title: Radiolabeled monoclonal antibodies specific to the extracellular domain of prostate-specific membrane antigen: preclinical studies in nude mice bearing LNCaP human prostate tumor.
abstract: Prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein, is highly expressed by virtually all prostate cancers. PSMA is also expressed on the tumor vascular endothelium of virtually all solid carcinomas and sarcomas but not on normal vascular endothelium. PSMA is currently the focus of several diagnostic and therapeutic strategies. We have previously reported on the radiolabeling and in vitro binding properties of monoclonal antibodies (mAbs) (J415, J533, and J591) that recognize and bind with high affinity to the extracellular domain of PSMA (PSMA(ext)). This article reports on the in vivo behavior and tumor uptake of (131)I- and (111)In-labeled antiPSMA(ext) mAbs (J415, J533, and J591) and their potential utility for radioimmunotherapy.
  
  
  METHODS
  In nude mice bearing PSMA-positive human LNCaP tumors, the pharmacokinetics, biodistribution, and tumor uptake of these antibodies was compared with (111)In-7E11 mAb, specific to the intracellular domain of PSMA (PSMA(int)). Autoradiographic studies were done to identify intratumoral distribution of radiolabeled mAbs.
  
  
  RESULTS
  With (131)I-labeled antibodies, the net tumor retention of radioactivity by day 6 was significantly higher with J415 (15.4% +/- 1.1%) and 7E11 (14.5% +/- 1.7%) than with J591 (9.58% +/- 1.1%). By contrast, the tumor uptake of (111)In-1,4,7,10-tetraazacyclododecane-N,N',N", N"'-tetraacetic acid-labeled J415 and J591 gradually increased with time and was quite similar to that of 7E11. In addition, the blood clearance of (111)In-labeled J415 and J591 antibodies was relatively faster than that of radiolabeled 7E11. As a consequence, the tumor-to-blood ratios with J415 and J591 were higher than that of 7E11. The localization of radiolabeled anti-PSMA(ext) antibodies in PSMA-positive LNCaP tumors was highly specific because the tumor uptake of (131)I-labeled J415 and J591 was more than twice that of a nonspecific antibody. Furthermore, the tumor uptake of (131)I-J591 was almost 20 times higher in PSMA-positive LNCaP tumors than in PSMA-negative PC3 and DU145 tumor xenografts. Autoradiographic studies suggested that 7E11 (anti-PSMA(int)) distinctly favors localization to areas of necrosis whereas J415 and J591 (anti-PSMA(ext)) demonstrated a distinct preferential accumulation in areas of viable tumor.
  
  
  CONCLUSIONS
  These results clearly demonstrate that PSMA-specific internalizing antibodies such as J415 and J591 may be the ideal mAbs for the development of novel therapeutic methods to target the delivery of beta-emitting radionuclides ((131)I, (90)Y, and (177)Lu) for the treatment of PSMA-positive tumors. In addition, because J591 and J415 mAbs are specific to PSMA(ext), thus targeting viable tumor, these immunoconjugates are better candidates for targeted radioimmunotherapy than are antibodies targeting PSMA(int).
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, New York Presbyterian Hospital-Weill Medical College of Cornell University, New York, NY 10021, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Smith-Jones
authors.forename: Shankar
authors.initials: S
authors.lastname: Vallabhajosula
authors.forename: Vincent
authors.initials: V
authors.lastname: Navarro
authors.forename: Diego
authors.initials: D
authors.lastname: Bastidas
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Goldsmith
authors.forename: Neil H
authors.initials: NH
authors.lastname: Bander
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000954:Antigens, Surface; D002268:Carboxypeptidases / Q000378:metabolism*; D043425:Glutamate Carboxypeptidase II; D006801:Humans; D007205:Indium Radioisotopes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009928:Organ Specificity; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism*; D011859:Radiography; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D012016:Reference Values; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D007205:Indium Radioisotopes; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D002268:Carboxypeptidases; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II