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

• Published in: Leukemia Vol. 19; no. 2; pp. 176 - 182
• Main Author: LINENBERGER, M. L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 01-02-2005; Nature Publishing Group
• Subjects: Acute myeloid leukemia; Aminoglycosides - therapeutic use; Antibodies; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Antigen (tumor-associated); Antigens; Antigens, CD - immunology; Antigens, Differentiation, Myelomonocytic - immunology; Biocompatibility; Biological and medical sciences; Blast cells; Calicheamicin; Cell death; Cell Survival - immunology; Clinical trials; Cytotoxicity; DNA damage; Drug resistance; Drug Resistance, Neoplasm - immunology; FDA approval; Gemtuzumab ozogamicin; Hematologic and hematopoietic diseases; Humans; Immunoconjugates; Immunoglobulin G; Internalization; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical research; Medical sciences; Monoclonal antibodies; Pluripotency; Sialic Acid Binding Ig-like Lectin 3; Stem cells; Toxicity; Tumors; United States > US; Immunochemotherapy; Treatment resistance; Calicheamicin; CMA-676; calicheamicin; immunoconjugate; targeted therapy; Hematology; Acute; Cytotoxicity; Malignant hemopathy; Immunoconjugate; Chemotherapy; Treatment; acute myeloid leukemia (AML); CD33; gemtuzumab ozogamicin Mylotarg; Mylotarg; Acute myelocytic leukemia
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/sj.leu.2403598

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 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.