A novel AML-selective TRAIL fusion protein that is superior to Gemtuzumab Ozogamicin in terms of in vitro selectivity, activity and stability. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K [Leukemia] Journal article | | Title | A novel AML-selective TRAIL fusion protein that is superior to Gemtuzumab Ozogamicin in terms of in vitro selectivity, activity and stability. | | Author(s) | Ten Cate B, Bremer E, de Bruyn M, Bijma T, Samplonius D, Schwemmlein M, Huls G, Fey G, Helfrich W | | Institution | [1] 1Laboratory for Tumor Immunology, Department of Pathology & Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands [2] 2Surgical Research Laboratories, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. | | Source | Leukemia 2009 Mar 5. | | 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 degrees 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.Leukemia advance online publication, 5 March 2009; doi:10.1038/leu.2009.34. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19262596 |
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