Journal
LEUKEMIA
Volume 19, Issue 2, Pages 176-182Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.leu.2403598
Keywords
acute myeloid leukemia (AML); CD33; gemtuzumab ozogamicin (Mylotarg (TM), CMA-676); calicheamicin; immunoconjugate; targeted therapy
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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, Mylotarg(TM)), a humanized IgG(4) anti-CD33 monoclonal antibody joined to a calicheamicin-gamma(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.
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