Targeting FLT3 with a new-generation antibody-drug conjugate in combination with kinase inhibitors for treatment of AML.

Autor:	Roas M; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; German Cancer Consortium (DKTK), Partner Site, Munich, Germany.; German Cancer Research Centre (DKFZ), Heidelberg, Germany.; Department of Biology II, Human Biology and Bioimaging, LMU Munich, Munich, Germany., Vick B; German Cancer Consortium (DKTK), Partner Site, Munich, Germany.; Research Unit Apoptosis in Hematopoietic Stem Cells (AHS), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Munich, Germany., Kasper MA; Chemical Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Campus Berlin, Berlin, Germany.; Department of Chemistry, Humboldt Universität zu Berlin, Berlin, Germany.; Tubulis GmbH, Munich, Germany., Able M; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany., Polzer H; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; German Cancer Consortium (DKTK), Partner Site, Munich, Germany.; German Cancer Research Centre (DKFZ), Heidelberg, Germany., Gerlach M; Tubulis GmbH, Munich, Germany., Kremmer E; Institute of Molecular Immunology, Helmholtz Zentrum München, German Research Center for Environmental Health, Core Facility Monoclonal Antibodies, Munich, Germany., Hecker JS; German Cancer Consortium (DKTK), Partner Site, Munich, Germany.; German Cancer Research Centre (DKFZ), Heidelberg, Germany.; Department of Medicine III, Technical University of Munich (TUM), Klinikum rechts der Isar, Munich, Germany., Schmitt S; Tubulis GmbH, Munich, Germany., Stengl A; Department of Biology II, Human Biology and Bioimaging, LMU Munich, Munich, Germany., Waller V; Department of Biology II, Human Biology and Bioimaging, LMU Munich, Munich, Germany., Hohmann N; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany., Festini M; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany., Ludwig A; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany., Rohrbacher L; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; Department of Translational Cancer Immunology, Gene Center Munich, LMU Munich, Munich, Germany., Herold T; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; German Cancer Consortium (DKTK), Partner Site, Munich, Germany.; German Cancer Research Centre (DKFZ), Heidelberg, Germany., Subklewe M; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; German Cancer Consortium (DKTK), Partner Site, Munich, Germany.; Department of Translational Cancer Immunology, Gene Center Munich, LMU Munich, Munich, Germany., Götze KS; German Cancer Consortium (DKTK), Partner Site, Munich, Germany.; German Cancer Research Centre (DKFZ), Heidelberg, Germany.; Department of Medicine III, Technical University of Munich (TUM), Klinikum rechts der Isar, Munich, Germany.; Bavarian Cancer Research Center (BZKF), Munich, Germany., Hackenberger CPR; Chemical Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Campus Berlin, Berlin, Germany.; Department of Chemistry, Humboldt Universität zu Berlin, Berlin, Germany., Schumacher D; Chemical Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Campus Berlin, Berlin, Germany.; Department of Chemistry, Humboldt Universität zu Berlin, Berlin, Germany.; Tubulis GmbH, Munich, Germany., Helma-Smets J; Department of Biology II, Human Biology and Bioimaging, LMU Munich, Munich, Germany.; Tubulis GmbH, Munich, Germany., Jeremias I; German Cancer Consortium (DKTK), Partner Site, Munich, Germany.; Research Unit Apoptosis in Hematopoietic Stem Cells (AHS), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Munich, Germany.; Department of Pediatrics, Dr. von Hauner Children's Hospital, LMU Munich, Munich, Germany., Leonhardt H; Department of Biology II, Human Biology and Bioimaging, LMU Munich, Munich, Germany.; Tubulis GmbH, Munich, Germany., Spiekermann K; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; German Cancer Consortium (DKTK), Partner Site, Munich, Germany.; German Cancer Research Centre (DKFZ), Heidelberg, Germany.; Bavarian Cancer Research Center (BZKF), Munich, Germany.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2023 Mar 02; Vol. 141 (9), pp. 1023-1035.
DOI:	10.1182/blood.2021015246
Abstrakt:	Fms-like tyrosine kinase 3 (FLT3) is often overexpressed or constitutively activated by internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations in acute myeloid leukemia (AML). Despite the use of receptor tyrosine kinase inhibitors (TKI) in FLT3-ITD-positive AML, the prognosis of patients is still poor, and further improvement of therapy is required. Targeting FLT3 independent of mutations by antibody-drug conjugates (ADCs) is a promising strategy for AML therapy. Here, we report the development and preclinical characterization of a novel FLT3-targeting ADC, 20D9-ADC, which was generated by applying the innovative P5 conjugation technology. In vitro, 20D9-ADC mediated potent cytotoxicity to Ba/F3 cells expressing transgenic FLT3 or FLT3-ITD, to AML cell lines, and to FLT3-ITD-positive patient-derived xenograft AML cells. In vivo, 20D9-ADC treatment led to a significant tumor reduction and even durable complete remission in AML xenograft models. Furthermore, 20D9-ADC demonstrated no severe hematotoxicity in in vitro colony formation assays using concentrations that were cytotoxic in AML cell line treatment. The combination of 20D9-ADC with the TKI midostaurin showed strong synergy in vitro and in vivo, leading to reduction of aggressive AML cells below the detection limit. Our data indicate that targeting FLT3 with an advanced new-generation ADC is a promising and potent antileukemic strategy, especially when combined with FLT3-TKI in FLT3-ITD-positive AML. (© 2023 by The American Society of Hematology.)
Databáze:	MEDLINE
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