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Issue 1, 2013
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Rational design of an immunoconjugate for selective knock-down of leukemia-specific E2A–PBX1 fusion gene expression in human Pre-B leukemia

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Abstract

The t(1;19)(q23;p13) is one of the most common chromosomal translocations in acute lymphoblastic leukemia (ALL) and results in production of the transforming oncoprotein E2A–PBX1. Here we first report a novel, biomarker-guided biotherapy strategy for personalized treatment of t(1;19)+ ALL. A supervised interrogation of the gene expression profiles of primary leukemic cells from a cohort of 207 children with high risk B-lineage ALL identified up-regulated CD19 gene expression as a biomarker for t(1;19)+ ALL. A disulfide-linked immunoconjugate of a 5-amino-modified 24 mer phosphorothioate anti-sense E2A–PBX1 oligonucleotide (AON) with a mAb specific for a CD19 receptor (αCD19–AON) was prepared as a CD19-directed and leukemia-specific biotherapeutic agent against E2A–PBX1+ B-lineage ALL. Treatment of E2A–PBX1+ leukemia cells with low nanomolar concentrations of αCD19–AON resulted in selective depletion of E2A–PBX1 transcripts and caused apoptotic destruction and abrogation of clonogenic growth. Subcutaneously administered αCD19–AON at a total dose level of 93 nmol kg−1 delivered over 14 days using a micro-osmotic pump more than doubled the leukemia-free survival time of SCID mice in a xenograft model of E2A–PBX1+ human B-lineage ALL (82.0 ± 1.9 days vs. 37.0 ± 0.1 days, P < 0.0001). Both the AON moiety and the targeting CD19-specific mAb moiety were required for the in vitro as well as in vivo anti-leukemic activity of αCD19–AON. The observed in vitro and in vivo anti-leukemic potency of the αCD19–AON immunoconjugate provides the first preclinical proof-of-principle that t(1;19)+ high risk B-lineage ALL can be treated with leukemia-specific biotherapeutic agents that knock-down E2A–PBX1 expression.

Graphical abstract: Rational design of an immunoconjugate for selective knock-down of leukemia-specific E2A–PBX1 fusion gene expression in human Pre-B leukemia

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Article information


Submitted
10 May 2012
Accepted
16 Aug 2012
First published
18 Sep 2012

Integr. Biol., 2013,5, 122-132
Article type
Paper

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