Introduction: Prostate-specific membrane antigen (PSMA) is an attractive target for antibody-targeted therapy of prostate cancer due to its abundant and selective expression on the surface of prostate cancer cells. We have generated a novel antibody-drug conjugate (ADC) by linking a fully human PSMA monoclonal antibody to monomethylauristatin-E (MMAE), a potent tubulin inhibitor. Here, we describe the use of PSMA ADC to treat SCID mice bearing LNCaP xenografts or LuCaP explants derived from surgical resections of prostate cancer patients.

Methods: PSMA expression in LNCaP and LuCaP tumor cells was evaluated by flow cytometry. Activity of PSMA ADC, assessed by decrease in tumor volume, was evaluated in LNCaP xenograft and LuCaP explant models. SCID mice were implanted subcutaneously with cultured LNCaP tumor cells or disaggregated human LuCaP 70 or LuCaP 77 prostate tumor tissue obtained from tumor-bearing mice. When average tumor size reached ∼300mm3, animals were randomized into groups of 9-10 mice and each animal was treated with a single intravenous dose of vehicle control, a control ADC of irrelevant specificity, or PSMA ADC. Treatment effects were assessed by measuring tumor volume and overall survival for up to 41 days post-treatment.

Results: Surface expression of PSMA was assessed by flow cytometry, with a rank order of expression as follows: LNCaP > LuCaP 70, LuCaP 77, LuCaP 105 > LuCaP 96.1 > LuCaP 35V, LuCaP 141. Single-dose PSMA ADC demonstrated significant activity against LNCaP xenografts at a dose of 5 mg/kg (p<0.0001 relative to either vehicle or control ADC) and against LuCaP 77 explants at a dose of 10 mg/kg (p=0.0003 relative to either vehicle or control ADC). A trend toward delayed tumor growth was observed in the LuCaP 70 tumor model.

Conclusion: Single-dose PSMA ADC showed activity against LNCaP xenografts and LuCaP explants derived from surgical resections of prostate cancer patients.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3668. doi:10.1158/1538-7445.AM2011-3668