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Chronic Lymphocytic Leukemia

Tumor antigen ROR1 targeted drug delivery mediated selective leukemic but not normal B-cell cytotoxicity in chronic lymphocytic leukemia

Leukemia volume 29, pages 346–355 (2015)Cite this article

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Abstract

Selective cytotoxicity to cancer cells without compromising their normal counterparts pose a huge challenge for traditional drug design. Here we developed a tumor antigen-targeted delivery of immunonanoparticle carrying a novel non-immunosuppressive FTY720 derivative OSU-2S with potent cytotoxicity against leukemic B cells. OSU-2S induces activation of protein phosphatase 2A (PP2A), phosphorylation and nuclear translocation of SHP1S591 and deregulation of multiple cellular processes in chronic lymphocytic leukemia (CLL) resulting in potent cytotoxicity. To preclude OSU-2S-mediated effects on these ubiquitous phosphatases in unintended cells and avoid potential adverse effects, we developed an OSU-2S-targeted delivery of immunonanoparticles (2A2-OSU-2S-ILP), that mediated selective cytotoxicity of CLL but not normal B cells through targeting receptor tyrosine kinase ROR1 expressed in leukemic but not normal B cells. Developing a novel spontaneous CLL mouse model expressing human ROR1 (hROR1) in all leukemic B cells, we demonstrate the therapeutic benefit of enhanced survival with 2A2-OSU-2S-ILP in vivo. The newly developed non-immunosuppressive OSU-2S, its delivery using human CLL directed immunonanoparticles and the novel transgenic (Tg) mouse model of CLL that expresses hROR1 exclusively in leukemic B cell surface are highly innovative and can be applied to CLL and other ROR1+ malignancies including mantle cell lymphoma and acute lymphoblastic leukemia.

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Acknowledgements

We are thankful to the patients who supported this research by providing their blood. This work was funded by Leukemia & Lymphoma Society Specialized Center of Research (SCOR) in leukemia grant LLS 7004-11, NCI-P50-CA140158, Harry Mangurian Foundation, D Warren Brown Foundation, Robert J Anthony Fund and NSF grant NSEC EEC-0914790.

Author contributions

RM planned, designed and performed majority of the in vitro and in vivo research, analyzed data, wrote the initial and subsequent drafts of the paper and approved the final version of the paper. YM synthesized and optimized targeted liposomes, designed and performed research, analyzed data, wrote the initial drafts of the paper. FF generated and characterized the ROR1 and ROR1 × TCL1 double Tg mice, assisted with the experiments. CC, JW, YZ, YW, and BY synthesized and characterized targeted liposomes, helped with experiments. RY synthesized OSU-2S. XM and LY participated in designing sample sizes for each experiment, performed the statistical analysis. JCB, JF, JJ, and LA contributed to the CLL patient care, patient sample acquisition and characterization, translation insight to the experimental designs. SB, CR, MAP, RJL and CSC and LJL provided necessary reagents, supported components of the research. NM oversaw the study, sought funding, participated in experimental design and generation of mouse models, data interpretation.

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Author notes

  1. R Mani and Y Mao: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA

    R Mani, F W Frissora, C-L Chiang, J Flynn, J Jones, L Andritsos, J C Byrd & N Muthusamy

  2. Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

    R Mani, Y Mao, F W Frissora, C-L Chiang, J Wang, B Yu, M A Phelps, C-S Chen, R J Lee, J C Byrd & N Muthusamy

  3. Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA

    R Mani, C-S Chen, J C Byrd & N Muthusamy

  4. Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA

    Y Mao, Y Zhao, M A Phelps & R J Lee

  5. Center for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, Columbus, OH, USA

    Y Mao, Y Wu, B Yu, R J Lee & L J Lee

  6. Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA

    R Yan, C-S Chen & J C Byrd

  7. Center for Biostatistics, The Ohio State University, Columbus, OH, USA

    X Mo & L Yu

  8. Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    S Baskar

  9. Department of Cancer Biology and Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL, USA

    C Rader

  10. Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, USA

    L J Lee

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  1. R Mani
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  2. Y Mao
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  11. L Yu
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  20. J C Byrd
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  21. L J Lee
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Corresponding author

Correspondence to N Muthusamy.

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Competing interests

A provisional patent has been filed for the use of OSU-2S to treat hematologic malignancies. The authors declare no additional competing financial interest.

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Supplementary Information accompanies this paper on the Leukemia website

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Mani, R., Mao, Y., Frissora, F. et al. Tumor antigen ROR1 targeted drug delivery mediated selective leukemic but not normal B-cell cytotoxicity in chronic lymphocytic leukemia. Leukemia 29, 346–355 (2015). https://doi.org/10.1038/leu.2014.199

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