title: Radioimmunotherapy of a human lung cancer xenograft with monoclonal antibody RS7: evaluation of (177)Lu and comparison of its efficacy with that of (90)Y and residualizing (131)I.
abstract: Tumor targeting and therapeutic efficacy of (177)Lu-labeled monoclonal antibody (mAb) RS7 (antiepithelial glycoprotein-1) was evaluated in a human nonsmall cell lung carcinoma xenograft model. The potential of (177)Lu-labeled RS7 was compared with that of RS7 labeled with (90)Y and a residualizing form of (131)I.
  
  
  METHODS
  A 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA) conjugate of RS7 was used for radiolabeling with (177)Lu-acetate or (88/90)Y-acetate. Biodistribution and therapy studies were conducted in nude mice with subcutaneous Calu-3 xenografts. Therapy studies were performed using the maximal tolerated doses (MTDs) of (90)Y-DOTA-RS7 (3.9 MBq [105 microCi]) and (177)Lu-DOTA-RS7 (10.2 MBq [275 microCi]) and compared with the data obtained using the MTD (13.0 MBq [350 microCi]) of a residualizing form of (131)I-RS7.
  
  
  RESULTS
  Radiolabeling of RS7-DOTA conjugate with (177)Lu-acetate was facile. (177)Lu-DOTA-RS7 displayed biodistribution results that were nearly identical to that of the (88)Y analog in a paired-label study. The mean percentage injected doses per gram (%ID/g) for (177)Lu-RS7 and (88)Y-RS7 (in parentheses) in tumor were 38.3 %ID/g (39.1 %ID/g), 63.0 %ID/g (66.0 %ID/g), 63.0 %ID/g (65.8 %ID/g), and 34.0 %ID/g (34.9 %ID/g) on days 1, 3, 7, and 14, respectively. Elimination of established tumors, with an initial mean tumor volume of 0.24 cm(3), was shown using doses of (177)Lu-DOTA-RS7 ranging from 5.6 to 9.3 MBq (150--250 microCi) per nude mouse, with no significant difference in response rate noted between the doses in this range. Specificity of the therapeutic effect was shown in an isotype-matched control experiment, in which (177)Lu-DOTA-RS7 was markedly more effective than the (177)Lu-DOTA control antibody. A comparison of the therapeutic efficacies of (177)Lu-DOTA-RS7 and (90)Y-DOTA-RS7, using mice with established tumors with an initial mean tumor volume of 0.85 cm(3), indicated similar tumor growth inhibition and similar tumor regrowth profiles. The therapy data were similar to those obtained with residualizing (131)I-RS7 obtained at the same time.
  
  
  CONCLUSIONS
  (177)Lu-RS7 is an effective radioimmunoconjugate for radioimmunotherapy. With its radiophysical properties similar to those of (131)I, coupled with its facile and stable attachment to mAb, (177)Lu promises to be an alternative to (131)I, and a complement to (90)Y, in radioimmunotherapy.
authors.affiliation: Garden State Cancer Center, Belleville NJ 07109, USA.
authors.forename: R
authors.initials: R
authors.lastname: Stein
authors.forename: S V
authors.initials: SV
authors.lastname: Govindan
authors.forename: S
authors.initials: S
authors.lastname: Chen
authors.forename: L
authors.initials: L
authors.lastname: Reed
authors.forename: H
authors.initials: H
authors.lastname: Richel
authors.forename: G L
authors.initials: GL
authors.lastname: Griffiths
authors.forename: H J
authors.initials: HJ
authors.lastname: Hansen
authors.forename: D M
authors.initials: DM
authors.lastname: Goldenberg
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006023:Glycoproteins / Q000276:immunology; D006573:Heterocyclic Compounds, 1-Ring; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000532:radiotherapy*; D008187:Lutetium / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D016499:Radioimmunotherapy; D011868:Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D015021:Yttrium Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000911:Antibodies, Monoclonal; D006023:Glycoproteins; D006573:Heterocyclic Compounds, 1-Ring; D007457:Iodine Radioisotopes; D011868:Radioisotopes; D015021:Yttrium Radioisotopes; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D008187:Lutetium