title: Preclinical characterization of AMG 330, a CD3/CD33-bispecific T-cell-engaging antibody with potential for treatment of acute myelogenous leukemia.
abstract: There is high demand for novel therapeutic options for patients with acute myelogenous leukemia (AML). One possible approach is the bispecific T-cell-engaging (BiTE, a registered trademark of Amgen) antibody AMG 330 with dual specificity for CD3 and the sialic acid-binding lectin CD33 (SIGLEC-3), which is frequently expressed on the surface of AML blasts and leukemic stem cells. AMG 330 binds with low nanomolar affinity to CD33 and CD3ε of both human and cynomolgus monkey origin. Eleven human AML cell lines expressing between 14,400 and 56,700 CD33 molecules per cell were all potently lysed with EC(50) values ranging between 0.4 pmol/L and 3 pmol/L (18-149 pg/mL) by previously resting, AMG 330-redirected T cells. Complete lysis was achieved after 40 hours of incubation. In the presence of AML cells, AMG 330 specifically induced expression of CD69 and CD25 as well as release of IFN-γ, TNF, interleukin (IL)-2, IL-10, and IL-6. Ex vivo, AMG 330 mediated autologous depletion of CD33-positive cells from cynomolgous monkey bone marrow aspirates. Soluble CD33 at concentrations found in bone marrow of patients with AML did not significantly affect activities of AMG 330. Neoexpression of CD33 on newly activated T cells was negligible as it was limited to 6% of T cells in only three out of ten human donors tested. Daily intravenous administration with as low as 0.002 mg/kg AMG 330 significantly prolonged survival of immunodeficient mice adoptively transferred with human MOLM-13 AML cells and human T cells. AMG 330 warrants further development as a potential therapy for AML.
authors.affiliation: Authors' Affiliations: Amgen Research (Munich) GmbH, Munich, Germany; and Pepscan Presto, Lelystad, the Netherlands.
authors.forename: Matthias
authors.initials: M
authors.lastname: Friedrich
authors.affiliation: Authors' Affiliations: Amgen Research (Munich) GmbH, Munich, Germany; and Pepscan Presto, Lelystad, the Netherlands.
authors.forename: Anja
authors.initials: A
authors.lastname: Henn
authors.affiliation: Authors' Affiliations: Amgen Research (Munich) GmbH, Munich, Germany; and Pepscan Presto, Lelystad, the Netherlands.
authors.forename: Tobias
authors.initials: T
authors.lastname: Raum
authors.affiliation: Authors' Affiliations: Amgen Research (Munich) GmbH, Munich, Germany; and Pepscan Presto, Lelystad, the Netherlands.
authors.forename: Monika
authors.initials: M
authors.lastname: Bajtus
authors.affiliation: Authors' Affiliations: Amgen Research (Munich) GmbH, Munich, Germany; and Pepscan Presto, Lelystad, the Netherlands.
authors.forename: Katja
authors.initials: K
authors.lastname: Matthes
authors.affiliation: Authors' Affiliations: Amgen Research (Munich) GmbH, Munich, Germany; and Pepscan Presto, Lelystad, the Netherlands.
authors.forename: Larissa
authors.initials: L
authors.lastname: Hendrich
authors.affiliation: Authors' Affiliations: Amgen Research (Munich) GmbH, Munich, Germany; and Pepscan Presto, Lelystad, the Netherlands.
authors.forename: Joachim
authors.initials: J
authors.lastname: Wahl
authors.affiliation: Authors' Affiliations: Amgen Research (Munich) GmbH, Munich, Germany; and Pepscan Presto, Lelystad, the Netherlands.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: Authors' Affiliations: Amgen Research (Munich) GmbH, Munich, Germany; and Pepscan Presto, Lelystad, the Netherlands.
authors.forename: Roman
authors.initials: R
authors.lastname: Kischel
authors.affiliation: Authors' Affiliations: Amgen Research (Munich) GmbH, Munich, Germany; and Pepscan Presto, Lelystad, the Netherlands.
authors.forename: Majk
authors.initials: M
authors.lastname: Kvesic
authors.affiliation: Authors' Affiliations: Amgen Research (Munich) GmbH, Munich, Germany; and Pepscan Presto, Lelystad, the Netherlands.
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Slootstra
authors.affiliation: Authors' Affiliations: Amgen Research (Munich) GmbH, Munich, Germany; and Pepscan Presto, Lelystad, the Netherlands baeuerle@amgen.com.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Baeuerle
authors.affiliation: Authors' Affiliations: Amgen Research (Munich) GmbH, Munich, Germany; and Pepscan Presto, Lelystad, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Kufer
authors.affiliation: Authors' Affiliations: Amgen Research (Munich) GmbH, Munich, Germany; and Pepscan Presto, Lelystad, the Netherlands.
authors.forename: Benno
authors.initials: B
authors.lastname: Rattel
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000008:administration & dosage*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008252:Macaca fascicularis / Q000276:immunology; D051379:Mice; D058990:Molecular Targeted Therapy; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D063268:Sialic Acid Binding Ig-like Lectin 3; C587103:AMG 330