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Able, M.* ; Kasper, M.A.* ; Vick, B. ; Schwach, J.* ; Gao, X.* ; Schmitt, S.* ; Tizazu, B.* ; Fischer, A.* ; Künzl, S.* ; Leilich, M.* ; Mai, I.* ; Ochtrop, P.* ; Stengl, A.* ; de Geus, M.A.R.* ; von Bergwelt-Baildon, M.* ; Schumacher, D.* ; Helma, J.* ; Hackenberger, C.P.R.* ; Götze, K.S.* ; Jeremias, I. ; Leonhardt, H.* ; Feuring, M.* ; Spiekermann, K.*

Effective eradication of acute myeloid leukemia stem cells with FLT3-directed antibody-drug conjugates.

Leukemia 39, 632-642 (2025)

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Refractory disease and relapse are major challenges in acute myeloid leukemia (AML) therapy attributed to survival of leukemic stem cells (LSC). To target LSCs, antibody-drug conjugates (ADCs) provide an elegant solution, combining the specificity of antibodies with highly potent payloads. We aimed to investigate if FLT3-20D9h3-ADCs delivering either the DNA-alkylator duocarmycin (DUBA) or the microtubule-toxin monomethyl auristatin F (MMAF) can eradicate quiescent LSCs. We show here that DUBA more potently kills cell-cycle arrested AML cells compared to microtubule-targeting auristatins. Due to limited stability of 20D9h3-DUBA ADC in vivo, we analyzed both ADCs in advanced in vitro stem cell assays. 20D9h3-DUBA successfully eliminated leukemic progenitors in vitro in colony-forming unit and long-term culture initiating cell assays, both in patient cells and in patient-derived xenograft (PDX) cells. Further, it completely prevented engraftment of AML PDX leukemia-initiating cells in NSG mice. 20D9h3-MMAF had a similar effect in engraftment assays, but a less prominent effect in colony assays. Both ADCs did not affect healthy stem and progenitor cells at comparable doses providing the rationale for FLT3 as therapeutic LSC target. Collectively, we show that FLT3-directed ADCs with DUBA or MMAF have potent activity against AML LSCs and represent promising candidates for further clinical development.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Aml; Flt3; Agents

ISSN (print) / ISBN 0887-6924

e-ISSN 1476-5551

Journal Leukemia

Quellenangaben Volume: 39, Issue: 3, Pages: 632-642

Publisher Nature Publishing Group

Publishing Place Campus, 4 Crinan St, London, N1 9xw, England

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)

Grants German Ministry of Education and Research (BMBF)
German Research Foundation (DFG)
Federal Ministry for Economic Affairs and Energy (EXIST Forschungstransfer II)
Federal Ministry for Economic Affairs and Energy (German Accelerator)
Federal Ministry of Education and Research (Rahmenprogramm Gesundheitsforschung)
LMU Munich
Alexander von Humboldt Foundation