PSMA is a highly restricted cell-surface protein whose expression is increased with grade, stage, and attenuated AR signaling. J591 is a mAb against the external domain of PSMA and has demonstrated safety in numerous human-studies with anti-tumor activity when radiolabeled and conjugated with drug, with PSA and CTC declines. It was originally engineered to elicit antibody-dependent cellular cytotoxicity (ADCC) and we have made 2 important options leading to the current prospective clinical trials. First, studies of 177Lu-J591 have demonstrated >90% CTC control. While initially thought to represent delivery of 177Lu into CTCs and tumors, we retrospectively observed 4 of 7 patients with CTC count decline with a small amount (20 mg) of J591 without an effector molecule when used for imaging. Second, we analyzed long-term follow up from a 2001 study in men with biochemically recurrent or metastatic CRPC where men received unlabeled J591 plus low dose IL-2. Using validated nomograms, pen with biochemical relapse survived a median on 87 months longer than predicted without metastatic disease and in the pre-docetaxel era, men with mCRPC lived a median of 28.5 months longer than predicted. Based upon the preliminary data pointing towards CTC clearance and long-term survival, we have launched 2 prospective clinical trials.
In study 1 [NCT02552394], men with progressive mCRPC by PCWG2 criteria and unfavorable CTC counts (>5 by CellSearch) on a stable hormonal regimen will receive a single dose of J591 in dose de-escalation cohorts followed by an expansion cohort at the lowest dose level with >4 of 6 men responding (i.e. achieve CTC 4 of the initial 10 men achieve the primary endpoint of peri-tumoral inflammation, an additional 20 will be treated. Additional endpoints include ADCC and lymphocyte subset analysis. Both studies include 89Zr-J591 PET/CT (pre- and post-therapy for the mCRPC CTC study and pre-op for the prostatectomy study). Each study has received IRB and FDA clearance and have begun enrollment.
Clinical trial identification
Clinicaltrials.gov NCT02552394 and NCT02693860
Legal entity responsible for the study
Weill Cornell Medicine
N. Bander: Patent holder for J591.
All other authors have declared no conflicts of interest.