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Production and evaluation of cellular effects of 153Sm-DOTA-cetuximab and 177Lu-DOTA-cetuximab radioconjugates

Document Type : Scientific Note

Authors

Nuclear Fuel Cycle Research School, Nuclear Science and Technology Research Institute, AEOI, P.O.Box: 11365-3486, Tehran - Iran

Abstract

Antibody-based radiopharmaceuticals are of increasing interest today in cancer imaging and radiotherapy. The cetuximab monoclonal antibody binds to the epidermal growth factor receptor (EGFR) and thus provides therapeutic and diagnostic protocols against this receptor. Following purification and conjugation with freshly prepared DOTA-NHS, the cetuximab antibody was labeled with lutetium 177 and samarium chloride-153. Labeling efficiency and in vitro stability were measured using thin-layer chromatography. Cellular tests were performed to determine radioimmunoactivity in cancer cells. The results showed that the labeling efficiencies of 177Lu-DOTA-cetuximab and 153Sm-DOTA-cetuximab were more than 97±1% and 96±2%, respectively. Also, the in vitro stability of the labeled products in fresh human serum after 96 hours was 83±  22% and 78%, respectively. Immunoreactivity was 91% for 177Lu-DOTA-cetuximab and 66±1% for 153Sm-DOTA-cetuximab. With different intensities based on time and beta energy, both products inhibited the growth of HT29 colon cancer cells. The results showed that the immunoconjugate complexes of 177Lu-DOTA-cetuximab and 153Sm-DOTA-cetuximab can be considered a novel radiopharmaceutical for cancer radioimmunotherapy.

Highlights

  1. R. Labianca, et al, Colo Cancer, Crit Rev Oncol Hematol, 51, 145-70 (2004).

 

  1. E.G. Luebeck, S.H. Moolgavkar, Multistage Carcinogenesis and the incidence of colorectal cancer, Proc Natl Acad Sci USA, 99, 15095-100, 15095-100 (2002).

 

  1. C. Waters, Colorectal cancer: An overview, Pharmaceut J, 276, 323-326 (2006).

 

  1. R. Ansari, et al, Incidence and age distribution of colorectal cancer in Iran: Results of a population-based cancer Registry, Cancer Lett, 240, 143-147 (2006).

 

  1. G. Golshani, Y. Zhang, Advances in immunotherapy for colorectal cancer: a review, Therap Adv Gastroenterol, 13, 1-11 (2020).

 

  1. E.S. Kim, F.R. Khuri, R.S. Herbst, Epidermal growth factor receptor biology (imcc225), Current Opinion in Oncology, 13(6), 506-513 (2001).

 

  1. M.E. Gross, R.L. Shazer, D.B. Agus, Targeting the HER-kinase axis in cancer, Seminars in Oncology, 31(1), 9-20 (2004).

 

  1. K.E. Matheny, et al, Inhibition of epidermal growth factor receptor signaling decreases p63 expression in head and neck squamous carcinoma cells, Laryngoscope, 113(6), 936-939 (2003).

 

  1. D.S. Salomon, et al, Epidermal growth factor-related peptides and their receptors in human malignancies, Critical Reviews in Oncology/Hematology, 19(3), 183-232 (1995).

 

  1. M. Nouri, et al, Profile of epidermal growth factor receptor (EGFr) expression in human malignancies: effects of exposure to EGF and its biological influence on established human tumour cell lines, International Journal of Molecular Medicine, 6(4), 495-500 (2000).

 

  1. T. Sasaki, K. Hiroki, Y. Yamashita, Role of Epidermal Growth Factor Receptor in Cancer Metastasis and Microenvironment, BioMed Research International, 546318 (2013).

 

  1. J. Mendelsohn, J. Baselga, The EGF receptor family as targets for cancer therapy, Oncogene, 19, 6550–6565 (2000).

 

  1. J. Harding, B. Burtness, Cetuximab: An epidermal growth factor receptor chemeric human-murine monoclonal antibody, Drugs Today, 41, 107-127 (2005).

