title: Rational design of an immunoconjugate for selective knock-down of leukemia-specific E2A-PBX1 fusion gene expression in human Pre-B leukemia.
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.
authors.affiliation: Developmental Therapeutics Program, Children's Hospital Los Angeles, Children's Center for Cancer and Blood Diseases, Los Angeles, CA 90027, USA.
authors.forename: Fatih M
authors.initials: FM
authors.lastname: Uckun
authors.forename: Sanjive
authors.initials: S
authors.lastname: Qazi
authors.forename: Ilker
authors.initials: I
authors.lastname: Dibirdik
authors.forename: Dorothea E
authors.initials: DE
authors.lastname: Myers
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000276:immunology*; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D015195:Drug Design; D055785:Gene Knockdown Techniques / Q000379:methods*; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D051379:Mice; D016513:Mice, SCID; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000276:immunology*; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D018796:Immunoconjugates; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; C407909:TCF3 protein, human; C083400:PBX1 protein, human