Pilot Trial of Unlabeled and Indium-111^Labeled Anti^Prostate- Specific MembraneAntigen AntibodyJ591for Castrate Metastatic Prostate Cancer MichaelJ. Morris, 1,6 Chaitanya R. Divgi, 2,3,4,6 NeetaPandit-Taskar, 2,3 Maria Batraki, 2 NyashaWarren, 4 Angelo Nacca, 3 Peter Smith-Jones, 2 LawrenceSchwartz, 3 W. Kevin Kelly, 1,6 Susan Slovin, 1,6 David Solit, 1,6 Jennifer Halpern, 1 Anthony Delacruz, 1 TracyCurley, 1 Ronald Finn, 3 Joseph A. O’Donoghue, 5 Philip Livingston, 4,6 Steven Larson, 2,3,4,6 and Howard I. Scher 1,6 Abstract Background: Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein primarilyexpressedonbenignandmalignantprostaticepithelialcells.J591isanIgG1monoclonal antibody that targets the external domain of the PSMA. The relationship among dose, safety, pharmacokinetics, and antibody-dependent cellular cytotoxicity (ADCC) activation for unlabeled J591hasnotbeenexplored. Patients and Methods: Patientswithprogressivemetastaticprostate cancerdespiteandrogen deprivation were eligible. Each patient received10, 25, 50, and100 mg ofJ591.Two milligrams of antibody, conjugated with the chelate1,4,7,10-tetraazacyclododecane-N, NV ,N 00 ,N 000 -tetraacetic acid, were labeled with 5 mCi indium-111 ( 111 In) as a tracer. One group of patients received unla- beledJ591before the labeled antibody; the other received both together.Toxicities,pharmacoki- netic properties, biodistribution, ADCC induction, immunogenicity, and clinical antitumor effects wereassessed. Results: Fourteen patients were treated (seven in each group).Treatment was well tolerated. Biodistribution of 111 In-labeledJ591was 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 111 In-labeled J591to 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: J591is 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 and100 mg for immunother- apy. Phase II studies usingJ591as a radioconjugate are under way. Prostate-specific membrane antigen (PSMA) is a 100-kDa type 2 transmembrane glycoprotein found on prostate epithelial cells (1). The protein has short internal and transmembrane domains, each of which is f20 amino acids long. The external domain, which is comprised of over 700 amino acids, is much larger and is responsible for its enzymatic action as a hydrolase (2). PSMA is present on both benign and malignant prostatic tissue and is expressed across the entire spectrum of the natural history of prostate cancer, from localized to metastatic disease. Expression increases following androgen withdrawal and is only minimally expressed in nonprostate tissues (3 – 6). For these reasons, antibodies against PSMA have been developed for both diagnostic and therapeutic purposes. Monoclonal antibodies can potentially treat prostate cancer either by inducing antibody-dependent cellular cytotoxicity (ADCC) using unla- beled antibody, or as carriers of radioactivity or chemotherapy. One such antibody is termed J591 (MLN591, Millennium Pharmaceuticals, Cambridge, MA), a monoclonal IgG1 mole- cule that targets the external domain of PSMA (7). To abrogate the possibility of inducing anti-J591 antibody responses in patients, J591 was ‘‘deimmunized‘‘ (DeImmunisation, Biova- tion Ltd., Aberdeen, United Kingdom) by replacing individual amino acid sequences in the antibody variable domains to Cancer Therapy: Clinical 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 Received 4/14/05; revised 6/12/05; accepted 7/15/05. Grant support: National Cancer Institute grants CA 102544 and CA 05826, Prostate Cancer Foundation, Sacerdote Fund, PepsiCo Foundation for Prostate Cancer, Mr.William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Cancer Foundation for Research, and Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center. The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Requests for reprints: Michael J. Morris, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 444, NewYork, NY 10021. Phone: 646-422-4469; Fax: 212-988-0701; E-mail: morrism@ mskcc.org. F 2005 American Associationfor Cancer Research. doi:10.1158/1078-0432.CCR-05-0826 www.aacrjournals.org Clin Cancer Res 2005;11(20) October15, 2005 7454 Research. on July 15, 2020. © 2005 American Association for Cancer clincancerres.aacrjournals.org Downloaded from