 

  1. G. Galizia, et al., Cetuximab, a chimeric human mouse antiepidermal growth factor receptor monoclonal antibody, in the treatment of human colorectal cancer, Oncogene, 26(25), 3654-3660 (2007).

 

  1. M. Fakih, M. Vincent, MD†Adverse events associated with anti-EGFR therapies for the treatment of metastatic colorectal cancer, Curr Oncol, 17(Suppl 1), S18–S30(2010).

 

  1. R.M. Sharkey, D.M. Goldenberg, Perspectives on cancer therapy with radiolabeled monoclonal antibodies, J. Nucl. Med, 46, 115-127 (2005).

 

  1. M.L. Steven, J.A. Carrasquillo, N.K.V. Cheung, Radioimmunotherapy of human tumours, Nature Reviews Cancer, 15(6), 347-360 (2015).

 

  1. M.W. Jordan, E.E. Freddy, T.V. Nerissa, Perspectives on metals-based radioimmunotherapy (RIT): moving forward, Theranostics, 11(13), 6293-6314 (2021).

 

  1. T.C. Karagiannis, Comparison of different classes of radionuclides for potential use in radioimmunotherapy, Journal of Nuclear Medicine, 10(2), 82-88 (2007).

 

  1. D. Zuzana, Production and chemical processing of 177Lu for nuclear medicine at the Munich research reactor FRM-II, Institute for Radiochemistry Technischen Universitat Munchen, (2007).

 

  1. A.H. Brouwers, et al., Optimization of radioimmunotherapy of renal cell carcinoma: labeling of monoclonal antibody cG250 with 131I, 90Y, 177Lu, or 186Re, Journal of Nuclear Medicine, 45(2), 327-337 (2004).

 

  1. G.J. Ehrhardt, A.R. Ketring, L.M. Ayers, Reactor-produced radionuclides at the University of Missouri Research Reactor, Applied Radiation and Isotopes, 49(4), 295-297 (1998).

 

  1. L.F. Mausner, S.C. Srivastava, Selection of radionuclides for radioimmunotherapy, Medical Physics, 20, 503–509 (1993).

 

  1. S. Lucas, et al, Monte Carlo Calculation of Radioimmunotherapy with 90Y-, 177Lu-, 131I-, 124I- and 188Re-Nanoobjects: Choice of the Best Radionuclide for Solid Tumour Treatment by Using TCP and NTCP Concepts, Computational and Mathematical Methods in Medicine Volume 2015, Article ID 284360, P 15.

 

  1. R. Osch, et al, A Handbook of Nuclear Chemistry: Radiochemistry and Radiopharmaceutical Chemistry in Life Sciences, Kluwer Academic Publishers, Amsterdam, 4 (2003).

 

  1. B.C. Ketcetu, et al., Development of radioimmunotherapeutic and diagnostic dntibodies: An inside-out view, Nuclear Medicine and Biology, 34(7), 757-778 (2007).

 

  1. Ada H. V. Repetto-Llamazares, et al, Advantage of Lutetium-177 versus Radioiodine Immunoconjugate in Targeted Radionuclide Therapy of B-cell Tumors, Anticancer Research July, 34(7), 3263-3269 (2014).

 

  1. K. Yavari, M. Ghannadi, Lutetium 177-Labeled Cetuximab Evaluation for Radioimmunotherapeutic Applications, Journal of Ardabil University Medical Sciences, 12(2), 204-212 (2012).

 

  1. C.G. Pippin, et al, Spectrophotometric method for the determination of a bifuctional DTPA ligand in DTPA-monoclonal antibody conjugates, Bioconjugate Chemistry, 3(4), 342-345 (1992).

 

  1. T. Lindmo, et al, Determination of the immunoreactive fraction of radiolabeled monoclonal antibodies by linear extrapolation to binding at infinite antigen excess, The Journal of Immunological Methods, 372(1), 77-89 (1984).

