2. Academic Validation
  3. TARGETING FLT3 BY NEW-GENERATION ANTIBODY-DRUG-CONJUGATE IN COMBINATION WITH KINASE INHIBITORS FOR TREATMENT OF AML

TARGETING FLT3 BY NEW-GENERATION ANTIBODY-DRUG-CONJUGATE IN COMBINATION WITH KINASE INHIBITORS FOR TREATMENT OF AML

  • Blood. 2022 Aug 18;blood.2021015246. doi: 10.1182/blood.2021015246.
Maike Roas 1,  Binje Vick 2,  Marc-André Kasper 3,  Marina Able 1,  Harald Polzer 1,  Marcus Gerlach 4,  Elisabeth Kremmer 5,  Judith S Hecker 2,  Saskia Schmitt 6,  Andreas Stengl 7,  Verena Waller 8,  Natascha Hohmann 1,  Moreno Festini 9,  Alexander Edmund Ludwig 1,  Lisa Rohrbacher 10,  Tobias Herold 11,  Marion Subklewe 10,  Katharina S Götze 2,  Christian P R Hackenberger 12,  Dominik Schumacher 3,  Jonas Helma-Smets 8,  Irmela Jeremias 2,  Heinrich Leonhardt 13,  Karsten Spiekermann 14
Affiliations

Affiliations

  • 1 LMU Klinikum, Munich, Germany.
  • 2 German Cancer Consortium (DKTK), Germany.
  • 3 Chemical Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Germany.
  • 4 Tubulis GmbH, Munich, Germany.
  • 5 LMU münchen, Neuherberg, Germany.
  • 6 Tubulis GmbH, Planegg-Martinsried, Germany.
  • 7 LMU Munich, Munich, Germany.
  • 8 LMU Munich, Germany.
  • 9 University Hospital, LMU Munich, Munich, Germany, Munich, Germany.
  • 10 Gene Center Munich, LMU, Germany.
  • 11 University Hospital, LMU Munich, Munich, Germany.
  • 12 Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany.
  • 13 LMU Munich, Martinsried, Germany.
  • 14 University Hospital Munich (LMU), Munich, Germany.
PMID: 35981498 DOI: 10.1182/blood.2021015246
Abstract

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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