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Updated: Mar 17, 2026
Analyzing Tumor and Tissue Distribution of Target Antigen Specific Therapeutic Antibody
Published on: May 16, 2020
Novel Targeted Therapy for Precursor B Cell Acute Lymphoblastic Leukemia: anti-CD22 Antibody-MXD3 Antisense
Noriko Satake1,2, Connie Duong1,2, Sakiko Yoshida1,2
1Department of Pediatrics.
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 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.
Insights
A novel antibody-oligonucleotide conjugate targets the MXD3 molecule in leukemia cells, significantly improving survival in preclinical models. This targeted approach offers a promising new strategy for treating precursor B cell acute lymphoblastic leukemia.
Area of Science:
- Oncology
- Molecular Biology
- Immunotherapy
Background:
- Advances in genomic data reveal numerous therapeutic targets for cancer.
- Oligonucleotide-based therapies show promise but face challenges in effective in vivo delivery, especially for systemic diseases like leukemia.
- Targeted delivery remains a critical hurdle for translating molecular therapies into effective cancer treatments.
Purpose of the Study:
- To develop a novel targeted delivery system for leukemia therapeutics.
- To investigate the efficacy of an antisense oligonucleotide (ASO) targeting MAX dimerization protein 3 (MXD3) conjugated to an anti-CD22 antibody (αCD22 Ab) for precursor B cell acute lymphoblastic leukemia (preB ALL).
Main Methods:
- Conjugation of an MXD3-targeting ASO to an αCD22 Ab.
- In vitro assessment of conjugate-mediated MXD3 protein knockdown and leukemia cell apoptosis.
- In vivo evaluation of conjugate efficacy and toxicity in preB ALL xenograft mouse models.
Main Results:
- The αCD22 Ab-ASO conjugate effectively reduced MXD3 protein levels and induced apoptosis in leukemia cells in vitro.
- The conjugate demonstrated specific cytotoxicity towards normal B cells, sparing other hematopoietic cells, including stem cells.
- Treatment with the conjugate significantly increased survival rates in both Reh and primary preB ALL xenograft models, more than doubling median survival time.
Conclusions:
- The developed αCD22 Ab-MXD3 ASO conjugate represents a promising targeted therapeutic strategy for preB ALL.
- Targeting the highly expressed MXD3 molecule in preB ALL cells via this novel conjugate shows significant therapeutic potential.
- This approach addresses the challenge of targeted delivery for oligonucleotide-based therapies in leukemia treatment.
