title: Therapeutic efficacy of c-kit-targeted radioimmunotherapy using 90Y-labeled anti-c-kit antibodies in a mouse model of small cell lung cancer.
abstract: Small cell lung cancer (SCLC) is an aggressive tumor and prognosis remains poor. Therefore, the development of more effective therapy is needed. We previously reported that high levels of an anti-c-kit antibody (12A8) accumulated in SCLC xenografts. In the present study, we evaluated the efficacy of two antibodies (12A8 and 67A2) for radioimmunotherapy (RIT) of an SCLC mouse model by labeling with the (90)Y isotope.
  
  
  METHODS
  (111)In- or (125)I-labeled antibodies were evaluated in vitro by cell binding, competitive inhibition and cellular internalization assays in c-kit-expressing SY cells and in vivo by biodistribution in SY-bearing mice. Therapeutic efficacy of (90)Y-labeled antibodies was evaluated in SY-bearing mice upto day 28 and histological analysis was conducted at day 7.
  
  
  RESULTS
  [(111)In]12A8 and [(111)In]67A2 specifically bound to SY cells with high affinity (8.0 and 1.9 nM, respectively). 67A2 was internalized similar to 12A8. High levels of [(111)In]12A8 and [(111)In]67A2 accumulated in tumors, but not in major organs. [(111)In]67A2 uptake by the tumor was 1.7 times higher than for [(111)In]12A8. [(90)Y]12A8, but not [(90)Y]67A2, suppressed tumor growth in a dose-dependent manner. Tumors treated with 3.7 MBq of [(90)Y]12A8, and 1.85 and 3.7 MBq of [(90)Y]67A2 (absorbed doses were 21.0, 18.0 and 35.9 Gy, respectively) almost completely disappeared approximately 2 weeks after injection, and regrowth was not observed except for in one mouse treated with 1.85 MBq [(90)Y]67A2. The area of necrosis and fibrosis increased depending on the RIT effect. Apoptotic cell numbers increased with increased doses of [(90)Y]12A8, whereas no dose-dependent increase was observed following [(90)Y]67A2 treatment. Body weight was temporarily reduced but all mice tolerated the RIT experiments well.
  
  
  CONCLUSIONS
  Treatment with [(90)Y]12A8 and [(90)Y]67A2 achieved a complete therapeutic response when SY tumors received an absorbed dose greater than 18 Gy and thus are promising RIT agents for metastatic SCLC cells at distant sites.
authors.affiliation: Diagnostic Imaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Chisato
authors.initials: C
authors.lastname: Yoshida
authors.forename: Atsushi B
authors.initials: AB
authors.lastname: Tsuji
authors.forename: Hitomi
authors.initials: H
authors.lastname: Sudo
authors.forename: Aya
authors.initials: A
authors.lastname: Sugyo
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kikuchi
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Koizumi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Arano
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Saga
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019009:Proto-Oncogene Proteins c-kit / Q000276:immunology / Q000378:metabolism*; D016499:Radioimmunotherapy / Q000379:methods*; D055752:Small Cell Lung Carcinoma / Q000628:therapy*; D015021:Yttrium Radioisotopes / Q000627:therapeutic use*
chemical_list: D000911:Antibodies, Monoclonal; D015021:Yttrium Radioisotopes; D019009:Proto-Oncogene Proteins c-kit