title: Pretargeted alpha emitting radioimmunotherapy using (213)Bi 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid-biotin.
abstract: OBJECTIVE
  The use of an alpha emitter for radioimmunotherapy has potential advantages compared with beta emitters. When administered systemically optimal targeting of intact antibodies requires >24 h, therefore limiting the use of short-lived alpha emitters. This study investigated the biodistribution of bismuth-labeled biotin in A431 tumor-bearing mice pretargeted with antibody B3-streptavidin (B3-SA) and examined the therapeutic efficacy of the alpha emitter, (213)Bi-labeled biotin.
  
  
  METHODS
  Biotinidase-resistant 7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA)-biotin was radiolabeled with (205,206)Bi or (213)Bi. Treatment of tumor-bearing mice began by administration of B3-SA (400 micro g) to target the tumor sites for 24 h. Then, an agent containing biotin and galactose groups was used to clear the conjugate from the circulation. Four h later, bismuth-radiolabeled DOTA-biotin was given, and biodistribution or therapy was evaluated. Dose escalation treatment from 3.7-74 MBq was performed, and the effects on tumors of different sizes were investigated. Tumor growth, complete blood cell counts, toxicity, and survival were monitored.
  
  
  RESULTS
  Radiolabeled biotin cleared rapidly. Rapid tumor uptake resulted in much higher tumor:nontumor targeting ratios than achieved with the directly labeled monoclonal antibody. Dose escalation revealed that 74 MBq caused acute death of mice, whereas 0.37-37 MBq doses inhibited tumor growth and prolonged survival significantly. Evidence of mild hematological toxicity was noted. At therapeutically effective doses renal toxicity was observed.
  
  
  CONCLUSIONS
  (213)Bi-DOTA-biotin, directed by the Pretarget method to tumor-targeted B3-SA, showed a therapeutic effect, although the therapeutic index was low. The source of the toxicity was most likely related to the renal toxicity.
authors.affiliation: Department of Nuclear Medicine, Warren G. Magnuson Clinical Center, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Zhengsheng
authors.initials: Z
authors.lastname: Yao
authors.forename: Meili
authors.initials: M
authors.lastname: Zhang
authors.forename: Kayhan
authors.initials: K
authors.lastname: Garmestani
authors.forename: Donald B
authors.initials: DB
authors.lastname: Axworthy
authors.forename: Robert W
authors.initials: RW
authors.lastname: Mallett
authors.forename: Alan R
authors.initials: AR
authors.lastname: Fritzberg
authors.forename: Lou J
authors.initials: LJ
authors.lastname: Theodore
authors.forename: Paul S
authors.initials: PS
authors.lastname: Plascjak
authors.forename: William C
authors.initials: WC
authors.lastname: Eckelman
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Waldmann
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
authors.forename: Chang H
authors.initials: CH
authors.lastname: Paik
authors.forename: Martin W
authors.initials: MW
authors.lastname: Brechbiel
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Carrasquillo
mesh_terms: D000512:Alpha Particles / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000493:pharmacokinetics; D001710:Biotin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001729:Bismuth / Q000737:chemistry / Q000493:pharmacokinetics; D001853:Bone Marrow / Q000473:pathology / Q000528:radiation effects; D045744:Cell Line, Tumor; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006801:Humans; D007668:Kidney / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009942:Organometallic Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016499:Radioimmunotherapy / Q000009:adverse effects / Q000379:methods*; D011868:Radioisotopes; D013154:Spleen / Q000473:pathology / Q000528:radiation effects; D016019:Survival Analysis; D013997:Time Factors; D014018:Tissue Distribution; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; C405616:DOTA-biotin; D009942:Organometallic Compounds; D011868:Radioisotopes; D001710:Biotin; D001729:Bismuth