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 C, Phelps M A, Chen C-S, Lee R J, Byrd J C, Lee L J, Muthusamy N
1] Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA [2] Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA [3] Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA.
1] Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA [2] Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA [3] Center for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, Columbus, OH, USA.
Leukemia. 2015 Feb;29(2):346-55. doi: 10.1038/leu.2014.199. Epub 2014 Jun 20.
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.
在不损害正常细胞的情况下对癌细胞产生选择性细胞毒性，这对传统药物设计构成了巨大挑战。在此，我们开发了一种肿瘤抗原靶向递送的免疫纳米颗粒，其携带一种新型非免疫抑制性FTY720衍生物OSU-2S，对白血病B细胞具有强大的细胞毒性。OSU-2S可诱导蛋白磷酸酶2A（PP2A）的激活、SHP1（S591）的磷酸化和核转位，并导致慢性淋巴细胞白血病（CLL）中多种细胞过程失调，从而产生强大的细胞毒性。为了避免OSU-2S对非靶细胞中这些普遍存在的磷酸酶产生影响并避免潜在的不良反应，我们开发了一种靶向递送OSU-2S的免疫纳米颗粒（2A2-OSU-2S-ILP），它通过靶向白血病B细胞而非正常B细胞中表达的受体酪氨酸激酶ROR1，介导对CLL而非正常B细胞的选择性细胞毒性。通过建立一种新型的在所有白血病B细胞中表达人ROR1（hROR1）的自发性CLL小鼠模型，我们证明了2A2-OSU-2S-ILP在体内具有延长生存期的治疗益处。新开发的非免疫抑制性OSU-2S、利用人CLL导向免疫纳米颗粒对其进行递送以及在白血病B细胞表面仅表达hROR1的新型CLL转基因（Tg）小鼠模型具有高度创新性，可应用于CLL以及其他ROR1阳性恶性肿瘤，包括套细胞淋巴瘤和急性淋巴细胞白血病。
