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 effective in vivo
cancer 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 apoptosis in 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.