ORCID: https://orcid.org/0000-0002-3301-4367; Kasper, Marc-André; Vick, Binje ORCID: https://orcid.org/0000-0003-1956-2778; Schwach, Jonathan; Gao, Xiang ORCID: https://orcid.org/0009-0002-6468-175X; Schmitt, Saskia ORCID: https://orcid.org/0009-0003-1362-9158; Tizazu, Belay; Fischer, Amrei ORCID: https://orcid.org/0009-0006-5526-9666; Künzl, Sarah ORCID: https://orcid.org/0009-0003-9721-9278; Leilich, Marit; Mai, Isabelle; Ochtrop, Philipp ORCID: https://orcid.org/0000-0003-4498-3136; Stengl, Andreas ORCID: https://orcid.org/0000-0002-8802-3260; Geus, Mark A. R. de ORCID: https://orcid.org/0000-0002-1639-5890; Bergwelt-Baildon, Michael von ORCID: https://orcid.org/0000-0002-1952-052X; Schumacher, Dominik ORCID: https://orcid.org/0000-0001-7095-6858; Helma, Jonas; Hackenberger, Christian P. R. ORCID: https://orcid.org/0000-0001-7457-4742; Götze, Katharina S. ORCID: https://orcid.org/0000-0002-6276-8002; Jeremias, Irmela; Leonhardt, Heinrich ORCID: https://orcid.org/0000-0002-5086-6449; Feuring, Michaela ORCID: https://orcid.org/0000-0002-3986-6691 und Spiekermann, Karsten ORCID: https://orcid.org/0000-0002-5139-4957
(2025):
Effective eradication of acute myeloid leukemia stem cells with FLT3-directed antibody-drug conjugates.
In: Leukemia, Bd. 39, Nr. 3: S. 632-642
[PDF, 4MB]
Abstract
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.
| Dokumententyp: | Zeitschriftenartikel |
|---|---|
| Fakultät: | Biologie
Medizin > Klinikum der LMU München > Medizinische Klinik und Poliklinik III (Onkologie) |
| Themengebiete: | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit |
| URN: | urn:nbn:de:bvb:19-epub-128114-8 |
| ISSN: | 0887-6924 |
| Sprache: | Englisch |
| Dokumenten ID: | 128114 |
| Datum der Veröffentlichung auf Open Access LMU: | 12. Aug. 2025 07:03 |
| Letzte Änderungen: | 12. Aug. 2025 07:03 |
| DFG: | Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 278529602 |
| DFG: | Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 217328187 |
- Dokument bearbeiten
