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Potent Antitumor Activity of an Auristatin-Conjugated, Fully Human Monoclonal Antibody to Prostate-Specific Membrane Antigen

Authors' Affiliations: ¹ PSMA Development Co. LLC, Tarrytown, New York, and ² Seattle Genetics, Inc., Bothell, Washington

Requests for reprints: Dangshe Ma, Progenics Pharmaceutiques, Inc., 777 Old Saw Mill River Road, Tarrytown, NY, 10591. Phone: 914-789-2800; Fax: 914-789-2807; E-mail: dma{at}progenics.com.

Prostate-specific membrane antigen (PSMA) is the prototypic cell-surface marker of prostate cancer and provides an attractive target for monoclonal antibody (mAb) targeted therapies. In this study, a novel antibody-drug conjugate (ADC) was generated by linking a fully human PSMA mAb to monomethylauristatin E (MMAE), a potent inhibitor of tubulin polymerization. The PSMA ADC was evaluated for antitumor activity in vitro and in a mouse xenograft model of androgen-independent human prostate cancer. The PSMA ADC eliminated PSMA-expressing cells with picomolar potency and >700-fold selectivity in culture. When used to treat mice with established human C4-2 tumors, the PSMA ADC significantly improved median survival 9-fold relative to vehicle or isotype-matched ADC (P = 0.0018) without toxicity. Treatment effects were also manifest as significant (P = 0.0068) reduction in serum levels of prostate-specific antigen (PSA). Importantly, 40% of treated animals had no detectable tumor or measurable PSA at day 500 and could be considered cured. The findings support development of PSMA antibody-auristatin conjugates for therapy of prostate cancer.

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