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ResearchIn-Press PreviewImmunologyTherapeutics Open Access | 10.1172/jci.insight.173469

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

Elissa K. Leonard,1 Jakub Tomala,2 Joseph R. Gould,1 Michael I. Leff,3 Jian-Xin Lin,4 Peng Li,4 Mitchell J. Porter,5 Eric R. Johansen,6 Ladaisha Thompson,1 Shanelle D. Cao,7 Shenda Hou,8 Tereza Henclova,2 Maros Huliciak,2 Paul R. Sargunas,7 Charina S. Fabilane,9 Ondřej Vaněk,10 Marek Kovar,11 Bohdan Schneider,2 Giorgio Raimondi,12 Warren J. Leonard,4 and Jamie B. Spangler1

1Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Institute of Biotechnology of the Academy of Sciences of the Czech Republic, Vestec, Czech Republic

3Biology, Johns Hopkins University, Baltimore, United States of America

4Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

5Chemistry, Johns Hopkins Univeristy, Baltimore, United States of America

6Chemistry, Johns Hopkins University, Baltimore, United States of America

7Chemical and Biomolecular Engineering, Johns Hopkins University School of Engineering, Baltimore, United States of America

8Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, United States of America

9Molecular Biophysics, Johns Hopkins University School of Medicine, Baltimore, United States of America

10Biochemistry, Charles University, Faculty of Science, Prague, Czech Republic

11Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic

12Vascularized Composite Allotransplantation Laboratory, Department of Plasti, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Institute of Biotechnology of the Academy of Sciences of the Czech Republic, Vestec, Czech Republic

3Biology, Johns Hopkins University, Baltimore, United States of America

4Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

5Chemistry, Johns Hopkins Univeristy, Baltimore, United States of America

6Chemistry, Johns Hopkins University, Baltimore, United States of America

7Chemical and Biomolecular Engineering, Johns Hopkins University School of Engineering, Baltimore, United States of America

8Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, United States of America

9Molecular Biophysics, Johns Hopkins University School of Medicine, Baltimore, United States of America

10Biochemistry, Charles University, Faculty of Science, Prague, Czech Republic

11Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic

12Vascularized Composite Allotransplantation Laboratory, Department of Plasti, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Institute of Biotechnology of the Academy of Sciences of the Czech Republic, Vestec, Czech Republic

3Biology, Johns Hopkins University, Baltimore, United States of America

4Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

5Chemistry, Johns Hopkins Univeristy, Baltimore, United States of America

6Chemistry, Johns Hopkins University, Baltimore, United States of America

7Chemical and Biomolecular Engineering, Johns Hopkins University School of Engineering, Baltimore, United States of America

8Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, United States of America

9Molecular Biophysics, Johns Hopkins University School of Medicine, Baltimore, United States of America

10Biochemistry, Charles University, Faculty of Science, Prague, Czech Republic

11Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic

12Vascularized Composite Allotransplantation Laboratory, Department of Plasti, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Institute of Biotechnology of the Academy of Sciences of the Czech Republic, Vestec, Czech Republic

3Biology, Johns Hopkins University, Baltimore, United States of America

4Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

5Chemistry, Johns Hopkins Univeristy, Baltimore, United States of America

6Chemistry, Johns Hopkins University, Baltimore, United States of America

7Chemical and Biomolecular Engineering, Johns Hopkins University School of Engineering, Baltimore, United States of America

8Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, United States of America

9Molecular Biophysics, Johns Hopkins University School of Medicine, Baltimore, United States of America

10Biochemistry, Charles University, Faculty of Science, Prague, Czech Republic

11Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic

12Vascularized Composite Allotransplantation Laboratory, Department of Plasti, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Institute of Biotechnology of the Academy of Sciences of the Czech Republic, Vestec, Czech Republic

3Biology, Johns Hopkins University, Baltimore, United States of America

4Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

5Chemistry, Johns Hopkins Univeristy, Baltimore, United States of America

6Chemistry, Johns Hopkins University, Baltimore, United States of America

7Chemical and Biomolecular Engineering, Johns Hopkins University School of Engineering, Baltimore, United States of America

8Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, United States of America

9Molecular Biophysics, Johns Hopkins University School of Medicine, Baltimore, United States of America

