title: Pretargeted radioimmunotherapy in tumored mice using an in vivo 212Pb/212Bi generator.
abstract: OBJECTIVE
  Pretargeting is the concept that combines optimal delivery of the antibody and rapid capture and elimination of the radioactivity. In this study, we evaluated the potential of antibody pretargeting to enable the tumor-targeting (212)Pb for in vivo generation of (212)Bi for alpha particle radiotherapy.
  
  
  METHODS
  The (212)Pb/(212)Bi chelate of DOTA-biotin, as well as their gamma-emitting analogues, (203)Pb and (205)Bi, was prepared and characterized. The radiolabeled compounds were injected in animals for evaluation of tumor targeting and normal tissue uptake and retention. In the pretargeting protocol, injection of 400 microg of NR-LU-10 antibody-streptavidin conjugate was given at t = 0 h, then 100 microg of N-acetyl-galatosamine-biotin clearing agent was injected at t = 20-24 h; finally, 1 microg of (212)Pb/(212)Bi-DOTA-biotin was injected 6 h later.
  
  
  RESULTS
  Both (203)Pb and (205)Bi-DOTA-biotin were stable for at least 4 days in the different challenging solutions including PBS, 10 mM DTPA and serum. Contrary to its gamma-emitting analogues, radiolabeled (212)Pb-DOTA-biotin was not stable. There was greater than 30% of free (212)Bi released 4 h after (212)Pb-labeled DOTA-biotin. The results of pretargeting protocol of (203)Pb and (205)Bi-DOTA-biotin showed that the tumor target reached 20% injected dose (ID)/g at 4 h postinjection and remained high for 5 days. The %ID/g in the whole blood and other nontarget organs was low after administration of labeled (203)Pb and (205)Bi-DOTA-biotin similar to the biodistribution of labeled DOTA-biotin alone. In the animals administered (212)Pb-DOTA-biotin, radioactivity in nontarget organs was low except the kidneys. The %ID/g in the kidney for (212)Bi was 14.5 at 2 h, higher than (212)Pb, but dropped to about 6% ID/g by 4 h. However, tumor uptake for (212)Pb and (212)Bi was >25% ID/g at 1 h postinjection and remained so through 24 h.
  
  
  CONCLUSIONS
  Antibody pretargeting system with Mab-streptavidin, clearing agent and DOTA-biotin provides the potential of (212)Bi for solid tumor radiotherapy despite the release of (212)Bi after (212)Pb decay. Dosimetry calculations resulted in tumor dose at 93 rad/muCi and ratios of tumor to marrow and kidney at 386:1 and 12:1, respectively.
authors.affiliation: NeoRx Corp., Seattle, WA 98119, USA.
authors.forename: Fu-Min
authors.initials: FM
authors.lastname: Su
authors.forename: Paul
authors.initials: P
authors.lastname: Beaumier
authors.forename: Don
authors.initials: D
authors.lastname: Axworthy
authors.forename: Robert
authors.initials: R
authors.lastname: Atcher
authors.forename: Alan
authors.initials: A
authors.lastname: Fritzberg
mesh_terms: D000818:Animals; D001710:Biotin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001729:Bismuth / Q000493:pharmacokinetics* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000532:radiotherapy; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D007856:Lead Radioisotopes / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D009928:Organ Specificity; D009942:Organometallic Compounds / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016499:Radioimmunotherapy / Q000379:methods*; D011868:Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: C405616:DOTA-biotin; D007856:Lead Radioisotopes; D009942:Organometallic Compounds; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D001710:Biotin; D001729:Bismuth