A novel AML-selective TRAIL fusion protein that is superior to Gemtuzumab Ozogamicin in terms of in vitro selectivity, activity and stability
| Autor: | Wijnand Helfrich, B. ten Cate, Georg H. Fey, M. de Bruyn, Gerwin Huls, Edwin Bremer, Theo Bijma, Douwe F. Samplonius, M. Schwemmlein |
|---|---|
| Přispěvatelé: | Targeted Gynaecologic Oncology (TARGON), Translational Immunology Groningen (TRIGR), Stem Cell Aging Leukemia and Lymphoma (SALL), Guided Treatment in Optimal Selected Cancer Patients (GUTS) |
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Cancer Research
ANTITUMOR-ACTIVITY TUMOR-CELLS CD33 Sialic Acid Binding Ig-like Lectin 3 Apoptosis TRAIL chemistry.chemical_compound Drug Delivery Systems Drug Stability AML hemic and lymphatic diseases Tumor Cells Cultured gemtuzumab ozogamicin SPECIFICITY Cells Cultured Chemistry Antibodies Monoclonal Biological activity Hematology Ligand (biochemistry) Gemtuzumab Neoplasm Proteins Oncology Leukemia Myeloid Acute Disease medicine.drug EXPRESSION Gemtuzumab ozogamicin Recombinant Fusion Proteins Antigens Differentiation Myelomonocytic Antineoplastic Agents ACUTE MYELOID-LEUKEMIA Antibodies Monoclonal Humanized Antigens CD VALPROIC ACID Calicheamicin medicine Humans mylotarg COMBINATION neoplasms APOPTOSIS INDUCTION Bystander Effect Fusion protein In vitro Immunoconjugate Enzyme Activation Aminoglycosides Immunology Cancer research Leukocytes Mononuclear Drug Screening Assays Antitumor LIGAND Single-Chain Antibodies RITUXIMAB THERAPY |
| Zdroj: | Leukemia, 23(8), 1389-1397. Nature Publishing Group |
| ISSN: | 0887-6924 |
| DOI: | 10.1038/leu.2009.34 |
| Popis: | 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 (2009) 23, 1389-1397; doi:10.1038/leu.2009.34; published online 5 March 2009 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|