title: 188Re-ZHER2:V2, a promising affibody-based targeting agent against HER2-expressing tumors: preclinical assessment.
abstract: Affibody molecules are small (7 kDa) nonimmunoglobulin scaffold proteins with favorable tumor-targeting properties. Studies concerning the influence of chelators on biodistribution of (99m)Tc-labeled Affibody molecules demonstrated that the variant with a C-terminal glycyl-glycyl-glycyl-cysteine peptide-based chelator (designated ZHER2:V2) has the best biodistribution profile in vivo and the lowest renal retention of radioactivity. The aim of this study was to evaluate (188)Re-ZHER2:V2 as a potential candidate for radionuclide therapy of human epidermal growth factor receptor type 2 (HER2)-expressing tumors.
  
  
  METHODS
  ZHER2:V2 was labeled with (188)Re using a gluconate-containing kit. Targeting of HER2-overexpressing SKOV-3 ovarian carcinoma xenografts in nude mice was studied for a dosimetry assessment.
  
  
  RESULTS
  Binding of (188)Re-ZHER2:V2 to living SKOV-3 cells was demonstrated to be specific, with an affinity of 6.4 ± 0.4 pM. The biodistribution study showed a rapid blood clearance (1.4 ± 0.1 percentage injected activity per gram [%ID/g] at 1 h after injection). The tumor uptake was 14 ± 2, 12 ± 2, 5 ± 2, and 1.8 ± 0.5 %IA/g at 1, 4, 24, and 48 h after injection, respectively. The in vivo targeting of HER2-expressing xenografts was specific. Already at 4 h after injection, tumor uptake exceeded kidney uptake (2.1 ± 0.2 %IA/g). Scintillation-camera imaging showed that tumor xenografts were the only sites with prominent accumulation of radioactivity at 4 h after injection. Based on the biokinetics, a dosimetry evaluation for humans suggests that (188)Re-ZHER2:V2 would provide an absorbed dose to tumor of 79 Gy without exceeding absorbed doses of 23 Gy to kidneys and 2 Gy to bone marrow. This indicates that future human radiotherapy studies may be feasible.
  
  
  CONCLUSIONS
  (188)Re-ZHER2:V2 can deliver high absorbed doses to tumors without exceeding kidney and bone marrow toxicity limits.
authors.affiliation: Division of Biomedical Radiation Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Altai
authors.affiliation: Division of Protein Technology, School of Biotechnology, KTH Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Wållberg
authors.affiliation: Division of Biomedical Radiation Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Hadis
authors.initials: H
authors.lastname: Honarvar
authors.affiliation: Division of Biomedical Radiation Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Joanna
authors.initials: J
authors.lastname: Strand
authors.affiliation: Preclinical PET Platform, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Orlova
authors.affiliation: Preclinical PET Platform, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
authors.forename: Zohreh
authors.initials: Z
authors.lastname: Varasteh
authors.affiliation: Nuclear Medicine and PET, Uppsala University, Uppsala, Sweden Medical Physics, Uppsala University Hospital, Uppsala, Sweden; and.
authors.forename: Mattias
authors.initials: M
authors.lastname: Sandström
authors.affiliation: Division of Protein Technology, School of Biotechnology, KTH Royal Institute of Technology, Stockholm, Sweden.
authors.forename: John
authors.initials: J
authors.lastname: Löfblom
authors.affiliation: Medical Radiation Physics, Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Larsson
authors.affiliation: Medical Radiation Physics, Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Sven-Erik
authors.initials: SE
authors.lastname: Strand
authors.affiliation: Nuclear Medicine and PET, Uppsala University, Uppsala, Sweden Medical Physics, Uppsala University Hospital, Uppsala, Sweden; and.
authors.forename: Mark
authors.initials: M
authors.lastname: Lubberink
authors.affiliation: Division of Protein Technology, School of Biotechnology, KTH Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Ståhl
authors.affiliation: Division of Biomedical Radiation Sciences, Uppsala University, Uppsala, Sweden vladimir.tolmachev@bms.uu.se.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Tolmachev
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry*; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry; D004353:Drug Evaluation, Preclinical; D005260:Female; D005942:Gluconates / Q000737:chemistry; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000737:chemistry; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D011829:Radiation Dosage; D011868:Radioisotopes / Q000627:therapeutic use*; D011874:Radiometry; D019275:Radiopharmaceuticals; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry*; D012211:Rhenium / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000906:Antibodies; D002614:Chelating Agents; D005942:Gluconates; D009842:Oligopeptides; D010455:Peptides; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D018719:Erb-b2 Receptor Tyrosine Kinases; D012211:Rhenium; C044514:glycyl-glycyl-cysteine; C508053:ERBB2 protein, human; C030691:gluconic acid
keywords: 188Re; Affibody molecule; HER2; dosimetry