Effective eradication of acute myeloid leukemia stem cells with FLT3-directed antibody-drug conjugates
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.
Authors
- Isabelle Mai (ORCID: https://orcid.org/0009-0002-1574-2683)
- Xiang Gao (ORCID: https://orcid.org/0009-0002-6468-175X)
- Marc‐André Kasper (ORCID: https://orcid.org/0000-0001-7742-7465)
- Karsten Spiekermann (ORCID: https://orcid.org/0000-0002-5139-4957)
- Mark A. R. de Geus (ORCID: https://orcid.org/0000-0002-1639-5890)
- Michael von Bergwelt‐Baildon (ORCID: https://orcid.org/0000-0002-1952-052X)
- Heinrich Leonhardt (ORCID: https://orcid.org/0000-0002-5086-6449)
- Dominik Schumacher (ORCID: https://orcid.org/0000-0001-7095-6858)
- Jonas Helma (ORCID: https://orcid.org/0000-0001-6158-452X)
- Saskia Schmitt (ORCID: https://orcid.org/0009-0003-1362-9158)
- Belay Tizazu
- Marina Able (ORCID: https://orcid.org/0000-0002-3301-4367)
- Binje Vick (ORCID: https://orcid.org/0000-0003-1956-2778)
- Jonathan Schwach (ORCID: https://orcid.org/0000-0002-2109-5585)
- Irmela Jeremias (ORCID: https://orcid.org/0000-0003-1773-7677)
- Philipp Ochtrop (ORCID: https://orcid.org/0000-0003-4498-3136)
- Katharina S. S. Götze (ORCID: https://orcid.org/0000-0002-6276-8002)
- Andreas Stengl (ORCID: https://orcid.org/0000-0002-8802-3260)
- Michaela Feuring (ORCID: https://orcid.org/0000-0002-3986-6691)
- Christian P. R. Hackenberger (ORCID: https://orcid.org/0000-0001-7457-4742)
- Amrei Fischer (ORCID: https://orcid.org/0009-0006-5526-9666)
- Marit Leilich
- Sarah Künzl (ORCID: https://orcid.org/0009-0003-9721-9278)
Institutions
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- Helmholtz Zentrum München (DE)
- LMU Klinikum (DE)
- Humboldt-Universität zu Berlin (DE)
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (DE)
- German Center for Infection Research (DE)
- Centre de Coopération Universitaire Franco-Bavarois (DE)
- University Hospital Ulm (DE)
- Urologische Klinik München (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Technical University of Munich (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Leukemia
- Published
- 2025-01-27
- DOI
- https://doi.org/10.1038/s41375-024-02510-5
- Citations
- 7
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 12.39
Funders
- Alexander von Humboldt-Stiftung
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Ludwig-Maximilians-Universität München
- Bundesministerium für Wirtschaft und Energie
- International Graduate School in Molecular Medicine Ulm