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.
Highlights
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
Similar to other folate-based SMDCs, E C262922 (Fig. 1a) was constructed using a modular d esign[23]. It contains the tumor-targeting ligand, folate, a hydrophilic peptide-polyethylene glycol (PEG) spacer consisting of L-Asp-L-Glu-L-Cys-PEG4, a self-immolative penicillamine protected disulfide and the pro-drug form of the potent-PBD dimer
The affinity of EC2629 for the FR was evaluated using a relative affinity assay that measures the ability of EC2629 to compete with folic acid for binding to cell surface FRs and further internalization
Summary
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. 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 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. In an attempt to reduce toxicity, antibody drug conjugates (ADCs) of PBD’s have been designed, combining the potent antitumor activity of the PBD dimer with the targeting ability of the antibody Two such agents under clinical evaluation are vadastuximab talirine and rovalpituzumab tesirine (Rova-T) that target CD33a in AML and DLL3 in SCLC, r espectively[20,21]. We report on our detailed in vivo investigation of a folate pro-PBD dimer conjugate (EC2629), with particular emphasis on effectively targeting and eradicating FR-expressing conventional, PDX and drug resistant tumors
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