Radioimmunotherapy of Metastatic Prostate Cancer with ¹⁷⁷Lu-DOTAhuJ591 Anti Prostate Specific Membrane Antigen Specific Monoclonal Antibody

Title:Radioimmunotherapy of Metastatic Prostate Cancer with ¹⁷⁷Lu-DOTAhuJ591 Anti Prostate Specific Membrane Antigen Specific Monoclonal Antibody

Volume: 9 Issue: 1

Author(s): Shankar Vallabhajosula, Anastasia Nikolopoulou, Yuliya S. Jhanwar, Gurveen Kaur, Scott T. Tagawa, David M. Nanus, Neil H. Bander and Stanley J. Goldsmith

Affiliation:

Keywords: ¹⁷⁷Lu-DOTA-huJ591 mAb, Castaration-resistant prostate cancer (CRPC), Prostate specific membrane antigen (PSMA), Radioimmunotherapy (RIT).

Abstract: 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.

Cite this article as:

Vallabhajosula Shankar, Nikolopoulou Anastasia, Jhanwar S. Yuliya, Kaur Gurveen, Tagawa T. Scott, Nanus M. David, Bander H. Neil and Goldsmith J. Stanley, Radioimmunotherapy of Metastatic Prostate Cancer with ¹⁷⁷Lu-DOTAhuJ591 Anti Prostate Specific Membrane Antigen Specific Monoclonal Antibody, Current Radiopharmaceuticals 2016; 9 (1) . https://dx.doi.org/10.2174/1874471008666150313114005