title: Novel Targeted Therapy for Precursor B Cell Acute Lymphoblastic Leukemia: anti-CD22 Antibody-MXD3 Antisense Oligonucleotide Conjugate.
abstract: The exponential rise in molecular and genomic data has generated a vast array of therapeutic targets. Oligonucleotide-based technologies to down regulate these molecular targets have promising therapeutic efficacy. However, there is relatively limited success in translating this into effectivein vivocancer therapeutics. The primary challenge is the lack of effective cancer cell-targeted delivery methods, particularly for a systemic disease such as leukemia. We developed a novel leukemia-targeting compound composed of a monoclonal antibody directly conjugated to an antisense oligonucleotide (ASO). Our compound uses an ASO that specifically targets the transcription factor MAX dimerization protein 3 (MXD3), which was previously identified to be critical for precursor B cell (preB) acute lymphoblastic leukemia (ALL) cell survival. The MXD3 ASO was conjugated to an anti-CD22 antibody (αCD22 Ab) that specifically targets most preB ALL. We demonstrated that the αCD22 Ab-ASO conjugate treatment showed MXD3 protein knockdown and leukemia cell apoptosisin vitro. We also demonstrated that the conjugate treatment showed cytotoxicity in normal B cells, but not in other hematopoietic cells, including hematopoietic stem cells. Furthermore, the conjugate treatment at the lowest dose tested (0.2mg/kg Ab for 6 doses - twice a week for 3 weeks) more than doubled the mouse survival time in both Reh (median survival time 20.5 vs. 42.5 days, p<0.001) and primary preB ALL (median survival time 29.3 vs. 63 days, p<0.001) xenograft models. Our conjugate that uses αCD22 Ab to target the novel molecule MXD3, which is highly expressed in preB ALL cells, appears to be a promising novel therapeutic approach.
authors.affiliation: Department of Pediatrics.|Stem Cell Program.
authors.forename: Noriko
authors.initials: N
authors.lastname: Satake
authors.affiliation: Department of Pediatrics.|Stem Cell Program.
authors.forename: Connie
authors.initials: C
authors.lastname: Duong
authors.affiliation: Department of Pediatrics.|Stem Cell Program.
authors.forename: Sakiko
authors.initials: S
authors.lastname: Yoshida
authors.affiliation: Isis Pharmaceuticals.
authors.forename: Michael
authors.initials: M
authors.lastname: Oestergaard
authors.affiliation: Department of Pediatrics.|Stem Cell Program.
authors.forename: Cathy
authors.initials: C
authors.lastname: Chen
authors.affiliation: Isis Pharmaceuticals.
authors.forename: Rachael
authors.initials: R
authors.lastname: Peralta
authors.affiliation: Isis Pharmaceuticals.
authors.forename: Shuling
authors.initials: S
authors.lastname: Guo
authors.affiliation: Isis Pharmaceuticals.
authors.forename: Punit P
authors.initials: PP
authors.lastname: Seth
authors.affiliation: Department of Public Health Sciences.
authors.forename: Yueju
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Public Health Sciences.
authors.forename: Laurel
authors.initials: L
authors.lastname: Beckett
authors.affiliation: Department of Pediatrics.
authors.forename: Jong
authors.initials: J
authors.lastname: Chung
authors.affiliation: Stem Cell Program.
authors.forename: Jan
authors.initials: J
authors.lastname: Nolta
authors.affiliation: Departments of Food Science & Technology and Biological & Agricultural Engineering.
authors.forename: Nitin
authors.initials: N
authors.lastname: Nitin
authors.affiliation: Department of Internal Medicine, University of California, Davis.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Tuscano
keywords: biochemistry; cell biology; gene expression; molecular biology; oncology; pediatrics