Synthetic affibody molecules : A novel class of affinity ligands for molecular imaging of HER2-expressing malignant tumors

• Published in: Cancer research (Chicago, Ill.) Vol. 67; no. 5; pp. 2178 - 2186
• Main Authors: ORLOVA, Anna, TOLMACHEV, Vladimir, PEHRSON, Rikard, LINDBORG, Malin, TRAN, Thuy, SANDSTRÖM, Mattias, NILSSON, Fredrik Y, WENNBORG, Anders, ABRAHMSEN, Lars, FELDWISCH, Joachim
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-03-2007
• Subjects: Adenocarcinoma - diagnosis; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Animals; Antibody Affinity; Antineoplastic agents; Biological and medical sciences; Diagnostic Imaging - methods; Female; Humans; Medical sciences; MEDICIN; Medicin och hälsovetenskap; MEDICINE; Mice; Mice, Inbred BALB C; Molecular Diagnostic Techniques - methods; Organometallic Compounds - pharmacokinetics; Ovarian Neoplasms - diagnosis; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Pharmacology. Drug treatments; Receptor, ErbB-2 - metabolism; Recombinant Fusion Proteins - chemical synthesis; Recombinant Fusion Proteins - pharmacokinetics; Tissue Distribution; Tumor Cells, Cultured; Tumors; Xenograft Model Antitumor Assays; Synthetic product; Ligand; C-Onc gene; erbB2 Gene; Affinity; Medical imagery; Malignant tumor; Gene expression; Protooncogene; Human Epidermal growth factor Receptor 2
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-06-2887

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.