10Biochemistry, Charles University, Faculty of Science, Prague, Czech Republic

11Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic

12Vascularized Composite Allotransplantation Laboratory, Department of Plasti, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Institute of Biotechnology of the Academy of Sciences of the Czech Republic, Vestec, Czech Republic

3Biology, Johns Hopkins University, Baltimore, United States of America

4Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

5Chemistry, Johns Hopkins Univeristy, Baltimore, United States of America

6Chemistry, Johns Hopkins University, Baltimore, United States of America

7Chemical and Biomolecular Engineering, Johns Hopkins University School of Engineering, Baltimore, United States of America

8Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, United States of America

9Molecular Biophysics, Johns Hopkins University School of Medicine, Baltimore, United States of America

10Biochemistry, Charles University, Faculty of Science, Prague, Czech Republic

11Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic

12Vascularized Composite Allotransplantation Laboratory, Department of Plasti, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Institute of Biotechnology of the Academy of Sciences of the Czech Republic, Vestec, Czech Republic

3Biology, Johns Hopkins University, Baltimore, United States of America

4Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

5Chemistry, Johns Hopkins Univeristy, Baltimore, United States of America

6Chemistry, Johns Hopkins University, Baltimore, United States of America

7Chemical and Biomolecular Engineering, Johns Hopkins University School of Engineering, Baltimore, United States of America

8Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, United States of America

9Molecular Biophysics, Johns Hopkins University School of Medicine, Baltimore, United States of America

10Biochemistry, Charles University, Faculty of Science, Prague, Czech Republic

11Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic

12Vascularized Composite Allotransplantation Laboratory, Department of Plasti, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Institute of Biotechnology of the Academy of Sciences of the Czech Republic, Vestec, Czech Republic

3Biology, Johns Hopkins University, Baltimore, United States of America

4Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

5Chemistry, Johns Hopkins Univeristy, Baltimore, United States of America

6Chemistry, Johns Hopkins University, Baltimore, United States of America

7Chemical and Biomolecular Engineering, Johns Hopkins University School of Engineering, Baltimore, United States of America

8Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, United States of America

9Molecular Biophysics, Johns Hopkins University School of Medicine, Baltimore, United States of America

10Biochemistry, Charles University, Faculty of Science, Prague, Czech Republic

11Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic

12Vascularized Composite Allotransplantation Laboratory, Department of Plasti, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Institute of Biotechnology of the Academy of Sciences of the Czech Republic, Vestec, Czech Republic

3Biology, Johns Hopkins University, Baltimore, United States of America

4Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

5Chemistry, Johns Hopkins Univeristy, Baltimore, United States of America

6Chemistry, Johns Hopkins University, Baltimore, United States of America

7Chemical and Biomolecular Engineering, Johns Hopkins University School of Engineering, Baltimore, United States of America

8Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, United States of America

9Molecular Biophysics, Johns Hopkins University School of Medicine, Baltimore, United States of America

10Biochemistry, Charles University, Faculty of Science, Prague, Czech Republic

11Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic

12Vascularized Composite Allotransplantation Laboratory, Department of Plasti, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Institute of Biotechnology of the Academy of Sciences of the Czech Republic, Vestec, Czech Republic

3Biology, Johns Hopkins University, Baltimore, United States of America

4Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

5Chemistry, Johns Hopkins Univeristy, Baltimore, United States of America

6Chemistry, Johns Hopkins University, Baltimore, United States of America

7Chemical and Biomolecular Engineering, Johns Hopkins University School of Engineering, Baltimore, United States of America

8Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, United States of America

9Molecular Biophysics, Johns Hopkins University School of Medicine, Baltimore, United States of America

10Biochemistry, Charles University, Faculty of Science, Prague, Czech Republic

11Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic

12Vascularized Composite Allotransplantation Laboratory, Department of Plasti, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Institute of Biotechnology of the Academy of Sciences of the Czech Republic, Vestec, Czech Republic

3Biology, Johns Hopkins University, Baltimore, United States of America

4Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

5Chemistry, Johns Hopkins Univeristy, Baltimore, United States of America

6Chemistry, Johns Hopkins University, Baltimore, United States of America

7Chemical and Biomolecular Engineering, Johns Hopkins University School of Engineering, Baltimore, United States of America

8Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, United States of America

9Molecular Biophysics, Johns Hopkins University School of Medicine, Baltimore, United States of America

10Biochemistry, Charles University, Faculty of Science, Prague, Czech Republic

11Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic

12Vascularized Composite Allotransplantation Laboratory, Department of Plasti, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Institute of Biotechnology of the Academy of Sciences of the Czech Republic, Vestec, Czech Republic

3Biology, Johns Hopkins University, Baltimore, United States of America

4Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

5Chemistry, Johns Hopkins Univeristy, Baltimore, United States of America

6Chemistry, Johns Hopkins University, Baltimore, United States of America

7Chemical and Biomolecular Engineering, Johns Hopkins University School of Engineering, Baltimore, United States of America

8Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, United States of America

9Molecular Biophysics, Johns Hopkins University School of Medicine, Baltimore, United States of America

10Biochemistry, Charles University, Faculty of Science, Prague, Czech Republic

11Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic

12Vascularized Composite Allotransplantation Laboratory, Department of Plasti, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Institute of Biotechnology of the Academy of Sciences of the Czech Republic, Vestec, Czech Republic

3Biology, Johns Hopkins University, Baltimore, United States of America

4Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

5Chemistry, Johns Hopkins Univeristy, Baltimore, United States of America

6Chemistry, Johns Hopkins University, Baltimore, United States of America

7Chemical and Biomolecular Engineering, Johns Hopkins University School of Engineering, Baltimore, United States of America

8Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, United States of America

9Molecular Biophysics, Johns Hopkins University School of Medicine, Baltimore, United States of America

10Biochemistry, Charles University, Faculty of Science, Prague, Czech Republic

11Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic

12Vascularized Composite Allotransplantation Laboratory, Department of Plasti, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Institute of Biotechnology of the Academy of Sciences of the Czech Republic, Vestec, Czech Republic

3Biology, Johns Hopkins University, Baltimore, United States of America

4Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

5Chemistry, Johns Hopkins Univeristy, Baltimore, United States of America

6Chemistry, Johns Hopkins University, Baltimore, United States of America

7Chemical and Biomolecular Engineering, Johns Hopkins University School of Engineering, Baltimore, United States of America

8Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, United States of America

9Molecular Biophysics, Johns Hopkins University School of Medicine, Baltimore, United States of America

10Biochemistry, Charles University, Faculty of Science, Prague, Czech Republic

11Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic

12Vascularized Composite Allotransplantation Laboratory, Department of Plasti, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Institute of Biotechnology of the Academy of Sciences of the Czech Republic, Vestec, Czech Republic

3Biology, Johns Hopkins University, Baltimore, United States of America

4Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

5Chemistry, Johns Hopkins Univeristy, Baltimore, United States of America

6Chemistry, Johns Hopkins University, Baltimore, United States of America

7Chemical and Biomolecular Engineering, Johns Hopkins University School of Engineering, Baltimore, United States of America

8Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, United States of America

9Molecular Biophysics, Johns Hopkins University School of Medicine, Baltimore, United States of America

10Biochemistry, Charles University, Faculty of Science, Prague, Czech Republic

11Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic

12Vascularized Composite Allotransplantation Laboratory, Department of Plasti, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Institute of Biotechnology of the Academy of Sciences of the Czech Republic, Vestec, Czech Republic

3Biology, Johns Hopkins University, Baltimore, United States of America

4Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

5Chemistry, Johns Hopkins Univeristy, Baltimore, United States of America

6Chemistry, Johns Hopkins University, Baltimore, United States of America

7Chemical and Biomolecular Engineering, Johns Hopkins University School of Engineering, Baltimore, United States of America

8Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, United States of America

9Molecular Biophysics, Johns Hopkins University School of Medicine, Baltimore, United States of America

10Biochemistry, Charles University, Faculty of Science, Prague, Czech Republic

11Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic

12Vascularized Composite Allotransplantation Laboratory, Department of Plasti, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Institute of Biotechnology of the Academy of Sciences of the Czech Republic, Vestec, Czech Republic

