BERKELEY, CA (UroToday.com) - Despite the recent introduction of new treatment options for advanced prostate cancer, metastatic disease remains incurable and claims the lives of more than 200,000 men annually worldwide.(1)
No conventional chemotherapy has demonstrated a survival advantage with the exception of the taxanes docetaxel and cabazitaxel, and no treatment regimen has demonstrated a surivival benefit beyond approximately 4 months. There is an urgent need for new treatment strategies.
Antibody-drug conjugates (ADCs) represent an emerging mode of cancer therapy.(2) ADCs combine the molecular targeting of monoclonal antibodies (mAbs) with the potent cell-killing properties of chemotherapeutic agents. ADCs are designed to selectively deliver chemotherapeutic agents to antigen-expressing tumors, while potentially reducing toxicity towards healthy cells and tissues. Following progressive improvements in drug-linker chemistry, newer ADCs have shown promising single-agent activity and tolerability in patients who are refractory to standard therapies.(3, 4)
Prostate-specific membrane antigen (PSMA) is the prototypic cell-surface marker of prostate cancer.(5) PSMA is an integral membrane glycoprotein that is expressed ubiquitously in prostate cancer, and its expression increases with disease progression and androgen suppression. In contrast, PSMA has limited expression in normal tissues other than prostate. These and other properties make PSMA an attractive target for ADC therapy of prostate cancer.(6)
In this report,(7) we preclinically evaluated the antitumor spectrum of PSMA ADC, which comprises a fully human anti-PSMA mAb that is linked to monomethylauristatin E (MMAE), a potent antitubulin agent.(8) In vitro, PSMA ADC exhibited potent cytotoxicity against prostate cancer cells that express PSMA, and cytotoxicity was dependent upon proper folding, glycosylation and internalization of PSMA. PSMA ADC was up to 9,000-fold more potent against cells with abundant PSMA expression (~105 copies per cell) than against PSMA-negative cells, and 104 copies per cell represented a threshold level of PSMA expression for selective cell killing in vitro. In contrast, the unconjugated anti-PSMA mAb showed no intrinsic cytotoxic activity in this study, and free MMAE showed no selectivity for PSMA-positive v. PSMA-negative cells (Figure 1).
We also examined the in vivo activity of this agent in a novel xenograft model of androgen-independent, taxane-refractory prostate cancer. PSMA ADC was highly active in treating animals whose tumors that had progressed to up to 700 mm3 in size while receiving docetaxel. Treatment with PSMA ADC resulted in significant tumor regressions and a significant survival benefit relative to continued treatment with docetaxel. No overt toxicity was noted in animals treated with PSMA ADC, whereas weight loss was associated with docetaxel treatment. The findings underscore the potential benefits of targeted therapies and are relevant to the ongoing clinical investigation of PSMA ADC in taxane-refractory prostate cancer.(9)
Figure 1. Cytotoxicity of PSMA ADC and free MMAE against prostate cancer cells with varying levels of PSMA expression. From left the right, the cells are PC-3, DU145, CWR22rv1, PC-3 transfected with PSMA, C4-2, LNCaP and MDA Pca2b. Unconjugated PSMA mAb did not exhibit cytotoxicity at a concentration of 1,000 nM.
- Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277-300.
- Alley SC, Okeley NM, Senter PD. Antibody-drug conjugates: targeted drug delivery for cancer. Curr Opin Chem Biol 2010;14:529-37.
- Younes A, Bartlett NL, Leonard JP, Kennedy DA, Lynch CM, Sievers EL, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 2010;363:1812-21.
- Burris HA, III, Rugo HS, Vukelja SJ, Vogel CL, Borson RA, Limentani S, et al. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2) -positive breast cancer after prior HER2-directed therapy. J Clin Oncol 2011;21:398-405.
- Ghosh A, Heston WD. Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer. J Cell Biochem 2004;91:528-39.
- Olson WC, Heston WDW, Rajasekaran AK. Clinical trials of cancer therapies targeting prostate-specific membrane antigen. Reviews on Recent Clinical Trials 2007;2:182-90.
- Wang X, Ma D, Olson WC, Heston WD. In vitro and in vivo responses of advanced prostate eumors to PSMA ADC, an auristatin-conjugated antibody to prostate-specific membrane antigen. Mol Cancer Ther 2011, epub ahead of print.
- Ma D, Donovan GP, Gardner JP, Schulke N, Cohen M, Morrissey DM, et al. Fully human anti-PSMA monocloncal antibodies for immunotherapy of metastatic prostate cancer. Cancer Biotherapy & Radiopharmaceuticals 2002;17:484.
- Petrylak D, Kantoff PW, Rotshteyn Y, Israel RJ, Olson WC, Ramakrishna T, et al. Prostate-specific membrane antigen antibody-drug conjugate (PSMA ADC): A phase 1 trial in taxane refractory prostate cancer. 2011 ASCO Genitourinary Cancers Symposium, Abstract #72560, Orlando, FL, February 17-19, 2011.
William Olson, PhD and Warren Heston, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.