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

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, Mylotargt), a humanized IgG 4 anti-CD33 monoclonal antibody joined to a calicheamicinc 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.

CD33 is expressed on plasma cells of a significant number of myeloma patients, and may represent a therapeutic target

“…CD33 is usually expressed in the myeloid lineage (but not in the B-cell lineage), 2 and has been targeted by monoclonal antibodies coupled with calicheamycin (gemtuzumab ozogamicin, Mylotarg s , Wyeth, Philadelphia). This modified antibody is now used in the treatment of patients with acute myeloid leukemia (AML) who express CD33 in more than 90% of the cases, with encouraging results.…”

Efficacy and resistance of gemtuzumab ozogamicin for acute myeloid leukemia

“…In their study, anti-CD33 blocking antibodies prevented the death of CD33-positive cells at low concentrations of GO, but not at higher concentrations. Another possible explanation is that CD33-negative leukemia cells may have a subthreshold low amount of CD33, which reacts substantially with GO [33]. These ideas may also explain the mechanism of liver dysfunction, which has been observed in the GO treatment.…”

“…These in vitro results were confirmed in phase I studies of GO. Good responders were more frequently observed in leukemia cases characterized by low dye efflux in vitro [33,35]. In GO, MDR modifiers theoretically work only on intracellularly incorporated calicheamicin in CD33-positive cells.…”

“…GO may thus be lost to some extent in the circulation before it reaches the bone marrow. This suggests that GO might be made more effective by the reduction of CD33 in peripheral blood by chemotherapy [33].…”

Sequence of administration and methylation of SOCS3 may govern response to gemtuzumab ozogamicin in combination with conventional chemotherapy in patients with refractory or relapsed acute myelogenous leukemia (AML)

“…However, the mechanism of the different response according to the sequence of GO and chemotherapy is not clear. Internalization and hydrolytic release of the toxic calicheamicin moiety causes DNA damage and cell cycle arrest [39]. Because most chemotherapeutic agents mainly target dividing cells, administration of GO before chemotherapy may lead to reduced efficacy of the following chemotherapy.…”