title: (186)Re-maSGS-Z (HER2:342), a potential Affibody conjugate for systemic therapy of HER2-expressing tumours.
abstract: OBJECTIVE
  Affibody molecules are a novel class of tumour-targeting proteins, which combine small size (7 kDa) and picomolar affinities. The Affibody molecule Z(HER2:342) has been suggested for imaging of HER2 expression in order to select patients for trastuzumab therapy. When optimizing chelators for (99m)Tc-labelling, we have found that synthetic Z(HER2:342) conjugated with mercaptoacetyl-glycyl-glycyl-glycyl (maGGG) and mercaptoacetyl-glycyl-seryl-glycyl (maGSG) chelators provides relatively low renal uptake of radioactivity and could be suitable for therapy.
  
  
  METHODS
  maGGG-Z(HER2:342) and maGSG-Z(HER2:342) were labelled with (186)Re and their biodistribution was studied in normal mice. Dosimetric evaluation and tumour targeting to HER2-overexpressed xenografts (SKOV-3) by (186)Re-maGSG-Z(HER2:342) were studied.
  
  
  RESULTS
  Gluconate-mediated labelling of maGGG-Z(HER2:342) and maGSG-Z(HER2:342) with (186)Re provided a yield of more than 95% within 60 min. The conjugates were stable and demonstrated specific binding to HER2-expressing SKOV-3 cells. Biodistribution in normal mice demonstrated rapid blood clearance, low accumulation of radioactivity in the kidney and other organs, accumulating free perrhenate. Both (186)Re-maGGG-Z(HER2:342) and (186)Re-maGSG-Z(HER2:342) demonstrated lower renal uptake than their (99m)Tc-labelled counterparts. (186)Re-maGSG-Z(HER2:342) provided the lowest uptake in healthy tissues. Biodistribution of (186)Re-maGSG-Z(HER2:342) in nude mice bearing SKOV-3 xenografts showed specific targeting of tumours. Tumour uptake 24 h after injection (5.84+/-0.54%ID/g) exceeded the concentration in blood by more than 500-fold, and uptake in kidneys by about 8-fold. Preliminary dosimetric evaluation showed that dose-to-tumour should exceed dose-to-kidney by approximately 5-fold.
  
  
  CONCLUSIONS
  Optimization of chelators improves biodistribution properties of rhenium-labelled small scaffold proteins and enables selection of promising radiotherapeutic agents based on the Affibody molecule.
authors.affiliation: Rudbeck Laboratory, Uppsala University, Uppsala, Sweden. anna.orlova@bms.uu.se
authors.forename: Anna
authors.initials: A
authors.lastname: Orlova
authors.forename: Thuy A
authors.initials: TA
authors.lastname: Tran
authors.forename: Torun
authors.initials: T
authors.lastname: Ekblad
authors.forename: Amelie Eriksson
authors.initials: AE
authors.lastname: Karlström
authors.forename: Vladimir
authors.initials: V
authors.lastname: Tolmachev
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D009928:Organ Specificity; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000532:radiotherapy; D011829:Radiation Dosage; D011868:Radioisotopes / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011874:Radiometry; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D012211:Rhenium / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D018719:Erb-b2 Receptor Tyrosine Kinases; D012211:Rhenium; C524056:Erbb2 protein, mouse