TARGETING FLT3 BY NEW-GENERATION ANTIBODY-DRUG-CONJUGATE IN COMBINATION WITH KINASE INHIBITORS FOR TREATMENT OF AML.
Maike RoasBinje VickMarc-André KasperMarina AbleHarald PolzerMarcus GerlachElisabeth KremmerJudith S HeckerSaskia SchmittAndreas StenglVerena WallerNatascha HohmannMoreno FestiniAlexander Edmund LudwigLisa RohrbacherTobias HeroldMarion SubkleweKatharina S GötzeChristian P R HackenbergerDominik SchumacherJonas Helma-SmetsIrmela JeremiasHeinrich LeonhardtKarsten SpiekermannPublished in: Blood (2022)
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.
Keyphrases
- acute myeloid leukemia
- tyrosine kinase
- allogeneic hematopoietic stem cell transplantation
- epidermal growth factor receptor
- induced apoptosis
- diffusion weighted imaging
- diffusion weighted
- cancer therapy
- cell cycle arrest
- end stage renal disease
- advanced non small cell lung cancer
- chronic kidney disease
- stem cells
- drug delivery
- peritoneal dialysis
- ejection fraction
- high throughput
- cell proliferation
- computed tomography
- big data
- deep learning
- drug induced
- contrast enhanced
- acute lymphoblastic leukemia
- label free