title: Evaluation of the first44Sc-labeled Affibody molecule for imaging of HER2-expressing tumors.
abstract: Affibody molecules are small (58 amino acids) high-affinity proteins based on a tri-helix non-immunoglobulin scaffold. A clinical study has demonstrated that PET imaging using Affibody molecules labeled with68Ga (T½=68min) can visualize metastases of breast cancer expressing human epidermal growth factor receptor type 2 (HER2) and provide discrimination between tumors with high and low expression level. This may help to identify breast cancer patients benefiting from HER2-targeting therapies. The best discrimination was at 4h post injection. Due to longer half-life, a positron-emitting radionuclide44Sc (T½=4.04h) might be a preferable label for Affibody molecules for imaging at several hours after injection.
  
  
  
  A synthetic second-generation anti-HER2 Affibody molecule ZHER2:2891was labeled with44Sc via a DOTA-chelator conjugated to the N-terminal amino group. Binding specificity, affinity and cellular processing44Sc-DOTA-ZHER2:2891and68Ga-DOTA-ZHER2:2891were compared in vitro using HER2-expressing cells. Biodistribution and imaging properties of44Sc-DOTA-ZHER2:2891and68Ga-DOTA-ZHER2:2891were evaluated in Balb/c nude mice bearing HER2-expression xenografts.
  
  
  
  The labeling yield of 98±2% and specific activity of 7.8GBq/μmol were obtained. The conjugate demonstrated specific binding to HER2-expressing SKOV3.ip cells in vitro and to SKOV3.ip xenografts in nude mice. The distribution of radioactivity at 3h post injection was similar for44Sc-DOTA-ZHER2:2891and68Ga-DOTA-ZHER2:2891, but the blood clearance of the44Sc-labeled variant was slower and the tumor-to-blood ratio was reduced (15±2 for44Sc-DOTA-ZHER2:2891vs 46±9 for68Ga-DOTA-ZHER2:2891). At 6h after injection of44Sc-DOTA-ZHER2:2891the tumor uptake was 8±2% IA/g and the tumor-to-blood ratio was 51±8. Imaging using small-animal PET/CT demonstrated that44Sc-DOTA-ZHER2:2891provides specific and high-contrast imaging of HER2-expressing xenografts.
  
  
  
  The44Sc- DOTA-ZHER2:2891Affibody molecule is a promising probe for imaging of HER2-expression in malignant tumors.
authors.affiliation: Institute for Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Hadis
authors.initials: H
authors.lastname: Honarvar
authors.affiliation: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, Villigen-PSI, Switzerland. Electronic address: cristina.mueller@psi.ch.
authors.forename: Cristina
authors.initials: C
authors.lastname: Müller
authors.affiliation: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, Villigen-PSI, Switzerland.
authors.forename: Susan
authors.initials: S
authors.lastname: Cohrs
authors.affiliation: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, Villigen-PSI, Switzerland.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Haller
authors.affiliation: Division of Protein Technology, School of Biotechnology, KTH Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Westerlund
authors.affiliation: Division of Protein Technology, School of Biotechnology, KTH Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Amelie Eriksson
authors.initials: AE
authors.lastname: Karlström
authors.affiliation: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, Villigen-PSI, Switzerland; Laboratory of Radiochemistry, Paul Scherrer Institut, Villigen-PSI, Switzerland; Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: van der Meulen
authors.affiliation: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, Villigen-PSI, Switzerland; Laboratory of Radiochemistry, Paul Scherrer Institut, Villigen-PSI, Switzerland; Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
authors.affiliation: Institute for Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Tolmachev
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007553:Isotope Labeling; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D011868:Radioisotopes; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000493:pharmacokinetics; D012538:Scandium; D014018:Tissue Distribution
chemical_list: D011868:Radioisotopes; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; D012538:Scandium; C508053:ERBB2 protein, human
keywords: (44)Sc; Affibody molecule; DOTA; HER2; PET imaging; Z(HER2:2891)