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CD33-directed therapy with gemtuzumab ozogamicin in acute myeloid leukemia: progress in understanding cytotoxicity and potential mechanisms of drug resistance

Leukemia volume 19, pages 176–182 (2005)Cite this article

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, Mylotarg™), a humanized IgG4 anti-CD33 monoclonal antibody joined to a calicheamicin-γ1 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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Acknowledgements

This work was supported by research funding from the Leukemia and Lymphoma Society (#7040-03). We thank Drs Roland Walter, Frederick Appelbaum and Deborah Banker for helpful discussions and review of the manuscript.

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    M L Linenberger

  2. Department of Medicine, University of Washington, Seattle, WA, USA

    M L Linenberger

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Linenberger, M. CD33-directed therapy with gemtuzumab ozogamicin in acute myeloid leukemia: progress in understanding cytotoxicity and potential mechanisms of drug resistance. Leukemia 19, 176–182 (2005). https://doi.org/10.1038/sj.leu.2403598

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