The objective of this Phase II SBIR grant is to advance the development of EC72, a novel folate-targeted drug conjugate that can safely deliver covalently attached mitomycin C (MMC) specifically to folate receptor (FR)-positive tumors in vivo. EC72 offers a number of advantages over standard chemotherapy agents. It is small (mw = 937), highly water soluble, tumor-targetable (via folate), and capable of releasing the active MMC drug upon entry into the target cell by an endocytic process. Plus, recent data strongly indicate that EC72 is not toxic to major organs, including the FR-positive kidneys and the bone marrow, and it can also manifest synergistic anti-proliferative activity in vivo when dosed in combination with Taxol. To facilitate the continued development of EC72, the following six Phase II specific aims are proposed: (1) determine EC72's pharmacokinetic tissue distribution, metabolism and excretion profile in mice as well as serum protein binding properties, (2) conduct additional pre-clinical pharmacology studies in mice to correlate therapeutic efficacy with respect to the tumor's net folate receptor expression level, (3) complete GLP toxicology studies required by the FDA to support Phase I clinical trials, (4) validate an LC/MS/MS method for measuring EC72 levels in human serum, (5) manufacture cGMP-grade drug products and conduct stability testing, and (6) submit an IND for EC72. ? ? ?
| Leamon, Christopher P; Reddy, Joseph A; Vlahov, Iontcho R et al. (2007) Preclinical antitumor activity of a novel folate-targeted dual drug conjugate. Mol Pharm 4:659-67 |
| Vlahov, Iontcho R; Santhapuram, Hari Krishna R; Wang, Yu et al. (2007) An assembly concept for the consecutive introduction of unsymmetrical disulfide bonds: synthesis of a releasable multidrug conjugate of folic acid. J Org Chem 72:5968-72 |
| Reddy, Joseph A; Westrick, Elaine; Vlahov, Iontcho et al. (2006) Folate receptor specific anti-tumor activity of folate-mitomycin conjugates. Cancer Chemother Pharmacol 58:229-36 |
