title: Targeting CD123 in acute myeloid leukemia using a T-cell-directed dual-affinity retargeting platform.
abstract: T-cell-directed killing of tumor cells using bispecific antibodies is a promising approach for the treatment of hematologic malignancies. Here we describe our preclinical work with a dual-affinity retargeting (DART) molecule generated from antibodies to CD3 and CD123, designed to redirect T cells against acute myeloid leukemia blasts. The CD3×CD123 DART (also referred to as MGD006/S80880) consists of 2 independent polypeptides, each composed of the VH of 1 antibody in tandem with the VL of the other antibody. The target antigen CD123 (interleukin 3RA) is highly and differentially expressed in acute myeloid leukemia (AML) blasts compared with normal hematopoietic stem and progenitor cells. In this study we demonstrate that the CD3×CD123 DART binds to both human CD3 and CD123 to mediate target-effector cell association, T-cell activation, proliferation, and receptor diversification. The CD3×CD123 DART also induces a dose-dependent killing of AML cell lines and primary AML blasts in vitro and in vivo. These results provide the basis for testing the CD3×CD123 DART in the treatment of patients with CD123(+) AML.
authors.affiliation: Division of Oncology, Department of Medicine, and.
authors.forename: Muneera
authors.initials: M
authors.lastname: Al-Hussaini
authors.affiliation: Division of Oncology, Department of Medicine, and.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Rettig
authors.affiliation: Division of Oncology, Department of Medicine, and.
authors.forename: Julie K
authors.initials: JK
authors.lastname: Ritchey
authors.affiliation: Division of Oncology, Department of Medicine, and.
authors.forename: Darja
authors.initials: D
authors.lastname: Karpova
authors.affiliation: Division of Oncology, Department of Medicine, and.
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Uy
authors.affiliation: Division of Oncology, Department of Medicine, and.
authors.forename: Linda G
authors.initials: LG
authors.lastname: Eissenberg
authors.affiliation: Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO;
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.affiliation: Division of Oncology, Department of Medicine, and.
authors.forename: William C
authors.initials: WC
authors.lastname: Eades
authors.affiliation: MacroGenics, Inc., Rockville, MD; and.
authors.forename: Ezio
authors.initials: E
authors.lastname: Bonvini
authors.affiliation: MacroGenics, Inc., Rockville, MD; and.
authors.forename: Gurunadh R
authors.initials: GR
authors.lastname: Chichili
authors.affiliation: MacroGenics, Inc., Rockville, MD; and.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Moore
authors.affiliation: MacroGenics, Inc., Rockville, MD; and.
authors.forename: Syd
authors.initials: S
authors.lastname: Johnson
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Lynne
authors.initials: L
authors.lastname: Collins
authors.affiliation: Division of Oncology, Department of Medicine, and.
authors.forename: John F
authors.initials: JF
authors.lastname: DiPersio
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology*; D017209:Apoptosis; D017252:CD3 Complex / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D005434:Flow Cytometry; D019673:Genes, T-Cell Receptor alpha / Q000235:genetics; D019674:Genes, T-Cell Receptor beta / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007124:Immunoenzyme Techniques; D053650:Interleukin-3 Receptor alpha Subunit / Q000276:immunology* / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D013601:T-Lymphocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D017252:CD3 Complex; D053650:Interleukin-3 Receptor alpha Subunit