ROR1 directed delivery of FTY720 derivative OSU-2S mediates potent cytotoxic activity against chronic lymphocytic leukemia but not normal B cells in-vitro and in ROR1 expressing transgenic CLL mouse model in-vivo (P3275)

Abstract

Abstract ROR1, a member of the receptor tyrosine kinase-like orphan receptor family is expressed in chronic lymphocytic leukemia (CLL) but not normal B cells. We describe here a novel anti-human ROR1 antibody (2A2-IgG) based immunoliposomal delivery system for CLL therapy with improved specificity in vitro and in vivo. 2A2-IgG immobilized onto the surface of the liposomes (2A2-IgG-ILP), was evaluated for targeted delivery of a recently described novel phosphatase activator, OSU-2S. 2A2-IgG-ILP-OSU-2S demonstrated improved cytotoxicity in ROR1 positive CLL cells but not in normal B cells in-vitro. To validate the in-vivo efficacy of the ROR1 directed 2A2-IgG-ILP-OSU-2S, we developed transgenic mice expressing hROR1 on B cells (hROR1 Tg). Crossing the hROR1 Tg mice to the previously described Eμ-Tcl1 CLL mice resulted in double Tg mice with progressive CLL like disease characterized by accumulation of CD5+CD19+ROR1+ B cells. 2A2-IgG-ILP-OSU-2S exhibited selective binding and delivery of OSU-2S to ROR1+ but not ROR1- B cells in-vitro and elimination of circulating ROR1+ B cells in-vivo. Additionally, preliminary pharmacokinetic analysis of the targeted and non-targeted ILP-OSU-2S in the ROR1 transgenic mouse revealed altered pharmacokinetic profiles with 2A2-IgG targeted formulation. These studies validate the ROR1 targeted immunoliposomal formulations and the novel transgenic mouse models for evaluation of therapeutic agents directed to ROR1 positive B cell malignancies.