CD33-directed therapy with gemtuzumab ozogamicin in acute myeloid leukemia: progress in understanding cytotoxicity and potential mechanisms of drug resistance
- 9 December 2004
- journal article
- review article
- Published by Springer Science and Business Media LLC in Leukemia
- Vol. 19 (2), 176-182
- https://doi.org/10.1038/sj.leu.2403598
Abstract
CD33 is expressed on the malignant blast cells in most cases of acute myeloid leukemia (AML) but not on normal hematopoietic pluripotent stem cells. Antibody-based therapies for AML have, therefore, focused on CD33 as a suitable tumor-associated target antigen. The most promising results have been obtained with gemtuzumab ozogamicin (GO, MylotargTM), a humanized IgG4 anti-CD33 monoclonal antibody joined to a calicheamicin-1 derivative. Engagement of CD33 by GO results in immunoconjugate internalization and hydrolytic release of the toxic calicheamicin moiety, which, in turn, causes DNA damage and cell death. Since 2000, when GO was approved for clinical use, treatment trials and pilot studies have revealed potential expanded applications along with additional limitations. At the same time, correlative biological and in vitro functional studies have further characterized CD33 expression patterns in AML, the significance of CD33–antibody interactions, pathways involved in GO-induced cytotoxicity and potential drug resistance mechanisms. This review summarizes the recent data addressing mechanisms of GO action and discusses their relevance with regard to clinical applications and the limitations of using experimental model systems to mimic in vivo conditions. As the first drug conjugate approved for clinical use, GO serves as an important paradigm for other immunoconjugates against internalizing tumor antigens.Keywords
This publication has 86 references indexed in Scilit:
- New agents in acute myeloid leukemia and other myeloid disordersCancer, 2004
- Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantationBlood, 2003
- Differential response of human acute myeloid leukemia cells to gemtuzumab ozogamicin in vitro: role of Chk1 and Chk2 phosphorylation and caspase 3Blood, 2003
- Cleavage of cellular DNA by calicheamicin γ1DNA Repair, 2003
- Transcriptional Effects of the Potent Enediyne Anti-Cancer Agent Calicheamicin γ1ICell Chemical Biology, 2002
- Pharmacokinetics of Gemtuzumab Ozogamicin, an Antibody‐Targeted Chemotherapy Agent for the Treatment of Patients with Acute Myeloid Leukemia in First RelapseThe Journal of Clinical Pharmacology, 2001
- Acute Myeloid LeukemiaNew England Journal of Medicine, 1999
- Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cellNature Medicine, 1997
- Sensitivity of fibroblasts derived from ataxia-telangiectasia patients to calicheamicin γ1IMutation Research Letters, 1990
- Modulation of nicotinamide adenine dinucleotide and poly(adenosine diphosphoribose) metabolism by calicheamicin γ1 in human HL-60 cellsCancer Letters, 1990