The Broad Anti-AML Activity of the CD33/CD3 BiTE Antibody Construct, AMG 330, Is Impacted by Disease Stage and Risk.

Kimberly H Harrington,Roland B Walter,Guang Chen,George S Laszlo,Angus M Sinclair,Roman Kischel,Chelsea J Gudgeon,Stanley R Frankel,Kathryn J Newhall,Ken Mills

doi:10.1371/journal.pone.0135945

Kimberly H Harrington, Roland B Walter + Show 8 more

Open Access

https://doi.org/10.1371/journal.pone.0135945

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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.

Highlights

Over the last several decades, the outcomes for many patients with acute myeloid leukemia (AML) have significantly improved
Among the few novel drugs have shown a benefit in randomized trials is the CD33 antibody-drug conjugate, gemtuzumab ozogamicin (GO), which has shown to improve survival in subsets of patients when added to intensive induction chemotherapy [6, 7]
Interest in this therapeutic approach has been renewed with the demonstration that very low doses of the CD19/CD3 bispecific T-cell engaging (BiTE) antibody construct, blinatumomab, can eliminate target cells in patients with non-Hodgkin’s lymphomas [22]

Summary

Introduction

Over the last several decades, the outcomes for many patients with acute myeloid leukemia (AML) have significantly improved Much of this progress is due to advances in supportive care, which have rendered curative-intent chemotherapy and allogeneic hematopoietic cell transplantation (HCT) safer and paved the way for intensified treatment algorithms [1,2,3]. Despite these improvements, a large proportion of AML patients is currently still expected to die of their disease or treatment-related complications. Together with drug transporter activity in AML cells, such limitations may explain why GO is ineffective in many patients and is currently no longer commercially available in most countries [4, 5]

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