Submitted January 14, 2008
Accepted March 5, 2008
Simultaneously targeting CD45 significantly increases cytotoxicity of the anti-CD33 immunoconjugate, gemtuzumab ozogamicin, against acute myeloid leukemia (AML) cells and improves survival of mice bearing human AML xenografts
Roland B. Walter*, Kelli M. Boyle, Frederick R. Appelbaum, Irwin D. Bernstein, and John M. Pagel
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, United States
Department of Pediatrics, University of Washington, Seattle, WA, United States
* Corresponding author; email: rwalter{at}fhcrc.org.
Targeting CD33 or CD45 is currently exploited for immunotherapy of acute myeloid leukemia (AML). Gemtuzumab ozogamicin (GO), an immunoconjugate of an anti-CD33 antibody that facilitates cellular uptake of a toxic calicheamicin-
1 derivative, induces complete remissions in a subset of patients with recurrent AML. We herein tested whether simultaneous targeting of CD45 could improve GO cytotoxicity against AML cell lines and primary AML cells. We found that the anti-CD45 antibody, BC8, dose-dependently increased cytotoxicity induced by GO, and, to a lesser degree, free calicheamicin-1. BC8 promoted CD33 endocytosis, suggesting that its effect on GO cytotoxicity may be, at least partly, due to increased uptake and intracellular GO availability. Finally, compared to either agent alone, BC8 combined with GO resulted in marked tumor growth inhibition and superior survival rates of mice bearing human AML xenografts. These data suggest that further study of this antibody combination for clinical use in AML is warranted.
