title: 5-azacytidine enhances the anti-leukemic activity of lintuzumab (SGN-33) in preclinical models of acute myeloid leukemia.
abstract: Despite therapeutic advances, the poor prognoses for acute myeloid leukemia (AML) and intermediate and high-risk myelodysplastic syndromes (MDS) point to the need for better treatment options. AML and MDS cells express the myeloid marker CD33, making it amenable to CD33-targeted therapy. Lintuzumab (SGN-33), a humanized monoclonal anti-CD33 antibody undergoing clinical evaluation, induced meaningful responses in a Phase 1 clinical trial and demonstrated anti-leukemic activity in preclinical models. Recently, it was reported that 5-azacytidine (Vidaza™) prolonged the overall survival of a group of high risk MDS and AML patients. To determine whether the combination of lintuzumab and 5-azacytidine would be beneficial, a mouse xenograft model of disseminated AML was used to evaluate the combination.  There was a significant reduction in tumor burden and an increase in overall survival in mice treated with lintuzumab and 5-azacytidine. The effects were greater than that obtained with either agent alone. As the in vivo anti-leukemic activity of lintuzumab was dependent upon the presence of mouse effector cells including macrophages and neutrophils, in vitro effector function assays were used to assess the impact of 5-azacytidine on lintuzumab activity. The results show that 5-azacytidine significantly enhanced the ability of lintuzumab to promote tumor cell killing through antibody-dependent cellular cytotoxicity (ADCC) and phagocytic (ADCP) activities. These results suggest that lintuzumab and 5-azacytidine act in concert to promote tumor cell killing. Additionally, these findings provide the rationale to evaluate this combination in the clinic.
authors.affiliation: Seattle Genetics, Inc.
authors.forename: May Kung
authors.initials: MK
authors.lastname: Sutherland
authors.affiliation: Seattle Genetics, Inc.
authors.forename: Changpu
authors.initials: C
authors.lastname: Yu
authors.affiliation: Seattle Genetics, Inc.
authors.forename: Martha
authors.initials: M
authors.lastname: Anderson
authors.affiliation: Seattle Genetics, Inc.
authors.forename: Weiping
authors.initials: W
authors.lastname: Zeng
authors.affiliation: Vrije Universiteit, Amsterdam.
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.affiliation: Seattle Genetics, Inc.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Sievers
authors.affiliation: Seattle Genetics, Inc.
authors.forename: Iqbal S
authors.initials: IS
authors.lastname: Grewal
authors.affiliation: Seattle Genetics, Inc.
authors.forename: Che-Leung
authors.initials: CL
authors.lastname: Law
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001374:Azacitidine / Q000008:administration & dosage*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000628:therapy*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D010587:Phagocytosis / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001374:Azacitidine; C477390:lintuzumab