title: Affibody-mediated PET imaging of HER3 expression in malignant tumours.
abstract: Human epidermal growth factor receptor 3 (HER3) is involved in the progression of various cancers and in resistance to therapies targeting the HER family. In vivo imaging of HER3 expression would enable patient stratification for anti-HER3 immunotherapy. Key challenges with HER3-targeting are the relatively low expression in HER3-positive tumours and HER3 expression in normal tissues. The use of positron-emission tomography (PET) provides advantages of high resolution, sensitivity and quantification accuracy compared to SPECT. Affibody molecules, imaging probes based on a non-immunoglobulin scaffold, provide high imaging contrast shortly after injection. The aim of this study was to evaluate feasibility of PET imaging of HER3 expression using (68)Ga-labeled affibody molecules. The anti-HER3 affibody molecule HEHEHE-Z08698-NOTA was successfully labelled with (68)Ga with high yield, purity and stability. The agent bound specifically to HER3-expressing cancer cells in vitro and in vivo. At 3 h pi, uptake of (68)Ga-HEHEHE-Z08698-NOTA was significantly higher in xenografts with high HER3 expression (BT474, BxPC-3) than in xenografts with low HER3 expression (A431). In xenografts with high expression, tumour-to-blood ratios were >20, tumour-to-muscle >15, and tumour-to-bone >7. HER3-positive xenografts were visualised using microPET 3 h pi. In conclusion, PET imaging of HER3 expression is feasible using (68)Ga-HEHEHE-Z08698-NOTA shortly after administration.
authors.affiliation: Preclinical PET Platform, Uppsala University, Uppsala, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Rosestedt
authors.affiliation: Division of Protein Technology, KTH Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Ken G
authors.initials: KG
authors.lastname: Andersson
authors.affiliation: Preclinical PET Platform, Uppsala University, Uppsala, Sweden.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Mitran
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Tolmachev
authors.affiliation: Division of Protein Technology, KTH Royal Institute of Technology, Stockholm, Sweden.
authors.forename: John
authors.initials: J
authors.lastname: Löfblom
authors.affiliation: Preclinical PET Platform, Uppsala University, Uppsala, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Orlova
authors.affiliation: Division of Protein Technology, KTH Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Ståhl
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005710:Gallium Radioisotopes; D064593:Heterografts; D006801:Humans; D007553:Isotope Labeling; D015335:Molecular Probes / Q000378:metabolism; D009369:Neoplasms / Q000175:diagnosis* / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed
chemical_list: D005710:Gallium Radioisotopes; D015335:Molecular Probes; D011993:Recombinant Fusion Proteins; D020893:Receptor, ErbB-3