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

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