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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)

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	Open Access Gold (Paid Option)

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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

Corresponding Author

Keywords Acute Myeloid-leukemia; Constitutive Activation; Stem-cell; Expression; Design

ISSN (print) / ISBN 0006-4971

e-ISSN 1528-0020

Journal Blood

Quellenangaben Volume: 141, Issue: 9, Pages: 1023-1035

Publisher American Society of Hematology

Publishing Place 2021 L St Nw, Suite 900, Washington, Dc 20036 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)
Institute of Molecular Immunology (IMI)

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)