3Biology, Johns Hopkins University, Baltimore, United States of America

4Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

5Chemistry, Johns Hopkins Univeristy, Baltimore, United States of America

6Chemistry, Johns Hopkins University, Baltimore, United States of America

7Chemical and Biomolecular Engineering, Johns Hopkins University School of Engineering, Baltimore, United States of America

8Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, United States of America

9Molecular Biophysics, Johns Hopkins University School of Medicine, Baltimore, United States of America

10Biochemistry, Charles University, Faculty of Science, Prague, Czech Republic

11Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic

12Vascularized Composite Allotransplantation Laboratory, Department of Plasti, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Institute of Biotechnology of the Academy of Sciences of the Czech Republic, Vestec, Czech Republic

3Biology, Johns Hopkins University, Baltimore, United States of America

4Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

5Chemistry, Johns Hopkins Univeristy, Baltimore, United States of America

6Chemistry, Johns Hopkins University, Baltimore, United States of America

7Chemical and Biomolecular Engineering, Johns Hopkins University School of Engineering, Baltimore, United States of America

8Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, United States of America

9Molecular Biophysics, Johns Hopkins University School of Medicine, Baltimore, United States of America

10Biochemistry, Charles University, Faculty of Science, Prague, Czech Republic

11Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic

12Vascularized Composite Allotransplantation Laboratory, Department of Plasti, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Institute of Biotechnology of the Academy of Sciences of the Czech Republic, Vestec, Czech Republic

3Biology, Johns Hopkins University, Baltimore, United States of America

4Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

5Chemistry, Johns Hopkins Univeristy, Baltimore, United States of America

6Chemistry, Johns Hopkins University, Baltimore, United States of America

7Chemical and Biomolecular Engineering, Johns Hopkins University School of Engineering, Baltimore, United States of America

8Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, United States of America

9Molecular Biophysics, Johns Hopkins University School of Medicine, Baltimore, United States of America

10Biochemistry, Charles University, Faculty of Science, Prague, Czech Republic

11Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic

12Vascularized Composite Allotransplantation Laboratory, Department of Plasti, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Institute of Biotechnology of the Academy of Sciences of the Czech Republic, Vestec, Czech Republic

3Biology, Johns Hopkins University, Baltimore, United States of America

4Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

5Chemistry, Johns Hopkins Univeristy, Baltimore, United States of America

6Chemistry, Johns Hopkins University, Baltimore, United States of America

7Chemical and Biomolecular Engineering, Johns Hopkins University School of Engineering, Baltimore, United States of America

8Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, United States of America

9Molecular Biophysics, Johns Hopkins University School of Medicine, Baltimore, United States of America

10Biochemistry, Charles University, Faculty of Science, Prague, Czech Republic

11Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic

12Vascularized Composite Allotransplantation Laboratory, Department of Plasti, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Leonard, W. in: JCI | PubMed | Google Scholar |

1Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Institute of Biotechnology of the Academy of Sciences of the Czech Republic, Vestec, Czech Republic

3Biology, Johns Hopkins University, Baltimore, United States of America

4Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

5Chemistry, Johns Hopkins Univeristy, Baltimore, United States of America

6Chemistry, Johns Hopkins University, Baltimore, United States of America

7Chemical and Biomolecular Engineering, Johns Hopkins University School of Engineering, Baltimore, United States of America

8Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, United States of America

9Molecular Biophysics, Johns Hopkins University School of Medicine, Baltimore, United States of America

10Biochemistry, Charles University, Faculty of Science, Prague, Czech Republic

11Laboratory of Tumor Immunology, Institute of Microbiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic

12Vascularized Composite Allotransplantation Laboratory, Department of Plasti, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Spangler, J. in: JCI | PubMed | Google Scholar |

Published August 8, 2024 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.173469.
Copyright © 2024, Leonard et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published August 8, 2024 - Version history
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Abstract

Progress in cytokine engineering is driving therapeutic translation by overcoming these proteins’ limitations as drugs. The interleukin-2 (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 anti-inflammatory 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 complexation with anti-IL-2 antibodies that bias the cytokine towards 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 multi-protein 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 towards 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 to 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.

Supplemental material

View Unedited blot and gel images

View IL2_602_Validation_Report

View IL2_F10_Validation_Report

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View Supplemental Table 8

Version history
  • Version 1 (August 8, 2024): In-Press Preview
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