title: Synthetic affibody molecules: a novel class of affinity ligands for molecular imaging of HER2-expressing malignant tumors.
abstract: The Affibody molecule Z(HER2:342-pep2), site-specifically and homogeneously conjugated with a 1,4,7,10-tetra-azacylododecane-N,N',N'',N'''-tetraacetic acid (DOTA) chelator, was produced in a single chemical process by peptide synthesis. DOTA-Z(HER2:342-pep2) folds spontaneously and binds HER2 with 65 pmol/L affinity. Efficient radiolabeling with >95% incorporation of (111)In was achieved within 30 min at low (room temperature) and high temperatures (up to 90 degrees C). Tumor uptake of (111)In-DOTA-Z(HER2:342-pep2) was specific for HER2-positive xenografts. A high tumor uptake of 23% injected activity per gram tissue, a tumor-to-blood ratio of >7.5, and high-contrast gamma camera images were obtained already 1 h after injection. Pretreatment with Herceptin did not interfere with tumor targeting, whereas degradation of HER2 using the heat shock protein 90 inhibitor 17-allylamino-geldanamycin before administration of (111)In-DOTA-Z(HER2:342-pep2) obliterated the tumor image. The present results show that radiolabeled synthetic DOTA-Z(HER2:342-pep2) has the potential to become a clinically useful radiopharmaceutical for in vivo molecular imaging of HER2-expressing carcinomas.
authors.affiliation: Affibody AB, Voltavagen 13, SE-16102 Bromma, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Orlova
authors.forename: Vladimir
authors.initials: V
authors.lastname: Tolmachev
authors.forename: Rikard
authors.initials: R
authors.lastname: Pehrson
authors.forename: Malin
authors.initials: M
authors.lastname: Lindborg
authors.forename: Thuy
authors.initials: T
authors.lastname: Tran
authors.forename: Mattias
authors.initials: M
authors.lastname: Sandström
authors.forename: Fredrik Y
authors.initials: FY
authors.lastname: Nilsson
authors.forename: Anders
authors.initials: A
authors.lastname: Wennborg
authors.forename: Lars
authors.initials: L
authors.lastname: Abrahmsén
authors.forename: Joachim
authors.initials: J
authors.lastname: Feldwisch
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000915:Antibody Affinity; D003952:Diagnostic Imaging / Q000379:methods*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D025202:Molecular Diagnostic Techniques / Q000379:methods; D009942:Organometallic Compounds / Q000493:pharmacokinetics; D010051:Ovarian Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D009942:Organometallic Compounds; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; C518744:111In-DOTA-Z(HER2-342-pep2)