Gemtuzumab ozogamicin in acute myeloid leukemia

Abstract

CD33 is variably expressed on leukemia blasts in almost all patients with acute myeloid leukemia (AML) and possibly leukemia stem cells in some. Efforts to target CD33 therapeutically have focused on gemtuzumab ozogamicin (GO; Mylotarg), an antibody-drug conjugate delivering a DNA-damaging calicheamicin derivative. GO is most effective in acute promyelocytic leukemia but induces remissions in other AML types and received accelerated approval in the US in 2000. However, because a large follow-up study showed no survival improvement and increased early deaths the drug manufacturer voluntarily withdrew the US New Drug Application in 2010. More recently, a meta-analysis of data from several trials reported better survival in adults with favorable- and intermediate-risk cytogenetics but not adverse-risk AML randomized to receive GO along with intensive induction chemotherapy. As a result, GO is being re-evaluated by regulatory agencies. Responses to GO are diverse and predictive biological response markers are needed. Besides cytogenetic risk, ATP-binding cassette transporter activity and possibly CD33 display on AML blasts may predict response, but established clinical assays and prospective validation are lacking. Single-nucleotide polymorphisms in CD33 may also be predictive, most notably rs12459419 where the minor T-allele leads to decreased display of full-length CD33 and preferential translation of a splice variant not recognized by GO. Data from retrospective analyses suggest only patients with the rs12459419 CC genotype may benefit from GO therapy but confirmation is needed. Most important may be markers for AML cell sensitivity to calicheamicin, which varies over 100 000-fold, but useful assays are unavailable. Novel CD33-targeted drugs may overcome some of GO's limitations but it is currently unknown whether such drugs will be more effective in patients benefitting from GO and/or improve outcomes in patients not benefitting from GO, and what the supportive care requirements will be to enable their safe use.

Conjugation of Indoles to Antibodies through a Novel Self‐Immolating Linker

“…Antibody‐drug conjugates (ADCs) are an important class of emerging cancer therapeutics with four examples currently marketed (Adcetris, Kadcyla, Besponsa, and Mylotarg) and more than fifty other entities in various stages of clinical trials . Many of these agents employ cleavable linkers that are stable in circulation but which readily release a potent cytotoxic payload following internalization into targeted cells.…”

CAR-Expressing Natural Killer Cells for Cancer Retargeting

“…The humanised CD33-directed IgG4 antibody gemtuzumab ozogamicin is conjugated to a bacterial toxin, which binds to DNA, thereby mediating DNA damage in targeted cells [39]. CD33 is expressed on both healthy and malignant myeloid cells [39 and references therein]. For the targeting of CD33, several different therapeutic approaches are under current investigation, including antibody-drug conjugates and bispecific antibodies [reviewed in 40].…”

“…Studies showing that CD33-binding antibodies were efficiently internalised upon antigen binding [37, 38] paved the way for therapeutic targeting of CD33. The humanised CD33-directed IgG4 antibody gemtuzumab ozogamicin is conjugated to a bacterial toxin, which binds to DNA, thereby mediating DNA damage in targeted cells [39]. CD33 is expressed on both healthy and malignant myeloid cells [39 and references therein].…”

A DNA-Interacting Payload Designed to Eliminate Cross-Linking Improves the Therapeutic Index of Antibody–Drug Conjugates (ADCs)

“…Indeed, the first ADC of a highly potent DNA interacting agent to be evaluated in the clinic was gemtuzumab ozogamicin, which incorporated calicheamicin, a compound that causes DNA double strand breaks. This ADC was approved by the FDA, but subsequently withdrawn from the market due to toxic side effects, notably veno-occlusive disease (16,17). This ADC was re-approved recently after a new, lower dose regimen in combination with chemotherapy displayed therapeutic benefit.…”