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Vascular Targeted Therapy With Anti–Prostate-Specific Membrane Antigen Monoclonal Antibody J591 in Advanced Solid Tumors

Matthew I. Milowsky, David M. Nanus, Lale Kostakoglu, Christine E. Sheehan, Shankar Vallabhajosula, Stanley J. Goldsmith, Jeffrey S. Ross, Neil H. Bander

From the Division of Hematology and Medical Oncology, Department of Medicine, Division of Nuclear Medicine, Department of Radiology, Department of Urology, Weill Medical College of Cornell University, New York; and Department of Pathology and Laboratory Medicine, Albany Medical Center, Albany, NY

Address reprint requests to Neil H. Bander, MD, Weill Medical College of Cornell University, 525 E 68th St, PO Box 23, New York, NY 10021; e-mail: nhbander{at}med.cornell.edu

Purpose Based on prostate-specific membrane antigen (PSMA) expression on the vasculature of solid tumors, we performed a phase I trial of antibody J591, targeting the extracellular domain of PSMA, in patients with advanced solid tumor malignancies. This was a proof-of-principle evaluation of PSMA as a potential neovascular target. The primary end points were targeting,toxicity, maximum-tolerated dose, pharmacokinetics (PK), and human antihuman antibody (HAHA) response.

Patients and Methods Patients had advanced solid tumors previously shown to express PSMA on the neovasculature. They received ¹¹¹Indium (¹¹¹ln)-J591 for scintigraphy and PK, followed 2 weeks later by J591 with a reduced amount of ¹¹¹In for additional PK measurements. J591 dose levels were 5, 10, 20, 40, and 80 mg. The protocol was amended for six weekly administrations of unchelated J591. Patients with a response or stable disease were eligible for re-treatment. Immunohistochemistry assessed PSMA expression in tumor tissues.

Results Twenty-seven patients received monoclonal antibody (mAb) J591. Treatment was well tolerated. Twenty (74%) of 27 patients had at least one area of known metastatic disease targeted by ¹¹¹In-J591, with positive imaging seen in patients with kidney, bladder, lung, breast, colorectal, and pancreatic cancers, and melanoma. Seven of 10 patient specimens available for immunohistochemical assessment of PSMA expression in tumor-associated vasculature demonstrated PSMA staining. No HAHA response was seen. Three patients of 27 with stable disease received re-treatment.

Conclusion Acceptable toxicity and excellent targeting of known sites of metastases were demonstrated in patients with multiple solid tumor types, highlighting a potential role for the anti-PSMA antibody J591 as a vascular-targeting agent.

Supported in part by National Center for Research Resources Grant No. M01RR00047 from the National Institutes of Health's General Clinical Research Center Program, Grant No. DAMD17-98-1-8594 from the US Department of Army, Cancer Research Institute, David H. Koch Foundation, Peter Sacerdote Foundation, Robert McCooey Cancer Research Fund, Laurent and Alberta Gerschel Foundation, the Yablans Family Foundation, and BZL Biologics Inc.

Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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