Lodamin, the oral formulation of TNP-470, a methionine aminopeptidase 2 (MetAp2) inhibitor, was previously shown to significantly inhibit angiogenesis and suppress the progression of fast growing murine tumors. Lodamins’ unique structure as a polymer micelle composed of poly(ethylene-glycol)-poly(lactic)acid (PEG-PLA) conjugate of TNP-470 is pharmacologically advantageous over the non-conjugated form. It shows better stability, oral availability, solubility in water and importantly, has an improved safety profile (Benny O. Folkman J et al, Nat Biotech, 2008). We now report the successful large scale synthesis of Lodamin, yielding pure and active product composed of mPEG-PLA-TNP-470 conjugate without residual free drug as confirmed by NMR and LC-MS/MS. The safety profile of Lodamin was studied in an acute high dose rat study (4 fold higher than therapeutic dose). Lodamin was administered at 10mg/kg or 60mg/kg via oral gavage while control rats were given vehicle only. After 7 days of daily treatment, no changes in body weight or behavior were observed compared to the control group. On day 8 post treatment, gross pathology of all rats was examined. This data showed Lodamin treatment had no adverse effect on tissue morphology. Lodamin is a potent antiangiogenic drug in numerous in vivo murine models including the corneal micropocket assay, matrigel assay, Delayed-Type Hypersensitivity (DTH) reaction and the choroidal neovascularization (CNV) model (Benny O. Folkman J et al, Nat Biotech, 2008, Benny O. D'Amato R et al, Plos One 2010). We now show that in addition to its dramatic anti-cancer effects on Lewis lung carcinoma and B16F10 melanoma murine tumors, Lodamin suppresses human tumors induced in nude mice. The volume of subcutaneous (s.c) human glioblastoma (U87MG) xenografts were reduced by 70% after 30 days, and 71% after 45 days when administered by gavage or in drinking water, respectively. Human breast tumor (MDA-MB231, s.c) growth was inhibited by 62% after 47 days of administration, and Human hepatocarcinoma (HepG2, s.c) tumor growth was inhibited by 60% after only 12 days. Taken together we have established Lodamin as a potent antiangiogenic drug which retains TNP-470 activity without TNP-470-associated side effects. Lodamin is a safe and efficacious drug in our animal models and hopefully will be reintroduced for the treatment of cancer in patients.

Citation Format: Ofra Benny, Lauren Bazinet, Robert D'Amato. Oral antiangiogenic therapy suppresses xenograft growth and is well tolerated in rats. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2140. doi:10.1158/1538-7445.AM2013-2140