CD33 as a target for selective ablation of acute myeloid leukemia

The CD33 antigen is a 67-kd glycosylated transmembrane protein of the sialic acid-binding immunoglobulinlike lectin (siglec) family with immunoreceptor tyrosine-based inhibitory motifs. It is expressed on the surface of normal mature and immature myeloid cells, including colony-forming progenitor cells, and on leukemic blasts from the majority of patients with acute myeloid leukemia (AML). CD33 is not expressed by the normal stem cells, suggesting that in vivo ablation of CD33-bearing normal and leukemic myeloid cells might lead to the establishment of normal hematopoiesis by the remaining normal stem cells. However, whether there are significant numbers of CD33(-) leukemic stem cells is controversial. Therapeutic trials using unmodified anti-CD33 antibodies have, thus far, met with limited success. Studies with a radiolabeled anti-CD33 antibody have demonstrated rapid saturation of, and internalization by, leukemic blast cells after intravenous administration, suggesting the possibility of using an anti-CD33 antibody to deliver a cytotoxic drug. Using gemtuzumab ozogamicin (Mylotarg's), a humanized anti-CD33 antibody conjugated with calicheamicin, the effectiveness of in vivo ablation of CD33(+) cells to treat patients with AML was borne out by the portion of patients who achieved remission. To what extent CD33(-) leukemic precursors are responsible for failure to respond or for relapse following gemtuzumab ozogamicin therapy remains to be determined.