The role of CD33 as therapeutic target in acute myeloid leukemia

Abstract

CD33 is a myeloid differentiation antigen that is displayed on acute myeloid leukemia (AML) blasts in most patients and, possibly, leukemic stem cells in some, and has thus served as target for antibody-based therapies for many years. Validation for this approach comes from the antibody–drug conjugate, gemtuzumab ozogamicin, which improves survival of some patients with AML when added to induction chemotherapy. Still, CD33 is a challenging target because of its low expression and slow internalization; these characteristics limit antibody-dependent cell-mediated cytotoxicity and intracellular drug accumulation and, consequently, the activity of unlabeled and toxin-carrying antibodies. Very promising preclinical data are now available from an improved antibody–drug conjugate and CD33-targeted strategies that redirect immune effector cells to eradicate the leukemia, most notably bispecific antibodies and chimeric antigen receptor T-cell immunotherapy. In parallel to their clinical testing, efforts will be needed to identify the patients that most likely benefit from such agents and the disease stage in which they are most efficacious. With enhanced activity of CD33-directed therapies, toxic effects on normal hematopoiesis will increase and require excellent supportive care measures, or even rescue with donor cells, to minimize morbidity and mortality from expected cytopenias and to optimize treatment outcomes with these therapeutics.

Keywords::

• acute myeloid leukemia
• antibody
• antibody–drug conjugate
• bispecific antibody
• bispecific T-cell engager
• CD33
• chimeric antigen receptor
• gemtuzumab ozogamicin
• immunotherapy