title: Cellular determinants for preclinical activity of a novel CD33/CD3 bispecific T-cell engager (BiTE) antibody, AMG 330, against human AML.
abstract: CD33 is a valid target for acute myeloid leukemia (AML) but has proven challenging for antibody-drug conjugates. Herein, we investigated the cellular determinants for the activity of the novel CD33/CD3-directed bispecific T-cell engager antibody, AMG 330. In the presence of T cells, AMG 330 was highly active against human AML cell lines and primary AML cells in a dose- and effector to target cell ratio-dependent manner. Using cell lines engineered to express wild-type CD33 at increased levels, we found a quantitative relationship between AMG 330 cytotoxicity and CD33 expression; in contrast, AMG 330 cytotoxicity was neither affected by common CD33 single nucleotide polymorphisms nor expression of the adenosine triphosphate-binding cassette (ABC) transporter proteins, P-glycoprotein or breast cancer resistance protein. Unlike bivalent CD33 antibodies, AMG 330 did not reduce surface CD33 expression. The epigenetic modifier drugs, panobinostat and azacitidine, increased CD33 expression in some cell lines and augmented AMG 330-induced cytotoxicity. These findings demonstrate that AMG 330 has potent CD33-dependent cytolytic activity in vitro, which can be further enhanced with other clinically available therapeutics. As it neither modulates CD33 expression nor is affected by ABC transporter activity, AMG 330 is highly promising for clinical exploration as it may overcome some limitations of previous CD33-targeted agents.
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;
authors: George S
authors: GS
authors: Laszlo
authors: Chelsea J
authors: CJ
authors: Gudgeon
authors: Kimberly H
authors: KH
authors: Harrington
authors: Justine
authors: J
authors: Dell'Aringa
authors: Kathryn J
authors: KJ
authors: Newhall
authors: Gary D
authors: GD
authors: Means
authors: Angus M
authors: AM
authors: Sinclair
authors: Roman
authors: R
authors: Kischel
authors: Stanley R
authors: SR
authors: Frankel
authors: Roland B
authors: RB
authors: Walter
mesh_terms: D000071916:AC133 Antigen; D000906:Antibodies / Q000737:chemistry; D018033:Antibodies, Bispecific / Q000737:chemistry*; D015703:Antigens, CD / Q000378:metabolism; D001374:Azacitidine / Q000737:chemistry; D017252:CD3 Complex / Q000378:metabolism; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry*; D044127:Epigenesis, Genetic; D015973:Gene Expression Regulation, Leukemic; D006023:Glycoproteins / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D007211:Indoles / Q000737:chemistry; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors; D000077767:Panobinostat; D010455:Peptides / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism
chemical_list: D000071916:AC133 Antigen; D000906:Antibodies; D018033:Antibodies, Bispecific; D015703:Antigens, CD; D017252:CD3 Complex; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D006877:Hydroxamic Acids; D007211:Indoles; D010455:Peptides; D063268:Sialic Acid Binding Ig-like Lectin 3; C587103:AMG 330; D000077767:Panobinostat; D019853:O(6)-Methylguanine-DNA Methyltransferase; D001374:Azacitidine