title: Development of positron emission tomography probe of 64Cu-labeled anti-C-kit 12A8 Fab to measure protooncogene C-kit expression.
abstract: BACKGROUND
  C-kit is an important diagnostic and therapeutic target molecule for several malignancies, and c-kit-targeted drugs have been used clinically. Because abundant c-kit expression in tumors is a prerequisite for successful c-kit-targeted therapy, imaging of c-kit expression is expected to play a pivotal role in the therapeutic decision for each patient. We evaluated (64)Cu-labeled Fab of anti-c-kit antibody 12A8 as a positron emission tomography (PET) imaging probe.
  
  
  METHODS
  (111)In- or (125)I-Labeled 12A8 Fab was evaluated in vitro by cell binding, competitive inhibition and cellular internalization assays, and in vivo by biodistribution in mice bearing c-kit-expressing and -non-expressing tumors. Next, Fab fragment was labeled with the positron emitter (64)Cu and evaluated by PET.
  
  
  RESULTS
  Radiolabeled 12A8 Fab showed specific binding to c-kit-expressing cells with high affinity and internalized into cells after binding to c-kit on cell surface. Although tumor accumulation of [(111)In]Fab was lower than that of [(111)In]IgG, the faster blood clearance of [(111)In]Fab provided higher tumor-to-blood ratio at 6 h postinjection onwards. Blood clearance of (64)Cu-labeled 12A8 Fab was slower than that of [(111)In]Fab, but PET using [(64)Cu]Fab clearly visualized the tumor at 6 h postinjection onwards.
  
  
  CONCLUSIONS
  The (64)Cu-labeled 12A8 Fab could be used for c-kit-specific PET imaging and might help in selecting appropriate patients for c-kit-targeted treatments.
authors.affiliation: Diagnostic Imaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555, 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: Chizuru
authors.initials: C
authors.lastname: Sogawa
authors.forename: Masayuki
authors.initials: M
authors.lastname: Inubushi
authors.forename: Tomoya
authors.initials: T
authors.lastname: Uehara
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Fukumura
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 / Q000276:immunology / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D003301:Copper Radioisotopes; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D007205:Indium Radioisotopes; D007457:Iodine Radioisotopes; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D019009:Proto-Oncogene Proteins c-kit / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D003301:Copper Radioisotopes; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D007205:Indium Radioisotopes; D007457:Iodine Radioisotopes; D019009:Proto-Oncogene Proteins c-kit