A New Antibody–Cytokine Construct Targeting Natural Killer Cells: An Immunotherapeutic Approach to Chronic Lymphocytic Leukemia
In chronic lymphocytic leukemia (CLL), natural killer (NK) cells show a dysfunctional phenotype that correlates with disease progression. Our aim was to restore NK cell functionality in CLL through a specifically targeted IL15-stimulating activity; IL15 targeting could, in fact, potentiate the activ...
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2025-01-01
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| Online Access: | https://www.mdpi.com/2218-273X/15/1/117 |
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| author | Michela Flego Mauro Andreotti Francesca Romana Mauro Maria Beatrice Arasi Silvia Zamboni Zuleika Michelini Sara Pepe Clementina Maria Galluzzo Roberta Amici Diego Moricoli Chiara Mazzei Alessandro Ascione Alessandra Mallano |
| author_facet | Michela Flego Mauro Andreotti Francesca Romana Mauro Maria Beatrice Arasi Silvia Zamboni Zuleika Michelini Sara Pepe Clementina Maria Galluzzo Roberta Amici Diego Moricoli Chiara Mazzei Alessandro Ascione Alessandra Mallano |
| author_sort | Michela Flego |
| collection | DOAJ |
| description | In chronic lymphocytic leukemia (CLL), natural killer (NK) cells show a dysfunctional phenotype that correlates with disease progression. Our aim was to restore NK cell functionality in CLL through a specifically targeted IL15-stimulating activity; IL15 targeting could, in fact, potentiate the activity of NK cells and reduce off-target effects. We designed and developed a cis-acting immunocytokine composed of an anti-CD56 single-chain Fragment variable (scFv) and IL15, labeled scFvB1IL15. scFvB1IL15 was tested in vitro on peripheral blood mononuclear cells (PBMCs) obtained from both different healthy donors (HDs) and CLL patients in order to evaluate its ability to target NK cells and enhance their activation and NK-mediated directed cytotoxicity. scFvB1IL15 specifically induced strong degranulation and cytokine and chemokine production in NK cells in both HD- and CLL patient-derived PBMC samples. Furthermore, compared to IL15 alone, it was able to induce higher levels of NKG2D- and NKp30-activating receptors and restore NK-mediated direct killing in the CLL patient-derived samples. The preliminary data presented in this work suggest that IL15’s targeting of NK cells via scFvB1 potentiates the effects of IL15 and that scFvB1IL15 can be a useful agent for overcoming NK functional gaps and contribute to NK-cell-based immunotherapies. |
| format | Article |
| id | doaj-art-17bec0669b3a418985dc554020ae1f5d |
| institution | Kabale University |
| issn | 2218-273X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj-art-17bec0669b3a418985dc554020ae1f5d2025-01-24T13:25:15ZengMDPI AGBiomolecules2218-273X2025-01-0115111710.3390/biom15010117A New Antibody–Cytokine Construct Targeting Natural Killer Cells: An Immunotherapeutic Approach to Chronic Lymphocytic LeukemiaMichela Flego0Mauro Andreotti1Francesca Romana Mauro2Maria Beatrice Arasi3Silvia Zamboni4Zuleika Michelini5Sara Pepe6Clementina Maria Galluzzo7Roberta Amici8Diego Moricoli9Chiara Mazzei10Alessandro Ascione11Alessandra Mallano12National Center for Global Health, Italian Institute of Health, 00161 Rome, ItalyNational Center for Global Health, Italian Institute of Health, 00161 Rome, ItalyHematology, Department of Translational and Precision Medicine, ‘Sapienza’ University, 00161 Rome, ItalyDepartment of Oncology and Molecular Medicine, Italian Institute of Health, 00161 Rome, ItalyDepartment of Neuroscience, Italian Institute of Health, 00161 Rome, ItalyNational Center for Global Health, Italian Institute of Health, 00161 Rome, ItalyHematology, Department of Translational and Precision Medicine, ‘Sapienza’ University, 00161 Rome, ItalyNational Center for Global Health, Italian Institute of Health, 00161 Rome, ItalyNational Center for Global Health, Italian Institute of Health, 00161 Rome, ItalyDiatheva s.r.l., Via Sant’Anna 131/135, 61030 Cartoceto, ItalyNational Center for Global Health, Italian Institute of Health, 00161 Rome, ItalyNational Center for Global Health, Italian Institute of Health, 00161 Rome, ItalyNational Center for Global Health, Italian Institute of Health, 00161 Rome, ItalyIn chronic lymphocytic leukemia (CLL), natural killer (NK) cells show a dysfunctional phenotype that correlates with disease progression. Our aim was to restore NK cell functionality in CLL through a specifically targeted IL15-stimulating activity; IL15 targeting could, in fact, potentiate the activity of NK cells and reduce off-target effects. We designed and developed a cis-acting immunocytokine composed of an anti-CD56 single-chain Fragment variable (scFv) and IL15, labeled scFvB1IL15. scFvB1IL15 was tested in vitro on peripheral blood mononuclear cells (PBMCs) obtained from both different healthy donors (HDs) and CLL patients in order to evaluate its ability to target NK cells and enhance their activation and NK-mediated directed cytotoxicity. scFvB1IL15 specifically induced strong degranulation and cytokine and chemokine production in NK cells in both HD- and CLL patient-derived PBMC samples. Furthermore, compared to IL15 alone, it was able to induce higher levels of NKG2D- and NKp30-activating receptors and restore NK-mediated direct killing in the CLL patient-derived samples. The preliminary data presented in this work suggest that IL15’s targeting of NK cells via scFvB1 potentiates the effects of IL15 and that scFvB1IL15 can be a useful agent for overcoming NK functional gaps and contribute to NK-cell-based immunotherapies.https://www.mdpi.com/2218-273X/15/1/117chronic lymphocytic leukemianatural killer cellsimmunocytokineIL15antibody therapeuticsscFv |
| spellingShingle | Michela Flego Mauro Andreotti Francesca Romana Mauro Maria Beatrice Arasi Silvia Zamboni Zuleika Michelini Sara Pepe Clementina Maria Galluzzo Roberta Amici Diego Moricoli Chiara Mazzei Alessandro Ascione Alessandra Mallano A New Antibody–Cytokine Construct Targeting Natural Killer Cells: An Immunotherapeutic Approach to Chronic Lymphocytic Leukemia Biomolecules chronic lymphocytic leukemia natural killer cells immunocytokine IL15 antibody therapeutics scFv |
| title | A New Antibody–Cytokine Construct Targeting Natural Killer Cells: An Immunotherapeutic Approach to Chronic Lymphocytic Leukemia |
| title_full | A New Antibody–Cytokine Construct Targeting Natural Killer Cells: An Immunotherapeutic Approach to Chronic Lymphocytic Leukemia |
| title_fullStr | A New Antibody–Cytokine Construct Targeting Natural Killer Cells: An Immunotherapeutic Approach to Chronic Lymphocytic Leukemia |
| title_full_unstemmed | A New Antibody–Cytokine Construct Targeting Natural Killer Cells: An Immunotherapeutic Approach to Chronic Lymphocytic Leukemia |
| title_short | A New Antibody–Cytokine Construct Targeting Natural Killer Cells: An Immunotherapeutic Approach to Chronic Lymphocytic Leukemia |
| title_sort | new antibody cytokine construct targeting natural killer cells an immunotherapeutic approach to chronic lymphocytic leukemia |
| topic | chronic lymphocytic leukemia natural killer cells immunocytokine IL15 antibody therapeutics scFv |
| url | https://www.mdpi.com/2218-273X/15/1/117 |
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