In Vivo Structural Activity and Optimization Studies of Folate−Tubulysin Conjugates

Abstract

Herein we report on the potencies of 4 related folate-conjugated tubulysins constructed with either tubulysin B hydrazide (EC0305), tubulysin A hydrazide (EC0510), the N,O-acetal derivative of natural tubulysins (EC0317) or a tubulysin B ester (EC0302). Our results confirmed that EC0305 is the most favorable conjugate of the group due to its potent antitumor activity [100% cures at 1 micromol/kg, three times a week (TIW) for 2 weeks] and its favorably low toxicity profile. In contrast, the natural tubulysin B drug proved to be inactive against a human nasopharyngeal tumor model when administered at doses near to or greater than the maximum tolerated dose (MTD). When tested against more chemoresistant folate receptor expressing M109 and 4T1-cl2 tumors, EC0305 displayed superior antitumor activity over a previously disclosed folate conjugate of desacetylvinblastine monohydrazide (EC145). These studies demonstrate that EC0305 has significant antiproliferative activity against FR expressing tumors, including those which are generally more chemoresistant, and that EC0305 should be considered for development as a candidate for the treatment of advanced FR-expressing human cancers.

Targeting folate receptor alpha for cancer treatment

“…Furthermore, a phase II trial, to compare the efficacy of IMGN853 to standard chemotherapies, is recruiting patients with FRα-positive tumors (NCT02631876). Folate-conjugated carboplatin was not considered a promising therapy due to neutralization by folate receptor-mediated endocytosis [83], but several other microtubule poisons have shown moderate promise in in vitro and in vivo models [84, 85]. …”

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

“…The agent is under investigation as a therapy for other FR þ tumors. EC1456, a conjugate of folic acid with a more potent than vinca alkaloid cytotoxic effector, tubulysin (17), demonstrated strong antitumor activity in human xenograft models (18), and recently entered a phase I study. Farletuzumab (MORAb-003), a humanized anti-FRa monoclonal antibody that was reported to exert antitumor activity through antibody-dependent cellular cytotoxicity and complementdependent cytotoxicity (19), has been evaluated in ovarian cancer patients as a single agent, and in combination with chemotherapy.…”

Sequence‐Defined Oligoamide Drug Conjugates of Pretubulysin and Methotrexate for Folate Receptor Targeted Cancer Therapy

“…The folate receptor (FR) is overexpressed in many types of tumors . Binding folic acid (FolA) and FolA‐derivatives with very high affinity, the FR offers a prominent approach to selectively target FR‐positive cancer cells in targeted drug delivery approaches . A clinical phase I study for the treatment of advanced solid tumors currently assesses a small molecular drug conjugate (SMDC) of FolA with tubulysin…”