title: Comparative evaluation of 111In-labeled NOTA‑conjugated affibody molecules for visualization of HER3 expression in malignant tumors.
abstract: Expression of human epidermal growth factor receptor type 3 (HER3) in malignant tumors has been associated with resistance to a variety of anticancer therapies. Several anti-HER3 monoclonal antibodies are currently under pre-clinical and clinical development aiming to overcome HER3-mediated resistance. Radionuclide molecular imaging of HER3 expression may improve treatment by allowing the selection of suitable patients for HER3-targeted therapy. Affibody molecules are a class of small (7 kDa) high-affinity targeting proteins with appreciable potential as molecular imaging probes. In a recent study, we selected affibody molecules with affinity to HER3 at a low picomolar range. The aim of the present study was to develop an anti-HER3 affibody molecule suitable for labeling with radiometals. The HEHEHE-Z08698-NOTA and HEHEHE-Z08699-NOTA HER3-specific affibody molecules were labeled with indium-111 (111In) and assessed in vitro and in vivo for imaging properties using single photon emission computed tomography (SPECT). Labeling of HEHEHE-Z08698-NOTA and HEHEHE-Z08699-NOTA with 111In provided stable conjugates. In vitro cell tests demonstrated specific binding of the two conjugates to HER3-expressing BT-474 breast carcinoma cells. In mice bearing BT-474 xenografts, the tumor uptake of the two conjugates was receptor-specific. Direct in vivo comparison of 111In-HEHEHE-Z08698-NOTA and 111In-HEHEHE-Z08699‑NOTA demonstrated that the two conjugates provided equal radioactivity uptake in tumors, although the tumor-to-blood ratio was improved for 111In-HEHEHE-Z08698-NOTA [12 ± 3 vs. 8 ± 1, 4 h post injection (p.i.)] due to more efficient blood clearance. 111In-HEHEHE-Z08698-NOTA is a promising candidate for imaging of HER3-expression in malignant tumors using SPECT. Results of the present study indicate that this conjugate could be used for patient stratification for anti-HER3 therapy.
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: Maria
authors.initials: M
authors.lastname: Rosestedt
authors.affiliation: Preclinical PET Platform, Uppsala University, Uppsala, Sweden.
authors.forename: Zohreh
authors.initials: Z
authors.lastname: Varasteh
authors.affiliation: Division of Protein Technology, KTH Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Malm
authors.affiliation: Nuclear Medicine and PET, Uppsala University, Uppsala, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Sandström
authors.affiliation: Institute of Immunology, Genetic 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: Division of Protein Technology, KTH Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Ståhl
authors.affiliation: Preclinical PET Platform, Uppsala University, Uppsala, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Orlova
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007205:Indium Radioisotopes / Q000737:chemistry*; D051379:Mice; D057054:Molecular Imaging; D009368:Neoplasm Transplantation; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics*; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D007205:Indium Radioisotopes; D019275:Radiopharmaceuticals; D011993:Recombinant Fusion Proteins; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3