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

Academic Article
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Overview

authors

  • Mani, R.
  • Mao, Y.
  • Frissora, F. W.
  • Chiang, C. L.
  • Wang, J.
  • Zhao, Y.
  • Wu, Y.
  • Yu, B.
  • Yan, R.
  • Mo, X.
  • Yu, L.
  • Flynn, J.
  • Jones, J.
  • Andritsos, L.
  • Baskar, S.
  • Rader, Christoph
  • Phelps, M. A.
  • Chen, C. S.
  • Lee, R. J.
  • Byrd, J. C.
  • Lee, L. J.
  • Muthusamy, N.

publication date

  • February 2015

journal

  • Leukemia  Journal

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 SHP1(S591) 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.

subject areas

  • Animals
  • Apoptosis
  • B-Lymphocytes
  • Cell Line, Tumor
  • Cell Survival
  • Drug Delivery Systems
  • Fingolimod Hydrochloride
  • Humans
  • Immunosuppressive Agents
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Liposomes
  • Lymphoma, Mantle-Cell
  • Mice
  • Mice, Transgenic
  • Nanoparticles
  • Oligonucleotide Array Sequence Analysis
  • Phosphorylation
  • Propylene Glycols
  • Protein Kinase C
  • Receptor Tyrosine Kinase-like Orphan Receptors
  • Sphingosine
  • Treatment Outcome
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Identity

PubMed Central ID

  • PMC4272672

International Standard Serial Number (ISSN)

  • 0887-6924

Digital Object Identifier (DOI)

  • 10.1038/leu.2014.199

PubMed ID

  • 24947019
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Additional Document Info

start page

  • 346

end page

  • 355

volume

  • 29

issue

  • 2

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