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Presentation at AACR 2007
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Evaluation of cancer-targeting, pharmacokinetics and antitumor activity of liposomal methotrexate with transferrin ligand, MBP-Y003.

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Tadashi Fujisawa(1), Mieko Nagasawa(1), Chizuko Hashimoto(1), Kazushi Okada(1), Mikihiko Naito(2), Donghyun Kim(1), Daniel D. Von Hoff(3).

(1)Mebiopharm Co., Ltd., Tokyo, Japan, (2)The University of Tokyo, Tokyo, Japan,

(3)Tgen, Phoenix, AZ

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Purpose:

MBP-Y003 is a novel liposomal methotrexate (MTX) modified with N-glutaryl phosphatidylethanolamine (NGPE) to avoid entrapment in the reticuloendothelial system and to enhance retention in blood. Transferrin (Tf) is adopted as a ligand to introduce an active targeting function to the liposome. For evaluating potency of clinical use, we investigated in vitro cancer-targeting, retention in blood in mice and efficacy of MBP-Y003 in human tumor-bearing mice.

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Methods:

Growth inhibitory activity to six kinds of human tumor cell line was compared using Tf conjugated liposomal MTX with non-Tf conjugated liposomal MTX. The binding of Tf of MBP-Y003 to the Tf receptor (Tf-R), and internalization were observed by Confocal Laser Microscopy using human tumor cells. MBP-Y003 and MTX were administered as a single iv dose of 30 mg/kg to evaluate blood retention in normal mice. MTX concentrations were measured in serum by fluorescence polarization immunoassay. The antitumor efficacy of MBP-Y003 (iv) and MTX (ip) was investigated in a human tumor xenograft model at each maximum tolerated dose (MTD) of 5 mg/kg and 45 mg/kg q4d x 3, respectively.

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Results:

Tf conjugated liposomal MTX MBP-Y003 showed higher growth inhibitory activity than non-Tf conjugated liposomal MTX in all cell lines that were tested. Regarding the binding between Tf of MBP-Y003 and Tf-R, at first, the binding of Tf-R and Tf was observed at the cell surfaces, and then internalized into the cytoplasm in a time dependent fashion. AUC0-24h and Cmax of total plasma MTX concentrations in the MBP-Y003 group were significantly higher than those in MTX group. Plasma terminal half-life of MBP-Y003 was also substantially improved compared to the naked MTX. The MBP-Y003 5 mg/kg group showed 89% tumor growth inhibition against PC-3 tumor in nude mice compared with the control group. The antitumor activity achieved with MBP-Y003 was also better than mice treated with standard MTX at 45 mg/kg. No death or change in clinical signs was observed in any group. It was concluded that retention in blood and anti-tumor effects of MBP-Y003 were significantly greater than those of standard MTX.

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Conclusion:

Present results suggest that MBP-Y003 has cancer-targeting activity via Tf - Tf-R interaction. MBP-Y003 has enhanced systemic exposure and efficacy compared to standard MTX at doses that appear well tolerated.


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