Radioimmunotherapy of prostate cancer in human xenografts using monoclonal antibodies specific to prostate specific membrane antigen (PSMA): studies in nude mice.
BACKGROUND
Prostate specific membrane antigen (PSMA), expressed by virtually all prostate cancers is an ideal target for targeted therapy of prostate cancer. Radiolabeled J591 monoclonal antibody (MAb) binds with high affinity to an extracellular epitope of PSMA and localizes specifically in PSMA positive LNCaP tumors in vivo.


METHODS
Pre-clinical radioimmunotherapy (RIT) studies using (131)I-huJ591 and (90)Y-1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA)-huJ591 MAbs were studied in nude mice bearing LNCaP xenografts.


RESULTS
A 15-90% reduction in mean tumor volume was observed after a single dose of (131)I-huJ591 (3.7-11.1 MBq) or (90)Y-DOTA-huJ591 (3.7-7.4 MBq). The median survival time increased 2-3 times relative to untreated controls. Multiple administrations of fractionated doses of (90)Y-DOTA-huJ591 were even more effective with minimal toxicity. Radiation dose to blood and tumor was higher with (90)Y than with (131)I. The maximum tolerated dose (MTD) is 5.55 MBq for (90)Y-DOTA-huJ591 and more than 11.1 MBq for (131)I-huJ591. For (90)Y-DOTA-huJ591 at MTD, dose to the tumor was 2,753 cGy.


CONCLUSIONS
In nude mice bearing PSMA positive tumors, radiation dose to the tumor with (90)Y-DOTA-J591 is greater for large tumors than with (131)I-J591. The theoretical and practical considerations strongly suggest that (90)Y-DOTA-huJ591 may be a suitable radiopharmaceutical for the treatment of prostate cancer.
Vallabhajosula
Shankar
S
Department of Radiology, New York Presbyterian Hospital, Weill Medical College of Cornell University, New York, New York 10021, USA. svallabh@med.cornell.edu
Smith-Jones
Peter M
PM
Navarro
Vincent
V
Goldsmith
Stanley J
SJ
Bander
Neil H
NH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000954:Antigens, Surface / Q000276:immunology*; D002614:Chelating Agents / Q000008:administration & dosage; D043425:Glutamate Carboxypeptidase II / Q000276:immunology*; D006573:Heterocyclic Compounds, 1-Ring / Q000008:administration & dosage; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000276:immunology / Q000628:therapy* / Q000662:veterinary; D016499:Radioimmunotherapy / Q000379:methods* / Q000662:veterinary; D011897:Random Allocation; D016019:Survival Analysis; D014183:Transplantation, Heterologous; D015021:Yttrium Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D002614:Chelating Agents; D006573:Heterocyclic Compounds, 1-Ring; D007457:Iodine Radioisotopes; D015021:Yttrium Radioisotopes; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II