title: Evaluating the potential of 188Re-SOCTA-trastuzumab as a new radioimmunoagent for breast cancer treatment.
abstract: BACKGROUND
  Radioimmunotherapy, which utilizes monoclonal antibodies and therapeutic radioisotopes against antigen-expressing tumor tissues, is an attractive therapeutic approach for cancer therapy. Trastuzumab (Herceptin) is a humanized anti-HER-2/neu monoclonal antibody for breast cancer treatment. In this paper, we introduce a new radioimmunoagent, (188)Re-trastuzumab, via a bifunctional ligand, succinimidyl 3,6-diaza-5-oxo-3-[2-((triphenylmethyl)thio)ethyl]-8-[(triphenylmethyl)thio]octanoate (SOCTA), and evaluate its potential to be a therapeutic radiopharmaceutical for breast cancer treatment.
  
  
  METHODS
  Equimolar amounts of SOCTA and trastuzumab were selected to react, and the conjugation ratio of SOCTA-trastuzumab was evaluated by the MALDI-TOF method. The immunoreactivity of SOCTA-trastuzumab was compared with nonconjugated trastuzumab in HER-2/neu overexpressing human breast cancer cell BT-474. Biodistribution experiment and microSPECT/CT images of (188)Re-SOCTA-trastuzumab being administered intravenously to SCID mice bearing xenografted BT-474 breast cancer were investigated to evaluate the tumor-targeting capability.
  
  
  RESULTS
  The covalent attachment of SOCTA to trastuzumab (at 1:1 molar ratio) resulted in the averaged conjugation ratio of 0.27+/-0.06 (n=3). The complex could easily be labeled with (188)Re and achieve 95% radiochemical purity (RCP) after 1 h of reaction at room temperature. The in vitro stability study also revealed that the RCP of (188)Re-SOCTA-trastuzumab was at a value of more than 85% after 48 h of incubation with human serum. The immunoreactivity evaluation showed that SOCTA-trastuzumab and nonconjugated trastuzumab had similar binding capacity (B(max)) to HER-2/neu receptor in BT-474 cells. The animal experiments showed that (188)Re-SOCTA-trastuzumab accumulated more intensively in the tumor site as compared to normal tissue.
  
  
  CONCLUSIONS
  We suggest that (188)Re-SOCTA-trastuzumab could be a potential candidate for radioimmunotherapy.
authors.affiliation: Isotope Application Division, Institute of Nuclear Energy Research, P.O. Box 3-27, Longtan, Taoyuan 325, Taiwan. tylo@iner.gov.tw
authors.forename: Tsai-Yueh
authors.initials: TY
authors.lastname: Luo
authors.forename: I-Chang
authors.initials: IC
authors.lastname: Tang
authors.forename: Yu-Long
authors.initials: YL
authors.lastname: Wu
authors.forename: Kwel-Luen
authors.initials: KL
authors.lastname: Hsu
authors.forename: Show-Wen
authors.initials: SW
authors.lastname: Liu
authors.forename: Hong-Chang
authors.initials: HC
authors.lastname: Kung
authors.forename: Ping-Shan
authors.initials: PS
authors.lastname: Lai
authors.forename: Wuu-Jyh
authors.initials: WJ
authors.lastname: Lin
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents / Q000737:chemistry; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006801:Humans; D051379:Mice; D009942:Organometallic Compounds / Q000737:chemistry*; D011854:Radiochemistry; D016499:Radioimmunotherapy / Q000379:methods*; D011868:Radioisotopes; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism; D012211:Rhenium / Q000737:chemistry*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013194:Staining and Labeling; D013696:Temperature; D013997:Time Factors; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003432:Cross-Linking Reagents; D066246:ErbB Receptors; D009942:Organometallic Compounds; D011868:Radioisotopes; D018719:Erb-b2 Receptor Tyrosine Kinases; D012211:Rhenium; D000068878:Trastuzumab; C539760:188Re-SOCTA-trastuzumab; C064740:epidermal growth factor receptor-neu receptor