Immuno-PET imaging and radioimmunotherapy of 64Cu-/177Lu-Labeled Anti-EGFR antibody in esophageal squamous cell carcinoma model

In Ho Song, Tae Sup Lee, Yong Serk Park, Jin Sook Lee, Byung Chul Lee, Byung Seok Moon, Gwang Il An, Hae Won Lee, Kwang Il Kim, Yong Jin Lee, Joo Hyun Kang, Sang Moo Lim

Research output: Contribution to journalArticle

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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 64Cu or 177Lu to evaluate the EGFR expression levels using immuno-PET and the feasibility of radioimmunotherapy in an esophageal squamous cell carcinoma (ESCC) model. Methods: Cetuximab was conjugated with p-SCN-Bn-PCTA and radiolabeled with 64Cu or 177Lu. 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 64Cu-cetuximab and biodistribution analysis. Micro-SPECT/CT imaging, biodistribution, and radioim-munotherapy studies of 177Lu-cetuximab were performed in the ESCC model. Therapeutic responses were monitored using 18F-FDG PET and immunohistochemical staining. Results: 64Cu-or 177Lu-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 64Cu- and 177Lu-cetuximab was peaked at 48 and 120 h, respectively. Radioimmunotherapy with 177Lu-cetuximab showed significant inhibition of tumor growth (P < 0.01) and marked reduction of 18F-FDG SUV compared with that of control (P < 0.05). Terminal deoxynucleotidyl transferase dUTP nick-end labeling pos-itivity and Ki-67 staining indices increased and decreased, respectively, in the radioimmunotherapy group compared with other groups (P < 0.01). Conclusion: 64Cu-cetuximab immuno-PET represented EGFR expression levels in ESCC tumors, and 177Lu-cetuximab radioimmunotherapy effectively inhibited the tumor growth. The diagnostic and therapeutic convergence radiopharmaceutical 64Cu-/177Lu-PCTA-cetuximab may be useful as a diagnostic tool in patient selection and a potent radioimmunotherapy agent in EGFR-positive ESCC tumors.

Original languageEnglish
Pages (from-to)1105-1111
Number of pages7
JournalJournal of Nuclear Medicine
Volume57
Issue number7
DOIs
StatePublished - 1 Jul 2016

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Radioimmunotherapy
Anti-Idiotypic Antibodies
Neoplasms
Fluorodeoxyglucose F18
Flow Cytometry
Staining and Labeling
Growth Factor Receptors
Radiopharmaceuticals
DNA Nucleotidylexotransferase
Cetuximab
Esophageal Squamous Cell Carcinoma
Antibodies
Therapeutics
Chelating Agents
Growth
Patient Selection
Phenotype

Keywords

  • Cetuximab
  • Cu
  • Immuno-PET
  • Lu
  • Radioimmunotherapy

Cite this

Song, In Ho ; Lee, Tae Sup ; Park, Yong Serk ; Lee, Jin Sook ; Lee, Byung Chul ; Moon, Byung Seok ; An, Gwang Il ; Lee, Hae Won ; Kim, Kwang Il ; Lee, Yong Jin ; Kang, Joo Hyun ; Lim, Sang Moo. / Immuno-PET imaging and radioimmunotherapy of 64Cu-/177Lu-Labeled Anti-EGFR antibody in esophageal squamous cell carcinoma model. In: Journal of Nuclear Medicine. 2016 ; Vol. 57, No. 7. pp. 1105-1111.
@article{58734cd963c94ce6bad690680a78d0d4,
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 64Cu or 177Lu to evaluate the EGFR expression levels using immuno-PET and the feasibility of radioimmunotherapy in an esophageal squamous cell carcinoma (ESCC) model. Methods: Cetuximab was conjugated with p-SCN-Bn-PCTA and radiolabeled with 64Cu or 177Lu. 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 64Cu-cetuximab and biodistribution analysis. Micro-SPECT/CT imaging, biodistribution, and radioim-munotherapy studies of 177Lu-cetuximab were performed in the ESCC model. Therapeutic responses were monitored using 18F-FDG PET and immunohistochemical staining. Results: 64Cu-or 177Lu-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 64Cu- and 177Lu-cetuximab was peaked at 48 and 120 h, respectively. Radioimmunotherapy with 177Lu-cetuximab showed significant inhibition of tumor growth (P < 0.01) and marked reduction of 18F-FDG SUV compared with that of control (P < 0.05). Terminal deoxynucleotidyl transferase dUTP nick-end labeling pos-itivity and Ki-67 staining indices increased and decreased, respectively, in the radioimmunotherapy group compared with other groups (P < 0.01). Conclusion: 64Cu-cetuximab immuno-PET represented EGFR expression levels in ESCC tumors, and 177Lu-cetuximab radioimmunotherapy effectively inhibited the tumor growth. The diagnostic and therapeutic convergence radiopharmaceutical 64Cu-/177Lu-PCTA-cetuximab may be useful as a diagnostic tool in patient selection and a potent radioimmunotherapy agent in EGFR-positive ESCC tumors.",
keywords = "Cetuximab, Cu, Immuno-PET, Lu, Radioimmunotherapy",
author = "Song, {In Ho} and Lee, {Tae Sup} and Park, {Yong Serk} and Lee, {Jin Sook} and Lee, {Byung Chul} and Moon, {Byung Seok} and An, {Gwang Il} and Lee, {Hae Won} and Kim, {Kwang Il} and Lee, {Yong Jin} and Kang, {Joo Hyun} and Lim, {Sang Moo}",
year = "2016",
month = "7",
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doi = "10.2967/jnumed.115.167155",
language = "English",
volume = "57",
pages = "1105--1111",
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}

