title: Immuno-PET Imaging and Radioimmunotherapy of 64Cu-/177Lu-Labeled Anti-EGFR Antibody in Esophageal Squamous Cell Carcinoma Model.
abstract: Immuno-PET provides valuable information about tumor location, phenotype, susceptibility to therapy, and treatment response, especially to targeted radioimmunotherapy. In this study, we prepared antiepidermal growth factor receptor (EGFR) antibody via identical chelator, 3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13-trience-3,6,9,-triacetic acid (PCTA), labeled with (64)Cu or (177)Lu to evaluate the EGFR expression levels using immuno-PET and the feasibility of radioimmunotherapy in an esophageal squamous cell carcinoma (ESCC) model.
  
  
  
  Cetuximab was conjugated with p-SCN-Bn-PCTA and radiolabeled with (64)Cu or (177)Lu. In vitro EGFR expression levels were determined and compared using flow cytometry and cell binding assay. In vivo EGFR expression levels were evaluated via immuno-PET imaging of (64)Cu-cetuximab and biodistribution analysis. Micro-SPECT/CT imaging, biodistribution, and radioimmunotherapy studies of (177)Lu-cetuximab were performed in the ESCC model. Therapeutic responses were monitored using (18)F-FDG PET and immunohistochemical staining.
  
  
  
  (64)Cu- or (177)Lu-labeled antibodies showed high radiolabeling yield (>98%), stability (>90%), and favorable immunoreactivity. In vitro EGFR status measured by cell binding assay was correlated with the flow cytometry data. Immuno-PET, micro-SPECT/CT, and biodistribution demonstrated specific uptake in ESCC tumors depending on the EGFR expression levels. Tumor accumulation of (64)Cu- and (177)Lu-cetuximab was peaked at 48 and 120 h, respectively. Radioimmunotherapy with (177)Lu-cetuximab showed significant inhibition of tumor growth (P < 0.01) and marked reduction of (18)F-FDG SUV compared with that of control (P < 0.05). Terminal deoxynucleotidyl transferase dUTP nick-end labeling positivity and Ki-67 staining indices increased and decreased, respectively, in the radioimmunotherapy group compared with other groups (P < 0.01).
  
  
  
  (64)Cu-cetuximab immuno-PET represented EGFR expression levels in ESCC tumors, and (177)Lu-cetuximab radioimmunotherapy effectively inhibited the tumor growth. The diagnostic and therapeutic convergence radiopharmaceutical (64)Cu-/(177)Lu-PCTA-cetuximab may be useful as a diagnostic tool in patient selection and a potent radioimmunotherapy agent in EGFR-positive ESCC tumors.
authors.affiliation: Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul, South Korea Department of Biomedical Laboratory Science, Yonsei University, Wonju, South Korea.
authors.forename: In Ho
authors.initials: IH
authors.lastname: Song
authors.affiliation: Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul, South Korea nobelcow@kirams.re.kr.
authors.forename: Tae Sup
authors.initials: TS
authors.lastname: Lee
authors.affiliation: Department of Biomedical Laboratory Science, Yonsei University, Wonju, South Korea.
authors.forename: Yong Serk
authors.initials: YS
authors.lastname: Park
authors.affiliation: Department of Anatomy, Yonsei University Wonju Collage of Medicine, Wonju, South Korea.
authors.forename: Jin Sook
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea.
authors.forename: Byung Chul
authors.initials: BC
authors.lastname: Lee
authors.affiliation: Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea.
authors.forename: Byung Seok
authors.initials: BS
authors.lastname: Moon
authors.affiliation: Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul, South Korea.
authors.forename: Gwang Il
authors.initials: GI
authors.lastname: An
authors.affiliation: Department of Thoracic Surgery, KIRAMS, Seoul, South Korea; and.
authors.forename: Hae Won
authors.initials: HW
authors.lastname: Lee
authors.affiliation: Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul, South Korea.
authors.forename: Kwang Il
authors.initials: KI
authors.lastname: Kim
authors.affiliation: Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul, South Korea.
authors.forename: Yong Jin
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul, South Korea.
authors.forename: Joo Hyun
authors.initials: JH
authors.lastname: Kang
authors.affiliation: Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul, South Korea Department of Nuclear Medicine, KIRAMS, Seoul, South Korea.
authors.forename: Sang Moo
authors.initials: SM
authors.lastname: Lim
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000627:therapeutic use; D002614:Chelating Agents / Q000737:chemistry; D003301:Copper Radioisotopes; D066246:ErbB Receptors / Q000096:biosynthesis / Q000276:immunology*; D004938:Esophageal Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000532:radiotherapy*; D006801:Humans; D020287:In Situ Nick-End Labeling; D008187:Lutetium; D000072078:Positron Emission Tomography Computed Tomography / Q000379:methods*; D016499:Radioimmunotherapy / Q000379:methods*; D019275:Radiopharmaceuticals / Q000627:therapeutic use; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D051598:Whole Body Imaging
chemical_list: D000970:Antineoplastic Agents; D002614:Chelating Agents; D003301:Copper Radioisotopes; D019275:Radiopharmaceuticals; D008187:Lutetium; D066246:ErbB Receptors; D000068818:Cetuximab
keywords: 177Lu; 64Cu; cetuximab; immuno-PET; radioimmunotherapy