Abstract 2145: PSMA-specific anti-tumor activity of the targeted-tubulysin conjugate, EC1169

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-04, Vol.73 (8_Supplement), p.2145-2145
• Main Authors: Reddy, Joseph A., Bloomfield, Alicia, Dorton, Ryan, Nelson, Melissa, Vetzel, Marilynn, Hahn, Spencer, Vlahov, Iontcho, Leamon, Christopher
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2013-2145

Prostate-specific membrane antigen (PSMA) is a biomarker that is overexpressed on prostate cancer, and it's also present on the neovasculature within many non-prostate solid tumors. We previously reported on EC0652, a 99mTc-labeled small molecule that specifically binds to PSMA-positive tumors and is currently being clinically evaluated for diagnostic imaging applications. Herein, we report on the construction and biological testing of novel tubulysin B-containing, companion therapeutic agents for the treatment of PSMA-expressing cancer. One of these compounds, EC1169, recently emerged as a lead candidate for preclinical development. This water-soluble conjugate was shown to have high affinity for PSMA-positive cells. When tested in vitro, EC1169 was found to inhibit the growth of PSMA-positive cells, but it displayed no activity against PSMA-negative cells. Brief treatment of nude mice bearing PSMA-positive LNCaP human xenografts with EC1169 led to complete remissions in 5/7 mice, and cures (i.e. tumor free >90 days post implantation) in 2/7 mice. Furthermore, this activity occurred in the absence of weight loss or major organ tissue degeneration. In contrast, the non-targeted tubulysin B drug proved to be inactive against the LNCaP tumor model when administered at doses near to or greater than the maximum tolerated level. PSMA-negative KB tumors did not appreciably respond to EC1169 therapy, thereby confirming this compound's targeted specificity for PSMA-expressing cells. Finally, treatment of LNCaP-bearing mice with docetaxel (the most active chemotherapeutic agent approved for prostate cancer), was found to produce only modest anti-tumor activity (2/4 partial responses, 1/4 cures), and this outcome was also associated with severe weight loss (18%). Taken together, these results strongly indicate that PSMA-positive tumors may be more effectively treated using highly potent, PSMA-targeted small-molecule drug conjugates using regimens that do not cause unwanted toxicity. Citation Format: Joseph A. Reddy, Alicia Bloomfield, Ryan Dorton, Melissa Nelson, Marilynn Vetzel, Spencer Hahn, Iontcho Vlahov, Christopher Leamon. PSMA-specific anti-tumor activity of the targeted-tubulysin conjugate, EC1169. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2145. doi:10.1158/1538-7445.AM2013-2145