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

Autor:	Leonard EK; Department of Biomedical Engineering, Johns Hopkins University School of Medicine; Baltimore, USA., Tomala J; Institute of Biotechnology of the Academy of Sciences of the Czech Republic; Vestec, Czech Republic., Gould JR; Department of Biomedical Engineering, Johns Hopkins University School of Medicine; Baltimore, USA., Leff MI; Department of Biology, Johns Hopkins University; Baltimore, USA., Lin JX; Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health; Bethesda, USA., Li P; Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health; Bethesda, USA., Porter MJ; Department of Chemistry, Johns Hopkins University; Baltimore, USA., Johansen ER; Department of Chemistry, Johns Hopkins University; Baltimore, USA., Thompson L; Department of Biomedical Engineering, Johns Hopkins University School of Medicine; Baltimore, USA., Cao SD; Department of Chemical & Biomolecular Engineering, Johns Hopkins University School of Engineering; Baltimore, 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., 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., Leonard WJ; Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health; Bethesda, USA., Spangler JB; Department of Biomedical Engineering, Johns Hopkins University School of Medicine; Baltimore, USA.; Department of Chemical & Biomolecular Engineering, Johns Hopkins University School of Engineering; Baltimore, USA.; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, USA.; Department of Oncology, Johns Hopkins University School of Medicine; Baltimore, USA.; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine; Baltimore, USA.; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine; Baltimore, USA.; Department of Ophthalmology, Johns Hopkins University School of Medicine; Baltimore, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 May 04. Date of Electronic Publication: 2023 May 04.
DOI:	10.1101/2023.05.03.539272
Abstrakt:	Progress in cytokine engineering is driving therapeutic translation by overcoming the inherent limitations of these proteins as drugs. The interleukin-2 (IL-2) cytokine harbors great promise as an immune stimulant for cancer treatment. However, the cytokine's concurrent activation of both pro-inflammatory immune effector cells and anti-inflammatory regulatory T cells, its toxicity at high doses, and its short serum half-life have limited clinical application. One promising approach to improve the selectivity, safety, and longevity of IL-2 is complexation with anti-IL-2 antibodies that bias the cytokine towards the activation of immune effector cells (i.e., effector T cells and natural killer cells). Although this strategy shows therapeutic potential in preclinical cancer models, clinical translation of a cytokine/antibody complex is complicated by challenges in formulating a multi-protein drug and concerns about complex stability. Here, we introduce 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's activities towards immune effector cells. We establish the optimal IC construction and further engineer the cytokine/antibody affinity to improve immune biasing function. We demonstrate that our IC preferentially activates and expands immune effector cells, leading to superior antitumor activity compared to natural IL-2 without inducing toxicities associated with IL-2 administration. Collectively, this work presents a roadmap for the design and translation of immunomodulatory cytokine/antibody fusion proteins. Competing Interests: Competing interests: Johns Hopkins University has filed patent #WO2020264321A1 entitled “Methods and materials for targeted expansion of immune effector cells” that covers compounds 602 IC and F10 IC as well as related compounds, with EKL, MIL, JT, and JBS as coinventors.
Databáze:	MEDLINE
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