CD33directed

CD33directed refers to therapeutic approaches that target the CD33 antigen, a transmembrane protein of the SIGLEC family expressed on myeloid lineage cells, including most acute myeloid leukemia blasts. CD33 expression is variable on normal cells, influencing both potential efficacy and toxicity of CD33directed therapies.

The most clinically advanced CD33directed therapies are antibody-based constructs designed to exploit CD33 to deliver cytotoxic payloads or recruit immune effector cells. Gemtuzumab ozogamicin (GO) is a CD33directed antibody-drug conjugate that links a humanized anti-CD33 antibody to calicheamicin. GO was approved in 2000 for CD33-positive AML, withdrawn in 2010, and reintroduced in 2017 with a lower, fractionated dosing schedule. Its use has shown survival benefits in select patient groups but carries risks of hepatotoxicity, including veno-occlusive disease, and cytopenias.

Other CD33directed agents include vadastuximab talirine (SGN-CD33A), an anti-CD33 antibody-drug conjugate that was in development but halted after safety concerns. Research has also explored CD33directed bispecific antibodies and CAR-based approaches to recruit or redirect T cells against CD33-expressing AML cells, but none has received regulatory approval as of 2024.

Clinical considerations for CD33directed therapies include patient selection based on CD33 expression, disease risk, and prior treatment, as well as the balance between potential benefit and toxicity. Common adverse events relate to cytopenias and liver injury; resistance can arise from downregulation of CD33 or clonal evolution.