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Roas, M.* ; Vick, B. ; Kasper, M.A.* ; Able, M.* ; Polzer, H.* ; Gerlach, M.* ; Kremmer, E. ; Hecker, J.S.* ; Schmitt, S.* ; Stengl, A.* ; Waller, V.* ; Hohmann, N.* ; Festini, M.* ; Ludwig, A.E.* ; Rohrbacher, L.* ; Herold, T.* ; Subklewe, M.* ; Götze, K.S.* ; Hackenberger, C.P.R.* ; Schumacher, D.* ; Helma-Smets, J.* ; Jeremias, I. ; Leonhardt, H.* ; Spiekermann, K.*

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

Blood 141, 1023-1035 (2023)
Postprint DOI PMC
Open Access Green
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. Further, 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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Acute Myeloid-leukemia; Constitutive Activation; Stem-cell; Expression; Design
ISSN (print) / ISBN 0006-4971
e-ISSN 1528-0020
Zeitschrift Blood
Quellenangaben Band: 141, Heft: 9, Seiten: 1023-1035 Artikelnummer: , Supplement: ,
Verlag American Society of Hematology
Verlagsort 2021 L St Nw, Suite 900, Washington, Dc 20036 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)
Institute of Molecular Immunology (IMI)
Förderungen German Ministry of Education and Research (BMBF)
Leibniz Association within the Leibniz Competition
European Union's Horizon 2020 Marie Sklodowska-Curie Innovative Training Network (MSCA-ITN)
German Jose Carreras Leukamiestiftung (DJCLS)
Bavarian Elite Graduate Training Network
Else-Kroener-Fresenius Stiftung
Bavarian Center for Cancer Research (BZKF)
German Research Foundation (DFG)