title: T lymphocytes can be effectively recruited for ex vivo and in vivo lysis of AML blasts by a novel CD33/CD3-bispecific BiTE antibody construct.
abstract: Patients with acute myelogenous leukemia (AML) are in high need of novel targeted therapies. Here we explored the ex vivo activity of AMG330, a novel T-cell-engaging BiTE (bi-specific T-cell engagers) antibody (Ab) construct, that is bispecific for the myeloid differentiation antigen, CD33 and CD3, in primary samples from AML patients (N=23) and AML cell lines. KG-1 and U937 cells were lysed in co-culture with healthy donor T-cells at AMG330 concentrations as low as 0.1 ng/ml (1.8 pM). T-cells derived from AML patient samples were found to be as active in redirected lysis by AMG330 as T-cells from healthy donors. In an autologous setting, AMG330 could activate and expand T-cells in primary AML patient samples, and effectively mediated the redirected lysis of AML blasts and normal myeloid cells. A deficiency in target-cell lysis was only observed in samples with very low initial effector-to-target (E:T) ratio. However, this could be overcome if previously stimulated autologous T-cells were tested in patient samples at a higher E:T ratio. In vivo experiments in immunodeficient mice demonstrated significant inhibition of tumor growth by AMG330 and an inducible infiltration of human T-cells into subcutaneous HL60 tumors. The activities of the CD33/CD3-bispecific BiTE Ab construct AMG330 warrant further development for the treatment of AML.
authors.affiliation: Department of Internal Medicine 5-Hematology/Oncology, University of Erlangen-Nuernberg, Erlangen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Aigner
authors.forename: J
authors.initials: J
authors.lastname: Feulner
authors.forename: S
authors.initials: S
authors.lastname: Schaffer
authors.forename: R
authors.initials: R
authors.lastname: Kischel
authors.forename: P
authors.initials: P
authors.lastname: Kufer
authors.forename: K
authors.initials: K
authors.lastname: Schneider
authors.forename: A
authors.initials: A
authors.lastname: Henn
authors.forename: B
authors.initials: B
authors.lastname: Rattel
authors.forename: M
authors.initials: M
authors.lastname: Friedrich
authors.forename: P A
authors.initials: PA
authors.lastname: Baeuerle
authors.forename: A
authors.initials: A
authors.lastname: Mackensen
authors.forename: S W
authors.initials: SW
authors.lastname: Krause
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000627:therapeutic use*; D001752:Blast Crisis / Q000188:drug therapy*; D017252:CD3 Complex / Q000276:immunology*; D002465:Cell Movement; D003602:Cytotoxicity, Immunologic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D020298:U937 Cells
chemical_list: D018033:Antibodies, Bispecific; D017252:CD3 Complex; D063268:Sialic Acid Binding Ig-like Lectin 3