title: Evaluation of [(111/114m)In]CHX-A''-DTPA-ZHER2:342, an affibody ligand coniugate for targeting of HER2-expressing malignant tumors.
abstract: OBJECTIVE
  Radionuclide imaging of the HER2 receptor, which is a target for trastuzumab therapy, can provide important diagnostic information. Further, targeting radionuclide therapy might be an option for treatment of HER2 expressing tumors. The phage-display selected Affibody ligand Z(HER2:342), which binds to HER2 with an affinity of 22 pM, may here play an important role. The small size of the Z(HER2:342), 7.5 kDa, enables quick tumor localization and fast blood clearance. Earlier, successful targeting of HER2-expressing xenografts using Z(HER2:342) labeled using [(111)In]benzyl-DTPA was reported. By changing to the CHX-A''-DTPA chelator, the stability and labeling kinetics of the radiometal-Z(HER2:342) conjugate can be improved. The aim of this study was to evaluate the labeling of the CHX-A''-DTPA-Z(HER2:342) conjugate with (111)In for diagnostic imaging and with (114m)In for locoregional radionuclide therapy.
  
  
  METHODS
  The isothiocyanate derivative of CHX-A''-DTPA was coupled to Z(HER2:342) in alkaline conditions at 37 degrees C. The conjugate was labeled with both (111)In and (114m)In and evaluated in vitro and in vivo.
  
  
  RESULTS
  Labeling with (111)In and (114m)In provided >95% yield after 30 min at RT. Specific radioactivity was 0.5 and 12 MBq/nmol, for (114m)In and (111)In, respectively. The radiolabeled conjugates demonstrated specific binding to HER2 expressing SKOV-3 cells. In mice bearing SKOV-3 xenografts, the tumor uptake of [(111)In]CHX-A''-DTPA-Z(HER2:342) 4 h postinjection was 10.3+/-3.6% IA/g and tumor-to-blood ratio about 190.
  
  
  CONCLUSIONS
  [(111)In]CHX-A''-DTPA-Z(HER2:342) is a promising candidate for the visualization of HER2 expression in malignant tumors. Labeled with (114m)In it could also be used for locoregional treatment of HER2 expressing tumors.
authors.affiliation: Affibody AB, Bromma, Sweden. anna.orlova@bms.uu.se
authors.forename: A
authors.initials: A
authors.lastname: Orlova
authors.forename: D
authors.initials: D
authors.lastname: Rosik
authors.forename: M
authors.initials: M
authors.lastname: Sandström
authors.forename: H
authors.initials: H
authors.lastname: Lundqvist
authors.forename: L
authors.initials: L
authors.lastname: Einarsson
authors.forename: V
authors.initials: V
authors.lastname: Tolmachev
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002470:Cell Survival / Q000528:radiation effects; D005260:Female; D008024:Ligands; D008657:Metabolic Clearance Rate; D051379:Mice; D009928:Organ Specificity; D010051:Ovarian Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000532:radiotherapy*; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D011878:Radiotherapy / Q000379:methods*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D008024:Ligands; D004369:Pentetic Acid; D019275:Radiopharmaceuticals; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; C529081:111In-CHX-A''-DTPA-Z(HER2;342) affibody