ANG1005, a new therapeutic drug able to cross the blood-brain barrier for the treatment of brain cancers.

LB-108 In the present study, we have investigated the utilization of a new peptide based drug delivery technology that provides a non-invasive and flexible platform for transporting drugs into the central nervous system. We have demonstrated that this family of peptides (Angiopeps) is able to physiologically cross the blood-brain barrier (BBB) as seen by in-vivo imaging in mice using a fluorescent marker cy 5.5 conjugated to an Angiopep peptide, and by in-situ brain perfusion. Based on this discovery, we have created several new drug entities, the most advanced of which is ANG1005 formed by chemical conjugation of the peptide vector (Angiopep-2) to three molecules of paclitaxel. Paclitaxel, which is normally restricted from brain, is transported very efficiently across the BBB after conjugation to Angiopep-2. Its rate of transport is 50 to 80 times higher than that of free paclitaxel measured using in-situ brain perfusion in rats. ANG1005 is also detected by LC-MS-MS analysis in normal brain and brain tumors in mice 30 minutes after IV injection at level of 300 nM which is above the therapeutic level of paclitaxel. ANG1005 inhibits cancer cell proliferation of various cell lines in vitro ; its cytotoxicity is comparable to paclitaxel with an IC 50 of 10 nM. ANG1005 is 3.5 times better tolerated than paclitaxel in single-dose rodent toxicity studies. In addition, the conjugate of paclitaxel to Angiopep (ANG1005) bypasses the drug efflux pump P-glycoprotein, which is highly expressed at the BBB. Based upon the higher distribution of ANG1005 in brain tumors, the effect of ANG1005 was evaluated on glioblastoma (U87) xenograft tumor growth in immune deficient mice. In this model, administration of ANG1005 reduced tumor growth in a dose-dependent manner.
 ANG1005 is currently under evaluation in two phase 1/2 clinical trials for the treatment of primary and secondary brain tumors in humans.
 Overall, these results indicate that conjugation of paclitaxel to Angiopep-vector could increase its efficacy against primary or metastatic brain cancers.