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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 Hybrid
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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Publication type Article: Journal article
Document type Scientific Article
Keywords Acute Myeloid-leukemia; Constitutive Activation; Stem-cell; Expression; Design
Language english
Publication Year 2023
Prepublished in Year 2022
HGF-reported in Year 2022
ISSN (print) / ISBN 0006-4971
e-ISSN 1528-0020
Journal Blood
Quellenangaben Volume: 141, Issue: 9, Pages: 1023-1035 Article Number: , Supplement: ,
Publisher American Society of Hematology
Publishing Place 2021 L St Nw, Suite 900, Washington, Dc 20036 Usa
Reviewing status Peer reviewed
Institute(s) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)
Institute of Molecular Immunology (IMI)
POF-Topic(s) 30204 - Cell Programming and Repair
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s) Stem Cell and Neuroscience
Immune Response and Infection
PSP Element(s) G-506600-001
G-501793-001
Grants 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)
DOI 10.1182/blood.2021015246
WOS ID 001004180200001
Scopus ID 85146845982
PubMed ID 35981498
Erfassungsdatum 2022-11-16
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