What Happened to Anti-CD33 Therapy for Acute Myeloid Leukemia?

Abstract

CD33, a 67-kDa glycoprotein expressed on the majority of myeloid leukemia cells as well as on normal myeloid and monocytic precursors, has been an attractive target for monoclonal antibody (mAb)-based therapy of acute myeloid leukemia (AML). Lintuzumab, an unconjugated, humanized anti-CD33 mAb, has modest single-agent activity against AML but failed to improve patient outcomes in two randomized trials when combined with conventional chemotherapy. Gemtuzumab ozogamicin, an anti-CD33 mAb conjugated to the antitumor antibiotic calicheamicin, improved survival in a subset of AML patients when combined with standard chemotherapy, but safety concerns led to US marketing withdrawal. The activity of these agents confirms that CD33 remains a viable therapeutic target for AML. Strategies to improve the results of mAb-based therapies for AML include antibody engineering to enhance effector function, use of alternative drugs and chemical linkers to develop safer and more effective drug conjugates, and radioimmunotherapeutic approaches.

Preclinical Characterization of AMG 330, a CD3/CD33-Bispecific T-Cell–Engaging Antibody with Potential for Treatment of Acute Myelogenous Leukemia

“…Most clinical experience was gained with CD33 as target antigen (4,5). It is predominantly expressed on myeloidderived cells and found overexpressed on bone marrow cells from patients with AML, chronic myelogenous leukemia, and myelodysplastic syndrome (6).…”

Anti-CD45 radioimmunotherapy using 211At with bone marrow transplantation prolongs survival in a disseminated murine leukemia model

“…Moreover, a-emitting reagents have a high linear energy transfer (LET) because of the high decay energy (5-8 MeV) deposited over short distances that allows for potent and efficient cell kill compared with b emitters such as 131 I and 90 Y with lower decay energies (0.66-2.3 MeV) and longer path lengths. 2 Only a few a-emitting radionuclides, however, are currently suitable for clinical application. 17 For the a emitters with favorable radiobiologic characteristics, other issues such as availability, labeling chemistry, and in vivo stability, especially of astatinated macromolecules, have had an impact on their use in RIT.…”

“…1 Monoclonal antibodies (mAbs) targeting hematologic-specific antigens have been used in radioimmunotherapy (RIT) studies as a means to deliver higher radiation doses prior to HSCT. [2][3][4][5][6] One such target is CD45, a cell surface antigen highly expressed on hematologic tissues (;200 000 binding sites per cell) with minimal expression on nonhematologic tissues. 7,8 CD45 is not extensively internalized after mAb binding, 9,10 further making anti-CD45 RIT a viable approach for therapy of high-risk AML.…”

A New Approach to Cancer Therapy: The Tumor Microenvironment as Target

“…The immunoconjugate gemtuzumab ozogamicin (Mylotarg, CMA-676), a calicheamicin conjugate that targets CD33, has been approved by the Food and Drug Administration (FDA) in 2000 for treatment of acute myelogenous leukemia (AML). Although gemtuzumab ozogamicin improved survival in a subset of AML patients when combined with standard chemotherapy, the drug was recently withdrawn by the FDA due to safety concerns [411]. However, the cytotoxic activity of the immunoconjugate confirms that CD33 remains a possible therapeutic target for AML.…”