Drug-free macromolecular therapeutics induce apoptosis of patient chronic lymphocytic leukemia cells
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A new drug-free nanotherapeutic approach for B-cell malignancies was developed. Exposure of B-cells to an anti-CD20 Fab’-morpholino oligonucleotide1 (MORF1) conjugate decorated the cell surface with MORF1; further exposure of the decorated cells to multivalent polymer-oligonucleotide2 conjugates (P-MORF2) resulted in CD20 clustering at the cell surface with induction of apoptosis. We evaluated this concept in chronic lymphocytic leukemia (CLL) cells isolated from ten patients. Apoptosis and cytotoxicity were observed in eight samples, including two samples with the 17p13 deletion, which suggested a p53-independent mechanism of apoptosis induction. When compared to an anti-CD20 monoclonal antibody (mAb), the nanotherapeutic showed significantly more potent apoptosis-inducing activity and cytotoxicity. This was due to the multivalency effect (eight binding sites per polymer chain) of our design in comparison to the divalent mAb. In conclusion, we have developed a novel and potent therapeutic system against CLL and other B-cell malignancies with significant advantages over conventional chemoimmunotherapy.
KeywordsCLL B-cell CD20 Apoptosis HPMA copolymer Nanomedicine
This work was supported in part by NIH grant GM95606 (to J.K.) from the National Institute of General Medical Sciences and the University of Utah Research Foundation. The authors thank Dr. Ruozhen Hu for assisting with cell cycle analysis and Dr. Jiyuan Yang and Dr. Rui Zhang for helpful discussions.
Conflict of interest
J.K. and T.-W.C. are inventors on a pending US patent application (PCT/US2014/023784; assigned to the University of Utah) related to this work. J.K. is Chief Scientific Advisor and P.J.S. Chief Medical Advisor for Bastion Biologics. Otherwise, the authors declare no relevant financial interests.
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study.
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