AACR 2014 Abstract: Pre-clinical development of EC1456: A potent Folate targeted Tubulysin SMDC
Folate targeted small molecule drug conjugates (SMDC) have shown promising results in early stage clinical trials with Vintafolide now being evaluated in a phase 3 trial in FR-positive ovarian cancer patients. We have now developed a new group of folate conjugated Tubulysins, of which EC1456 has emerged as a lead candidate for clinical development. Treatment of nude mice bearing folate receptor (FR) positive human xenografts with EC1456 led to complete remissions (CR’s) or cures in 100% of the mice at various doses and schedules. The observed activity was not accompanied by any noticeable weight loss or major organ tissue degeneration. In contrast, no significant anti-tumor activity (0 % CR’s) was observed in EC1456-treated animals that were co-dosed with an excess of a benign folate ligand, thus demonstrating EC1456’s target-specific activity. The enhanced therapeutic index due to folate conjugation was also evidenced by the fact that the un-targeted free drug (tubulysin B or its hydrazide form) was found to be completely inactive even when administered at highly toxic dose levels. Furthermore, when challenged with larger tumors, EC1456 again displayed remarkable anti-tumor activity with 100% cures in tumors up to 750 mm3. Complete cures were also observed in other FR positive models such as MDA-MB-231 TNBC and M109 lung tumor models. In support of our clinical strategy to treat drug resistant FR-positive cancer patients we have also shown that EC1456 was highly active against FR expressing paclitaxel and cisplatin-resistant cell lines. Taken together, these studies demonstrated that EC1456 has significant anti-tumor growth activity and tolerability, thus lending support to the ongoing Phase 1 clinical evaluation of EC1456 for advanced malignancies.