Reddy, Joseph, Nelson, Melissa, Dircksen, Christina, Vetzel, Marilynn, Johnson, Theresa, Cross, Vicky, Westrick, Elaine, Qi, LongWu, Hahn, Spencer, Santhapuram, Hari Krishna, Parham, Garth, Wang, Kevin, Vaughn, Jeremy F, Pugh, Michael, Lu, June, Klein, Pat, Vlahov, Iontcho and Leamon, Christopher (2020) Pre-clinical studies of EC2629, a highly potent folate- receptor-targeted DNA crosslinking agent. Scientific reports, 10 (1). ISSN 20452322

Abstract

Folate receptor (FR)-targeted small molecule drug conjugates (SMDCs) have shown promising results in early stage clinical trials with microtubule destabilizing agents, such as vintafolide and EC1456. In our effort to develop FR-targeted SMDCs with varying mechanisms of action, we synthesized EC2629, a folate conjugate of a DNA crosslinking agent based on a novel DNA-alkylating moiety. This agent was found to be extremely potent with an in vitro IC50 ~ 100× lower than folate SMDCs constructed with various microtubule inhibitors. EC2629 treatment of nude mice bearing FR-positive KB human xenografts led to cures in 100% of the test animals with very low dose levels (300 nmol/kg) following a convenient once a week schedule. The observed activity was not accompanied by any noticeable weight loss (up to 20 weeks post end of dosing). Complete responses were also observed against FR-positive paclitaxel (KB-PR) and cisplatin (KB-CR) resistant models. When evaluated against FR-positive patient derived xenograft (PDX) models of ovarian (ST070), endometrial (ST040) and triple negative breast cancers (ST502, ST738), EC2629 showed significantly greater anti-tumor activity compared to their corresponding standard of care treatments. Taken together, these studies thus demonstrated that EC2629, with its distinct DNA reacting mechanism, may be useful in treating FR-positive tumors, including those that are classified as drug resistant.

Item Type:	Article
Date Deposited:	01 Sep 2020 00:45
Last Modified:	01 Sep 2020 00:45
URI:	https://oak.novartis.com/id/eprint/41901