Scientific Reports (Jul 2020)

Pre-clinical studies of EC2629, a highly potent folate- receptor-targeted DNA crosslinking agent

  • Joseph A. Reddy,
  • Melissa Nelson,
  • Christina Dircksen,
  • Marilynn Vetzel,
  • Theresa Johnson,
  • Vicky Cross,
  • Elaine Westrick,
  • LongWu Qi,
  • Spencer Hahn,
  • Hari Krishna Santhapuram,
  • Garth Parham,
  • Kevin Wang,
  • Jeremy F. Vaughn,
  • Albert Felten,
  • Michael Pugh,
  • June Lu,
  • Patrick Klein,
  • Iontcho R. Vlahov,
  • Christopher P. Leamon

DOI
https://doi.org/10.1038/s41598-020-69682-9
Journal volume & issue
Vol. 10, no. 1
pp. 1 – 13

Abstract

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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.