Preclinical Evaluation of EC145, a Folate-Vinca Alkaloid Conjugate

Abstract

We recently developed a new group of folate-conjugated Vinca alkaloids, one of which, EC145, emerged as a candidate for clinical development. Brief treatment of nude mice bearing f100 mm 3 folate receptor-positive human xenografts led to complete response (CR) in 5/5 mice and cures (i.e., remission without a relapse for >90 days post-tumor implantation) in 4/5 mice. Multiple CRs and cures were also noted when EC145 was used to treat mice initially bearing tumors as large as 750 mm 3 . Likewise, complete cures (5/5) resulted following the treatment of an aggressive folate receptor-positive J6456 lymphoma model. The activity of EC145 was not accompanied by noticeable weight loss or major organ tissue degeneration. Furthermore, no significant antitumor activity (0/5 CR) was observed in EC145-treated animals that were co-dosed with an excess of a benign folate ligand, thus demonstrating the target-specific activity of EC145. The enhanced therapeutic index due to folate conjugation was also evidenced by the fact that the unconjugated drug (desacetylvinblastine monohydrazide) was found to be completely inactive when administered at nontoxic dose levels and only marginally active when given at highly toxic dose levels. Subsequent dose regimen studies confirmed that EC145 given on a more frequent, qdx5 schedule resulted in the most effective antitumor response as compared with an equivalent total dose given on thrice-or single-injection-per-week schedule. Taken together, these studies show that EC145 has significant antiproliferative activity and tolerability, thus lending support to an ongoing phase 1 trial for the treatment of advanced malignancies. [Cancer Res 2007;67(9):4434-42]

IMGN853, a Folate Receptor-α (FRα)–Targeting Antibody–Drug Conjugate, Exhibits Potent Targeted Antitumor Activity against FRα-Expressing Tumors

“…Vintafolide is a small-molecule conjugate of folate with a cytotoxic vinca alkaloid, which is selectively internalized into cells through binding and uptake by FRs (14,15). Vintafolide showed promising clinical activity in a randomized phase II study in combination with pegylated liposomal doxorubicin for treatment of FR þ , platinum-resistant, ovarian cancer (16), but a phase III study failed to confirm the clinical benefit of vintafolide in this setting.…”

DOTA Conjugate with an Albumin-Binding Entity Enables the First Folic Acid–Targeted 177Lu-Radionuclide Tumor Therapy in Mice

“…Among these, the most successful approach was the conjugation of folic acid to highly toxic low-molecular-weight chemotherapeutics (5,12). With several of these folate-based drug conjugates, respectable anticancer effects were achieved in preclinical (13)(14)(15)(16) and clinical studies (17). If b 2 -particle-emitting radioisotopes are used for targeted therapy, cancer cells are irradiated not only by decays taking place at or within the targeted cells but also by decays in neighboring or distant cells by the so-called cross-fire effect (18).…”

Folate receptor-α expression in resectable hepatic colorectal cancer metastases: patterns and significance

“…14,15 Several FRa-targeted therapeutic agents have entered into the early-phase human clinical trials for treatment of ovarian cancers, and have shown promising results. [16][17][18][19][20] Data on FRa expression in colorectal carcinomas are limited and FRa-targeted approaches have not been investigated in this cancer. In a previous study utilizing tissue microarray and immunohistochemistry, we analyzed the status of FRa expression in primary colorectal cancers.…”