title: HER2-positive tumors imaged within 1 hour using a site-specifically 11C-labeled Sel-tagged affibody molecule.
abstract: A rapid, reliable method for distinguishing tumors or metastases that overexpress human epidermal growth factor receptor 2 (HER2) from those that do not is highly desired for individualizing therapy and predicting prognoses. In vivo imaging methods are available but not yet in clinical practice; new methodologies improving speed, sensitivity, and specificity are required.
  
  
  METHODS
  A HER2-binding Affibody molecule, Z(HER2:342), was recombinantly fused with a C-terminal selenocysteine-containing tetrapeptide Sel-tag, allowing site-specific labeling with either (11)C or (68)Ga, followed by biodistribution studies with small-animal PET. Dosimetry data for the 2 radiotracers were compared. Imaging of HER2-expressing human tumor xenografts was performed using the (11)C-labeled Affibody molecule.
  
  
  RESULTS
  Both the (11)C- and (68)Ga-labeled tracers initially cleared rapidly from the blood, followed by a slower decrease to 4-5 percentage injected dose per gram of tissue at 1 h. Final retention in the kidneys was much lower (>5-fold) for the (11)C-labeled protein, and its overall absorbed dose was considerably lower. (11)C-Z(HER2:342) showed excellent tumor-targeting capability, with almost 10 percentage injected dose per gram of tissue in HER2-expressing tumors within 1 h. Specificity was demonstrated by preblocking binding sites with excess ligand, yielding significantly reduced radiotracer uptake (P = 0.002), comparable to uptake in tumors with low HER2 expression.
  
  
  CONCLUSIONS
  To our knowledge, the Sel-tagging technique is the first that enables site-specific (11)C-radiolabeling of proteins. Here we present the finding that, in a favorable combination between radionuclide half-life and in vivo pharmacokinetics of the Affibody molecules, (11)C-labeled Sel-tagged Z(HER2:342) can successfully be used for rapid and repeated PET studies of HER2 expression in tumors.
authors.affiliation: Division of Molecular Biotechnology, School of Biotechnology, AlbaNova University Center, Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Wållberg
authors.forename: Jonas
authors.initials: J
authors.lastname: Grafström
authors.forename: Qing
authors.initials: Q
authors.lastname: Cheng
authors.forename: Li
authors.initials: L
authors.lastname: Lu
authors.forename: Hanna-Stina
authors.initials: HS
authors.lastname: Martinsson Ahlzén
authors.forename: Erik
authors.initials: E
authors.lastname: Samén
authors.forename: Jan-Olov
authors.initials: JO
authors.lastname: Thorell
authors.forename: Katarina
authors.initials: K
authors.lastname: Johansson
authors.forename: Finn
authors.initials: F
authors.lastname: Dunås
authors.forename: Maria Hägg
authors.initials: MH
authors.lastname: Olofsson
authors.forename: Sharon
authors.initials: S
authors.lastname: Stone-Elander
authors.forename: Elias S J
authors.initials: ES
authors.lastname: Arnér
authors.forename: Stefan
authors.initials: S
authors.lastname: Ståhl
mesh_terms: D000818:Animals; D002250:Carbon Radioisotopes; D002294:Carcinoma, Squamous Cell / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D005710:Gallium Radioisotopes; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007553:Isotope Labeling; D051379:Mice; D008958:Models, Molecular; D010051:Ovarian Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D049268:Positron-Emission Tomography / Q000379:methods*; D011487:Protein Conformation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D017279:Selenocysteine; D013997:Time Factors
chemical_list: D002250:Carbon Radioisotopes; D005710:Gallium Radioisotopes; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D017279:Selenocysteine; C533351:affibody (ZHER2-342)2