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

Department of Medicine, Cornell University, Итак, New York, United States
Journal of Clinical Oncology (Impact Factor: 18.43). 03/2007; 25(5):540-7. DOI: 10.1200/JCO.2006.07.8097
Source: PubMed


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 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.
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.
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.

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    • "It has also been shown that PSMA is involved in tumor angiogenesis of many solid tumors, and it is expressed in the endothelial lumen in tumors. Normal vascular endothelium in non-cancerous tissue is PSMA negative (92, 93). PSMA displays several features that qualify it as a suitable target for immunotherapy. "
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    • "Such agents are presently in multiple Phase II clinical trials for prostate tumors and other cancers (; [25,26]. "
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    • "This deregulation may result in production of prostate specific markers such as the secreted protease prostate-specific antigen (PSA) and the cell surface prostate-specific membrane antigen (PSMA) [4]. A transmembrane glycoprotein expressed in the human prostate parenchyma, from where it was first cloned and named prostate-specific membrane antigen (PSMA) [5] has gained increased attention in diagnosis, monitoring and treatment of PC [6]. PSMA is a metallopeptidase belonging to the peptidase family M28 [7] and has apparent molecular masses of 84-100 kDa [8] with a unique three-part structure: a short cytoplasmic amino terminus that interacts with an actin filament, a single membrane-spanning domain and a large extracellular domain [9]. "
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