and promote antitumor activity.

Autor:	Leonard EK; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Tomala J; Institute of Biotechnology of the Academy of Sciences of the Czech Republic, Vestec, Czech Republic.; Department of Chemical & Biomolecular Engineering and., Gould JR; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Leff MI; Department of Biology, Johns Hopkins University, Baltimore, Maryland, USA., Lin JX; Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA., Li P; Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA., Porter MJ; Department of Chemistry, Johns Hopkins University, Baltimore, Maryland, USA., Johansen ER; Department of Chemistry, Johns Hopkins University, Baltimore, Maryland, USA., Thompson L; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Cao SD; Department of Chemical & Biomolecular Engineering and., Hou S; Department of Plastic & Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Henclova T; Institute of Biotechnology of the Academy of Sciences of the Czech Republic, Vestec, Czech Republic., Huliciak M; Institute of Biotechnology of the Academy of Sciences of the Czech Republic, Vestec, Czech Republic.; Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, USA., Sargunas PR; Department of Chemical & Biomolecular Engineering and., Fabilane CS; Program in Molecular Biophysics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Vaněk O; Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic., Kovar M; Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic., Schneider B; Institute of Biotechnology of the Academy of Sciences of the Czech Republic, Vestec, Czech Republic., Raimondi G; Vascularized Composite Allotransplantation Laboratory, Department of Plastic and Reconstructive Surgery., Leonard WJ; Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA., Spangler JB; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Department of Chemical & Biomolecular Engineering and.; Translational Tissue Engineering Center.; Department of Oncology.; Bloomberg-Kimmel Institute for Cancer Immunotherapy.; Sidney Kimmel Comprehensive Cancer Center; and.; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2024 Sep 24; Vol. 9 (18). Date of Electronic Publication: 2024 Sep 24.
DOI:	10.1172/jci.insight.173469
Abstrakt:	Progress in cytokine engineering is driving therapeutic translation by overcoming these proteins' limitations as drugs. The IL-2 cytokine is a promising immune stimulant for cancer treatment but is limited by its concurrent activation of both pro-inflammatory immune effector cells and antiinflammatory regulatory T cells, toxicity at high doses, and short serum half-life. One approach to improve the selectivity, safety, and longevity of IL-2 is complexing with anti-IL-2 antibodies that bias the cytokine toward immune effector cell activation. Although this strategy shows potential in preclinical models, clinical translation of a cytokine/antibody complex is complicated by challenges in formulating a multiprotein drug and concerns regarding complex stability. Here, we introduced a versatile approach to designing intramolecularly assembled single-agent fusion proteins (immunocytokines, ICs) comprising IL-2 and a biasing anti-IL-2 antibody that directs the cytokine toward immune effector cells. We optimized IC construction and engineered the cytokine/antibody affinity to improve immune bias. We demonstrated that our IC preferentially activates and expands immune effector cells, leading to superior antitumor activity compared with natural IL-2, both alone and combined with immune checkpoint inhibitors. Moreover, therapeutic efficacy was observed without inducing toxicity. This work presents a roadmap for the design and translation of cytokine/antibody fusion proteins.
Databáze:	MEDLINE
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