Induction of NK cell reactivity against acute myeloid leukemia by Fc-optimized CD276 (B7-H3) antibody
Abstract Acute myeloid leukemia (AML) remains a therapeutic challenge despite recent therapeutic advances. Although monoclonal antibodies (mAbs) engaging natural killer (NK) cells via antibody-dependent cellular cytotoxicity (ADCC) hold promise in cancer therapy, almost none have received clinical a...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-04-01
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| Series: | Blood Cancer Journal |
| Online Access: | https://doi.org/10.1038/s41408-024-01050-6 |
| _version_ | 1827277383098433536 |
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| author | Sylwia A. Stefańczyk Ilona Hagelstein Martina S. Lutz Stefanie Müller Samuel J. Holzmayer Grace Jarjour Latifa Zekri Jonas S. Heitmann Helmut R. Salih Melanie Märklin |
| author_facet | Sylwia A. Stefańczyk Ilona Hagelstein Martina S. Lutz Stefanie Müller Samuel J. Holzmayer Grace Jarjour Latifa Zekri Jonas S. Heitmann Helmut R. Salih Melanie Märklin |
| author_sort | Sylwia A. Stefańczyk |
| collection | DOAJ |
| description | Abstract Acute myeloid leukemia (AML) remains a therapeutic challenge despite recent therapeutic advances. Although monoclonal antibodies (mAbs) engaging natural killer (NK) cells via antibody-dependent cellular cytotoxicity (ADCC) hold promise in cancer therapy, almost none have received clinical approval for AML, so far. Recently, CD276 (B7-H3) has emerged as a promising target for AML immunotherapy, due to its high expression on leukemic blasts of AML patients. Here, we present the preclinical development of the Fc-optimized CD276 mAb 8H8_SDIE with enhanced CD16 affinity. We demonstrate that 8H8_SDIE specifically binds to CD276 on AML cell lines and primary AML cells and induces pronounced NK cell activation and degranulation as measured by CD69, CD25, and CD107a. Secretion of IFNγ, TNF, granzyme B, granulysin, and perforin, which mediate NK cell effector functions, was induced by 8H8_SDIE. A pronounced target cell-restricted lysis of AML cell lines and primary AML cells was observed in cytotoxicity assays using 8H8_SDIE. Finally, xenograft models with 8H8_SDIE did not cause off-target immune activation and effectively inhibited leukemia growth in vivo. We here present a novel attractive immunotherapeutic compound that potently induces anti-leukemic NK cell reactivity in vitro and in vivo as treatment option for AML. |
| first_indexed | 2024-04-24T07:18:55Z |
| format | Article |
| id | doaj.art-d7bb9722631649bdb4aa52e985e69282 |
| institution | Directory Open Access Journal |
| issn | 2044-5385 |
| language | English |
| last_indexed | 2024-04-24T07:18:55Z |
| publishDate | 2024-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Blood Cancer Journal |
| spelling | doaj.art-d7bb9722631649bdb4aa52e985e692822024-04-21T11:08:58ZengNature Publishing GroupBlood Cancer Journal2044-53852024-04-0114111010.1038/s41408-024-01050-6Induction of NK cell reactivity against acute myeloid leukemia by Fc-optimized CD276 (B7-H3) antibodySylwia A. Stefańczyk0Ilona Hagelstein1Martina S. Lutz2Stefanie Müller3Samuel J. Holzmayer4Grace Jarjour5Latifa Zekri6Jonas S. Heitmann7Helmut R. Salih8Melanie Märklin9Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital of TübingenClinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital of TübingenClinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital of TübingenClinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital of TübingenClinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital of TübingenClinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital of TübingenClinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital of TübingenClinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital of TübingenClinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital of TübingenClinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital of TübingenAbstract Acute myeloid leukemia (AML) remains a therapeutic challenge despite recent therapeutic advances. Although monoclonal antibodies (mAbs) engaging natural killer (NK) cells via antibody-dependent cellular cytotoxicity (ADCC) hold promise in cancer therapy, almost none have received clinical approval for AML, so far. Recently, CD276 (B7-H3) has emerged as a promising target for AML immunotherapy, due to its high expression on leukemic blasts of AML patients. Here, we present the preclinical development of the Fc-optimized CD276 mAb 8H8_SDIE with enhanced CD16 affinity. We demonstrate that 8H8_SDIE specifically binds to CD276 on AML cell lines and primary AML cells and induces pronounced NK cell activation and degranulation as measured by CD69, CD25, and CD107a. Secretion of IFNγ, TNF, granzyme B, granulysin, and perforin, which mediate NK cell effector functions, was induced by 8H8_SDIE. A pronounced target cell-restricted lysis of AML cell lines and primary AML cells was observed in cytotoxicity assays using 8H8_SDIE. Finally, xenograft models with 8H8_SDIE did not cause off-target immune activation and effectively inhibited leukemia growth in vivo. We here present a novel attractive immunotherapeutic compound that potently induces anti-leukemic NK cell reactivity in vitro and in vivo as treatment option for AML.https://doi.org/10.1038/s41408-024-01050-6 |
| spellingShingle | Sylwia A. Stefańczyk Ilona Hagelstein Martina S. Lutz Stefanie Müller Samuel J. Holzmayer Grace Jarjour Latifa Zekri Jonas S. Heitmann Helmut R. Salih Melanie Märklin Induction of NK cell reactivity against acute myeloid leukemia by Fc-optimized CD276 (B7-H3) antibody Blood Cancer Journal |
| title | Induction of NK cell reactivity against acute myeloid leukemia by Fc-optimized CD276 (B7-H3) antibody |
| title_full | Induction of NK cell reactivity against acute myeloid leukemia by Fc-optimized CD276 (B7-H3) antibody |
| title_fullStr | Induction of NK cell reactivity against acute myeloid leukemia by Fc-optimized CD276 (B7-H3) antibody |
| title_full_unstemmed | Induction of NK cell reactivity against acute myeloid leukemia by Fc-optimized CD276 (B7-H3) antibody |
| title_short | Induction of NK cell reactivity against acute myeloid leukemia by Fc-optimized CD276 (B7-H3) antibody |
| title_sort | induction of nk cell reactivity against acute myeloid leukemia by fc optimized cd276 b7 h3 antibody |
| url | https://doi.org/10.1038/s41408-024-01050-6 |
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