title: A CD3xCD123 bispecific DART for redirecting host T cells to myelogenous leukemia: preclinical activity and safety in nonhuman primates.
abstract: Current therapies for acute myeloid leukemia (AML) are largely ineffective, and AML patients may benefit from targeted immunotherapy approaches. MGD006 is a bispecific CD3xCD123 dual-affinity re-targeting (DART) molecule that binds T lymphocytes and cells expressing CD123, an antigen up-regulated in several hematological malignancies including AML. MGD006 mediates blast killing in AML samples, together with concomitant activation and expansion of residual T cells. MGD006 is designed to be rapidly cleared, and therefore requires continuous delivery. In a mouse model of continuous administration, MGD006 eliminated engrafted KG-1a cells (an AML-M0 line) in human PBMC (peripheral blood mononuclear cell)-reconstituted NSG/β2m(-/-) mice at doses as low as 0.5 μg/kg per day for ~7 days. MGD006 binds to human and cynomolgus monkey antigens with similar affinities and redirects T cells from either species to kill CD123-expressing target cells. MGD006 was well tolerated in monkeys continuously infused with 0.1 μg/kg per day escalated weekly to up to 1 μg/kg per day during a 4-week period. Depletion of circulating CD123-positive cells was observed as early as 72 hours after treatment initiation and persisted throughout the infusion period. Cytokine release, observed after the first infusion, was reduced after subsequent administrations, even when the dose was escalated. T cells from animals with prolonged in vivo exposure exhibited unperturbed target cell lysis ex vivo, indicating no exhaustion. A transient decrease in red cell mass was observed, with no neutropenia or thrombocytopenia. These studies support clinical testing of MGD006 in hematological malignancies, including AML.
authors.affiliation: MacroGenics Inc., 9640 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Gurunadh R
authors.initials: GR
authors.lastname: Chichili
authors.affiliation: MacroGenics Inc., 9640 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Huang
authors.affiliation: MacroGenics Inc., 9640 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: MacroGenics Inc., 9640 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Burke
authors.affiliation: MacroGenics Inc., 9640 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Leilei
authors.initials: L
authors.lastname: He
authors.affiliation: MacroGenics Inc., 9640 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Tang
authors.affiliation: MacroGenics Inc., 9640 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Jin
authors.affiliation: MacroGenics Inc., 9640 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Gorlatov
authors.affiliation: MacroGenics Inc., 9640 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Valentina
authors.initials: V
authors.lastname: Ciccarone
authors.affiliation: MacroGenics Inc., 9640 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Francine
authors.initials: F
authors.lastname: Chen
authors.affiliation: MacroGenics Inc., 9640 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Koenig
authors.affiliation: MacroGenics Inc., 9640 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Shannon
authors.affiliation: MacroGenics Inc., 9640 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Alderson
authors.affiliation: MacroGenics Inc., 9640 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Moore
authors.affiliation: MacroGenics Inc., 9640 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Syd
authors.initials: S
authors.lastname: Johnson
authors.affiliation: MacroGenics Inc., 9640 Medical Center Drive, Rockville, MD 20850, USA. bonvinie@macrogenics.com.
authors.forename: Ezio
authors.initials: E
authors.lastname: Bonvini
mesh_terms: D000818:Animals; D015703:Antigens, CD; D001853:Bone Marrow / Q000473:pathology; D017252:CD3 Complex / Q000378:metabolism*; D016923:Cell Death; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006410:Hematopoiesis; D006801:Humans; D053650:Interleukin-3 Receptor alpha Subunit / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D011485:Protein Binding; D015202:Protein Engineering; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D017252:CD3 Complex; D016207:Cytokines; D053650:Interleukin-3 Receptor alpha Subunit