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  • Original Article
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Therapy

A novel AML-selective TRAIL fusion protein that is superior to Gemtuzumab Ozogamicin in terms of in vitro selectivity, activity and stability

Leukemia volume 23, pages 1389–1397 (2009)Cite this article

Abstract

Gemtuzumab ozogamicin (GO, Mylotarg) is a targeted therapeutic agent in which an anti-CD33 antibody is chemically coupled to a highly cytotoxic calicheamicin derivative through a hydrolysable linker. GO has improved the treatment outcome for a subgroup of acute myeloid leukemia (AML) patients, but its use is associated with severe myelosuppression and hepatotoxicity. Here, we report on a novel anti-leukemia agent, designated scFvCD33:sTRAIL, in which an anti-CD33 single chain fragment of variable regions (scFv) antibody fragment is genetically linked to soluble tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL). Normal CD33-positive monocytes were fully resistant to prolonged treatment with scFvCD33:sTRAIL, whereas treatment with GO resulted in substantial cytotoxicity. The activity of scFvCD33:sTRAIL towards AML cells was up to 30-fold higher than GO. The CD33-restricted anti-leukemia activity of scFvCD33:sTRAIL remained stable during prolonged storage at 37 °C, whereas GO showed a rapid increase in CD33-independent cytotoxicity. Moreover, scFvCD33:sTRAIL showed potent anti-leukemia activity towards CD33+ CML cells when treatment was combined with the Bcr-Abl tyrosine kinase inhibitor, Gleevec. Importantly, ex vivo treatment of patient-derived CD33+ AML tumor cells with scFvCD33:sTRAIL resulted in potent apoptosis induction that was enhanced by valproic acid, mitoxantrone and 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG). Taken together, scFvCD33:sTRAIL is superior to GO in terms of tumor selectivity, activity and stability, warranting its further development for the treatment of CD33-positive leukemias.

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Acknowledgements

The authors would like to thank J Dokter-Fokkens, G Mesander and D Jager for their excellent technical assistance. This work was supported by grants from the Dutch Cancer Society (RUG 2002-2668 and 2005-3358) to WH.

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Author notes

  1. B ten Cate and E Bremer: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology & Medical Biology, Laboratory for Tumor Immunology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    B ten Cate

  2. Department of Surgery, Surgical Research Laboratories, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    B ten Cate, M de Bruyn, T Bijma, D Samplonius & W Helfrich

  3. Department of Molecular Internal Medicine, Medical Clinic and Polyclinic II, University of Wuerzburg, Wuerzburg, Germany

    E Bremer

  4. Chair of Genetics, Institute of Biology, University of Erlangen-Nuremberg, Erlangen, Germany

    M Schwemmlein & G Fey

  5. Division of Hematology, Department of Medicine, University Medical Center Groningen, Groningen, The Netherlands

    G Huls

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  1. B ten Cate
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Correspondence to W Helfrich.

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ten Cate, B., Bremer, E., de Bruyn, M. et al. A novel AML-selective TRAIL fusion protein that is superior to Gemtuzumab Ozogamicin in terms of in vitro selectivity, activity and stability. Leukemia 23, 1389–1397 (2009). https://doi.org/10.1038/leu.2009.34

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