Song, IH, Lee, TS, Park, YS, Lee, JS, Lee, BC, Moon, BS, An, GI, Lee, HW, Kim, KI, Lee, YJ, Kang, JH & Lim, SM 2016, 'Immuno-PET imaging and radioimmunotherapy of 64Cu-/177Lu-Labeled Anti-EGFR antibody in esophageal squamous cell carcinoma model', Journal of Nuclear Medicine, vol. 57, no. 7, pp. 1105-1111. https://doi.org/10.2967/jnumed.115.167155

Immuno-PET imaging and radioimmunotherapy of 64Cu-/177Lu-Labeled Anti-EGFR antibody in esophageal squamous cell carcinoma model. / Song, In Ho; Lee, Tae Sup; Park, Yong Serk; Lee, Jin Sook; Lee, Byung Chul; Moon, Byung Seok; An, Gwang Il; Lee, Hae Won; Kim, Kwang Il; Lee, Yong Jin; Kang, Joo Hyun; Lim, Sang Moo.

In: Journal of Nuclear Medicine, Vol. 57, No. 7, 01.07.2016, p. 1105-1111.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Immuno-PET imaging and radioimmunotherapy of 64Cu-/177Lu-Labeled Anti-EGFR antibody in esophageal squamous cell carcinoma model

AU - Song, In Ho

AU - Lee, Tae Sup

AU - Park, Yong Serk

AU - Lee, Jin Sook

AU - Lee, Byung Chul

AU - Moon, Byung Seok

AU - An, Gwang Il

AU - Lee, Hae Won

AU - Kim, Kwang Il

AU - Lee, Yong Jin

AU - Kang, Joo Hyun

AU - Lim, Sang Moo

PY - 2016/7/1

Y1 - 2016/7/1

N2 - 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 64Cu or 177Lu to evaluate the EGFR expression levels using immuno-PET and the feasibility of radioimmunotherapy in an esophageal squamous cell carcinoma (ESCC) model. Methods: Cetuximab was conjugated with p-SCN-Bn-PCTA and radiolabeled with 64Cu or 177Lu. 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 64Cu-cetuximab and biodistribution analysis. Micro-SPECT/CT imaging, biodistribution, and radioim-munotherapy studies of 177Lu-cetuximab were performed in the ESCC model. Therapeutic responses were monitored using 18F-FDG PET and immunohistochemical staining. Results: 64Cu-or 177Lu-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 64Cu- and 177Lu-cetuximab was peaked at 48 and 120 h, respectively. Radioimmunotherapy with 177Lu-cetuximab showed significant inhibition of tumor growth (P < 0.01) and marked reduction of 18F-FDG SUV compared with that of control (P < 0.05). Terminal deoxynucleotidyl transferase dUTP nick-end labeling pos-itivity and Ki-67 staining indices increased and decreased, respectively, in the radioimmunotherapy group compared with other groups (P < 0.01). Conclusion: 64Cu-cetuximab immuno-PET represented EGFR expression levels in ESCC tumors, and 177Lu-cetuximab radioimmunotherapy effectively inhibited the tumor growth. The diagnostic and therapeutic convergence radiopharmaceutical 64Cu-/177Lu-PCTA-cetuximab may be useful as a diagnostic tool in patient selection and a potent radioimmunotherapy agent in EGFR-positive ESCC tumors.

AB - 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 64Cu or 177Lu to evaluate the EGFR expression levels using immuno-PET and the feasibility of radioimmunotherapy in an esophageal squamous cell carcinoma (ESCC) model. Methods: Cetuximab was conjugated with p-SCN-Bn-PCTA and radiolabeled with 64Cu or 177Lu. 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 64Cu-cetuximab and biodistribution analysis. Micro-SPECT/CT imaging, biodistribution, and radioim-munotherapy studies of 177Lu-cetuximab were performed in the ESCC model. Therapeutic responses were monitored using 18F-FDG PET and immunohistochemical staining. Results: 64Cu-or 177Lu-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 64Cu- and 177Lu-cetuximab was peaked at 48 and 120 h, respectively. Radioimmunotherapy with 177Lu-cetuximab showed significant inhibition of tumor growth (P < 0.01) and marked reduction of 18F-FDG SUV compared with that of control (P < 0.05). Terminal deoxynucleotidyl transferase dUTP nick-end labeling pos-itivity and Ki-67 staining indices increased and decreased, respectively, in the radioimmunotherapy group compared with other groups (P < 0.01). Conclusion: 64Cu-cetuximab immuno-PET represented EGFR expression levels in ESCC tumors, and 177Lu-cetuximab radioimmunotherapy effectively inhibited the tumor growth. The diagnostic and therapeutic convergence radiopharmaceutical 64Cu-/177Lu-PCTA-cetuximab may be useful as a diagnostic tool in patient selection and a potent radioimmunotherapy agent in EGFR-positive ESCC tumors.

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