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Pilot Trial of Unlabeled and Indium-111–Labeled Anti–Prostate-Specific Membrane Antigen Antibody J591 for Castrate Metastatic Prostate Cancer

Authors' Affiliations: ¹ Genitourinary Oncology Service, Department of Medicine; ² Nuclear Medicine Service, Department of Radiology; ³ Department of Radiology; ⁴ Clinical Immunology Service, Department of Medicine; ⁵ Department of Medical Physics, Memorial Sloan-Kettering Cancer Center; and ⁶ Department of Medicine, Weill Medical College of Cornell University, New York, New York

Requests for reprints: Michael J. Morris, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 444, New York, NY 10021. Phone: 646-422-4469; Fax: 212-988-0701; E-mail: morrism{at}mskcc.org.

Background: Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein primarily expressed on benign and malignant prostatic epithelial cells. J591 is an IgG1 monoclonal antibody that targets the external domain of the PSMA. The relationship among dose, safety, pharmacokinetics, and antibody-dependent cellular cytotoxicity (ADCC) activation for unlabeled J591 has not been explored.

Patients and Methods: Patients with progressive metastatic prostate cancer despite androgen deprivation were eligible. Each patient received 10, 25, 50, and 100 mg of J591. Two milligrams of antibody, conjugated with the chelate 1,4,7,10-tetraazacyclododecane-N, N',N'',N'''-tetraacetic acid, were labeled with 5 mCi indium-111 (¹¹¹In) as a tracer. One group of patients received unlabeled J591 before the labeled antibody; the other received both together. Toxicities, pharmacokinetic properties, biodistribution, ADCC induction, immunogenicity, and clinical antitumor effects were assessed.

Results: Fourteen patients were treated (seven in each group). Treatment was well tolerated. Biodistribution of ¹¹¹In-labeled J591 was comparable in both groups. The mean T_1/2 was .96, 1.9, 2.75, and 3.47 days for the 10, 25, 50, and 100 mg doses, respectively. Selective targeting of ¹¹¹In-labeled J591 to tumor was seen. Hepatic saturation occurred by the 25-mg dose. ADCC activity was proportional to dose. One patient showed a >50% prostate-specific antigen decline.

Conclusions: J591 is well tolerated in repetitive dose-escalating administrations. The rate of serum clearance decreases with increasing antibody mass. ADCC activation is proportional to antibody mass. The optimal dose is 25 mg for radioimmunotherapy and 100 mg for immunotherapy. Phase II studies using J591 as a radioconjugate are under way.

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