title: 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.
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.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA. rwalter@fhcrc.org
authors.forename: Roland B
authors.initials: RB
authors.lastname: Walter
authors.forename: Kelli M
authors.initials: KM
authors.lastname: Boyle
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Appelbaum
authors.forename: Irwin D
authors.initials: ID
authors.lastname: Bernstein
authors.forename: John M
authors.initials: JM
authors.lastname: Pagel
mesh_terms: D000617:Aminoglycosides; D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000276:immunology*; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology*; D004347:Drug Interactions; D000079982:Gemtuzumab; D006801:Humans; D018796:Immunoconjugates; D007167:Immunotherapy / Q000379:methods*; D015470:Leukemia, Myeloid, Acute / Q000628:therapy*; D017493:Leukocyte Common Antigens / Q000276:immunology*; D051379:Mice; D063268:Sialic Acid Binding Ig-like Lectin 3; D015996:Survival Rate; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000617:Aminoglycosides; D000906:Antibodies; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; C571165:Cd33 protein, mouse; D018796:Immunoconjugates; D063268:Sialic Acid Binding Ig-like Lectin 3; D000079982:Gemtuzumab; D017493:Leukocyte Common Antigens