Induction of NK cell reactivity against acute myeloid leukemia by Fc-optimized CD276 (B7-H3) antibody.

Autor: Stefańczyk SA; Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital of Tübingen, Tübingen, Germany.; Cluster of Excellence iFIT (EXC 2180) 'Image-Guided and Functionally Instructed Tumor Therapies', Eberhard Karls University of Tübingen, Tübingen, Germany., Hagelstein I; Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital of Tübingen, Tübingen, Germany.; Cluster of Excellence iFIT (EXC 2180) 'Image-Guided and Functionally Instructed Tumor Therapies', Eberhard Karls University of Tübingen, Tübingen, Germany., Lutz MS; Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital of Tübingen, Tübingen, Germany.; Cluster of Excellence iFIT (EXC 2180) 'Image-Guided and Functionally Instructed Tumor Therapies', Eberhard Karls University of Tübingen, Tübingen, Germany., Müller S; Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital of Tübingen, Tübingen, Germany.; Cluster of Excellence iFIT (EXC 2180) 'Image-Guided and Functionally Instructed Tumor Therapies', Eberhard Karls University of Tübingen, Tübingen, Germany., Holzmayer SJ; Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital of Tübingen, Tübingen, Germany.; Cluster of Excellence iFIT (EXC 2180) 'Image-Guided and Functionally Instructed Tumor Therapies', Eberhard Karls University of Tübingen, Tübingen, Germany., Jarjour G; Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital of Tübingen, Tübingen, Germany.; Cluster of Excellence iFIT (EXC 2180) 'Image-Guided and Functionally Instructed Tumor Therapies', Eberhard Karls University of Tübingen, Tübingen, Germany., Zekri L; Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital of Tübingen, Tübingen, Germany.; Cluster of Excellence iFIT (EXC 2180) 'Image-Guided and Functionally Instructed Tumor Therapies', Eberhard Karls University of Tübingen, Tübingen, Germany., Heitmann JS; Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital of Tübingen, Tübingen, Germany.; Cluster of Excellence iFIT (EXC 2180) 'Image-Guided and Functionally Instructed Tumor Therapies', Eberhard Karls University of Tübingen, Tübingen, Germany., Salih HR; Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital of Tübingen, Tübingen, Germany.; Cluster of Excellence iFIT (EXC 2180) 'Image-Guided and Functionally Instructed Tumor Therapies', Eberhard Karls University of Tübingen, Tübingen, Germany., Märklin M; Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital of Tübingen, Tübingen, Germany. Melanie.Maerklin@med.uni-tuebingen.de.; Cluster of Excellence iFIT (EXC 2180) 'Image-Guided and Functionally Instructed Tumor Therapies', Eberhard Karls University of Tübingen, Tübingen, Germany. Melanie.Maerklin@med.uni-tuebingen.de.
Jazyk: angličtina
Zdroj: Blood cancer journal [Blood Cancer J] 2024 Apr 18; Vol. 14 (1), pp. 67. Date of Electronic Publication: 2024 Apr 18.
DOI: 10.1038/s41408-024-01050-6
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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