Background: The abundant expression of prostate specific membrane antigen (PSMA) on prostate cancer cells provides a rationale for antibody therapy. PSMA ADC, a fully human antibody to PSMA linked to the microtubule disrupting agent monomethyl auristatin E (MMAE), binds PSMA and is internalized within the prostate cancer cell where cleavage by lysosomal enzymes release free MMAE, causing cell cycle arrest and apoptosis. We have completed a phase 1 dose escalation study of PSMA ADC in subjects with taxane-refractory mCRPC. Methods: Eligibility requirements include progressive mCRPC following taxane-containing chemotherapy and ECOG status of 0 or 1. PSMA ADC was administered by IV infusion Q3W for up to 4 cycles. Safety, pharmacokinetics (PK), PSA, circulating tumor cells (CTC), clinical disease progression and immunogenicity to PSMA ADC were assessed. Serum PSMA ADC and total antibody were measured by ELISA, and free MMAE was measured by LC/MS/MS.The dosing cohorts ranged from 0.4 mg/kg to 2.8 mg/kg. Results: 52 subjects with mCRPC were dosed in nine dose levels. All subjects received prior docetaxel, 5 also received cabazitaxel and 3 subjects also received paclitaxel. PSMA ADC was generally well tolerated with the most commonly seen adverse events being anorexia and fatigue. Peripheral neuropathy was reported by 7 subjects after repeated doses. Two were grade 3. Dose limiting toxicities (DLT) seen at 2.8 mg/kg were neutropenia (one death) and reversible liver function tests (LFTs) elevations. Antitumor activity was manifested as reductions either in PSA or CTCs at ≥ 1.8 mg/kg PSMA ADC in approximately 50% of patients. Exposure to PSMA ADC increased with dose and was ~1,000-fold greater than MMAE exposure and no accumulation was observed. Conclusions: PSMA ADC in this study was generally well tolerated in doses up to 2.8 mg/kg every three weeks in subjects with mCRPC, previously treated with taxane. Antitumor activity was seen at higher dose levels. DLTs were neutropenia and reversible LFT abnormalities. The maximum tolerated dose of PSMA ADC was determined to be 2.5 mg/kg. A phase 2 trial in taxane refractory mCRPC has been initiated. Clinical trial information: NCT01414283.