Prostate specific membrane antigen (PSMA) is the single most well-validated prostate cancer
(PCa)-specific cell membrane antigen known. It is present in high levels in 95% of PCa, and is an
ideal target to develop radiopharmaceuticals for imaging studies and radionuclide therapy. Humanized
J591 monoclonal antibody (mAb) binds specifically with nanomolar affinity to the extracellular domain
of PSMA. After binding, the PSMA–antibody complex is rapidly internalized, increasing the potential
utility of PSMA as a target for the delivery of mAb-conjugated radionuclides or cytotoxins.
J591 mAb was labeled with 177Lu at a high specific activity (10-30 mCi/mg) using DOTA as the bifunctional
chelate. The preclinical data in PSMA positive xenografts, strongly suggested that 177Lu-J591 mAb is an ideal
radiopharmaceutical for RIT of metastatic PCa. Since October 2000, five clinical studies (phase I and II) were performed
in subjects with metastatic castration-resistant prostate cancer (CRPC) using 177Lu-J591. The methodology and the results
of these clinical studies are briefly reviewed in this article.
The maximum tolerated dose (MTD) as a single dose was 70 mCi/m2. Based on dose fractionation (DF), MTD was 90
mCi/m2 (2 doses of 45 mCi/m2, 2 wks apart). Phase II study in patients with progressive metastatic CRPC, at a dose of 65-
70 mCi/m2 resulted in significant PSA declines in 60% of the patients. While myelosuppression was the dose limiting toxicity,
DF alone or in combination with docetaxel also resulted in significant PSA declines with much less toxicity. 177Lu
imaging studies demonstrated accurate targeting of known metastatic sites in >90% of patients and those with stronger
PSMA expression by semi-quantitative imaging had more PSA declines. These clinical studies clearly documented the
potential therapeutic value of radioimmunotherapy (RIT) in metastatic PCa.