title: The Broad Anti-AML Activity of the CD33/CD3 BiTE Antibody Construct, AMG 330, Is Impacted by Disease Stage and Risk.
abstract: The CD33/CD3-bispecific T-cell engaging (BiTE) antibody construct, AMG 330, potently lyses CD33+ leukemic cells in vitro. Using specimens from 41 patients with acute myeloid leukemia (AML), we studied the factors that might contribute to clinical response or resistance. For this purpose, thawed aliquots of primary AML samples were immunophenotypically characterized and subjected to various doses of AMG 330 in the presence or absence of healthy donor T-cells. After 48 hours, drug-specific cytotoxicity was quantified and correlated with CD33 expression levels, amounts of T-cells present, and other disease characteristics. AMG 330 caused modest cytotoxicity that was correlated with the amount of autologous T-cells (P = 0.0001) but not CD33 expression, as AMG 330 exerted marked cytotoxic effects in several specimens with minimal CD33 expression. With healthy donor T-cells added, AMG 330 cytotoxicity depended on the drug dose and effector:target (E:T) cell ratio. High cytotoxic activity was observed even with minimal CD33 expression, and AMG 330 cytotoxicity and CD33 expression correlated only at high E:T cell ratio and high AMG 330 doses (P<0.003). AMG 330 resulted in significantly higher cytotoxicity in specimens from patients with newly diagnosed AML than those with relapsed/refractory disease despite similar levels of CD33 on myeloblasts. AMG 330 cytotoxicity also appeared greater in specimens from patients with favorable-risk disease as compared to other specimens. Together, our data demonstrate that AMG 330 is highly active in primary AML specimens across the entire disease spectrum, while suggesting the presence of yet undefined, CD33-independent, relative resistance mechanisms in specific patient subsets.
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors: Kimberly H
authors: KH
authors: Harrington
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors: Chelsea J
authors: CJ
authors: Gudgeon
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors: George S
authors: GS
authors: Laszlo
authors: Amgen, Inc., Seattle, Washington, United States of America.
authors: Kathryn J
authors: KJ
authors: Newhall
authors: Amgen, Inc., Thousand Oaks, California, United States of America.
authors: Angus M
authors: AM
authors: Sinclair
authors: Amgen, Inc., Rockville, Maryland, United States of America.
authors: Stanley R
authors: SR
authors: Frankel
authors: Amgen Research (Munich) GmbH, Munich, Germany.
authors: Roman
authors: R
authors: Kischel
authors: Amgen, Inc., Seattle, Washington, United States of America.
authors: Guang
authors: G
authors: Chen
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Department of Medicine, Division of Hematology, University of Washington, Seattle, Washington, United States of America; Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.
authors: Roland B
authors: RB
authors: Walter
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018033:Antibodies, Bispecific / Q000008:administration & dosage* / Q000009:adverse effects; D017252:CD3 Complex / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D016130:Immunophenotyping; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D018033:Antibodies, Bispecific; D017252:CD3 Complex; D063268:Sialic Acid Binding Ig-like Lectin 3; C587103:AMG 330