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.

Publication Type:

Journal Article

Source:

Blood, Volume 111, Issue 9, p.4813-6 (2008)

Keywords:

2008, Aminoglycosides, Animals, Antibodies, Antibodies, Monoclonal, Antibody Development Core Facility, Antigens, CD, Antigens, CD45, Antigens, Differentiation, Myelomonocytic, Biologics Production Core Facility, Center-Authored Paper, Clinical Research Division, Comparative Medicine Core Facility, Drug Interactions, Flow Cytometry Core Facility, Humans, Immunoconjugates, IMMUNOTHERAPY, Leukemia, Myeloid, Acute, MICE, Shared Resources, Survival Rate, Transplantation, Heterologous, Tumor Burden

Abstract:

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-gamma(1) derivative, induces complete remissions in a subset of patients with 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-gamma(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 with 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.