Targeted therapy of acute myeloid leukemia with monoclonal antibodies and immunoconjugates

Traditional chemotherapy for acute leukemia often causes life-threatening toxic effects due to a lack of specificity for hematopoietic cells, Monoclonal antibodies and fusion proteins that target cell surface antigens on leukemic blasts are being evaluated for their cytotoxic effects and as a means of delivering chemotherapeutic agents or radiation directly to malignant cells. It is hoped that this strategy might selectively ablate malignant cells without many of the toxic effects commonly associated with conventional chemotherapy. In acute myeloid leukemia (AML), the cell surface antigens CD33 and CD45 are especially suitable targets. Although CD33 is expressed on AML blast cells from about 90% of patients, normal hematopoietic stem cells lack this antigen, as do essentially all nonhematopoietic tissues. For that reason, anti-CD33 antibodies have been created to target malignant myeloid and immature normal cells selectively while sparing normal stem cells. Anti-CD33 antibodies have also been used to deliver radiation or a cytotoxic agent directly to leukemic cells. Since the vast majority of leukemias and normal stem cells express the cell surface antigen CD45, another targeting approach allows the delivery of myeloablative radiation to bone marrow and spleen, common sites of leukemic involvement. Consequently, I-131-labeled anti-CD45 antibody has been combined with traditional preparative regimens for patients receiving bone marrow transplantation for acute leukemia. Finally, fusion proteins such as those combining diphtheria toxin with granulocyte-macrophage colony-stimulating factor (GMCSF) to target the GM-CSF receptor are now being evaluated in clinical trials. Both unconjugated and conjugated antibodies have shown promise in early clinical trials, and may represent appealing therapeutic alternatives for patients with AML.