 

  1. J.B. Vermorken, et al, Platinum-based chemotherapy plus cetuximab in head and neck cancer, N. Engl. J. Med, 359, 1116-27 (2008).

 

  1. R. Pirker, et al, Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial, Lancet, 373, 1525-31 (2009).

 

  1. E. Van Cutsem, et al, Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer, N. Engl. J. Med, 360, 1408-17 (2009).

 

  1. J. Mendelsohn, Z. Fan, Epidermal growth factor receptor family and chemosensitization, J. Natl. Cancer Inst, 89, 341-3 (1997).

 

  1. L. Milas, et al, In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody, Clin Cancer Res, 6, 701-8 (2000).

 

  1. M. Krause, et al, Heterogeneity of tumour response to combined radiotherapy and EGFR inhibitors: differences between antibodies and TK inhibitors, Int. J. Radiat. Biol, 85, 934-54 (2009).

 

  1. G. Niu, et al, Cetuximab-based immunotherapy and radioimmunotherapy of head and neck squamous cell carcinoma, Clin Cancer Res, 16, 2095-105 (2010).

 

  1. Z. Liu Z, et al, 177Lu-labeled antibodies for EGFR-targeted SPECT/CT imaging and radioimmunotherapy in a preclinical head and neck carcinoma model, Mol Pharm, 11, 800-7 (2014).

 

  1. R. Benedetto, et al, Development of radioimmunoconjugate for diagnosis and management of head-and-neck subclinical cancer and colorectal carcinoma Braz, J. Pharm Sci, 53, e170039 (2017).

 

  1. R. Chakravarty, et al, 90Y/177Lu-labelled Cetuximab immunoconjugates: radiochemistry optimization to clinical dose formulation, J. Label Compd Radiopharm, 59(9), 354-63 (2016).

 

  1. W. Sihver, et al, Radiolabeled cetuximab conjugates for EGFR targeted cancer diagnostics and therapy, Pharmaceuticals, 7, 311-338 (2014).

 

  1. E. May, M. Thoennessen, Discovery of Samarium, Europium, Gadolinium, and Terbium Isotopes, Atomic Data and Nuclear Data Tables, (June 13, 2011).

 

  1. I.H. Song, T.S. Lee, Y.S. Park, Immuno-PET Imaging and Radioimmunotherapy of 64Cu-/ 177 Lu-Labeled Anti-EGFR Antibody in Esophageal Squamous Cell Carcinoma Model, J. Nucl. Med, 57, 1105-1111 ( 2016).

 

  1. R. Shabbir, et al., EGFR targeting of [177 Lu] gold nanoparticles to colorectal and breast tumour cells: Affinity, duration of binding and growth inhibition of Cetuximab-resistant cells, Science, 33(7), 101573 (2021)

Keywords

References
  1. R. Labianca, et al, Colo Cancer, Crit Rev Oncol Hematol, 51, 145-70 (2004).

 

  1. E.G. Luebeck, S.H. Moolgavkar, Multistage Carcinogenesis and the incidence of colorectal cancer, Proc Natl Acad Sci USA, 99, 15095-100, 15095-100 (2002).

 

  1. C. Waters, Colorectal cancer: An overview, Pharmaceut J, 276, 323-326 (2006).

 

  1. R. Ansari, et al, Incidence and age distribution of colorectal cancer in Iran: Results of a population-based cancer Registry, Cancer Lett, 240, 143-147 (2006).

 

  1. G. Golshani, Y. Zhang, Advances in immunotherapy for colorectal cancer: a review, Therap Adv Gastroenterol, 13, 1-11 (2020).

 

  1. E.S. Kim, F.R. Khuri, R.S. Herbst, Epidermal growth factor receptor biology (imcc225), Current Opinion in Oncology, 13(6), 506-513 (2001).

 

  1. M.E. Gross, R.L. Shazer, D.B. Agus, Targeting the HER-kinase axis in cancer, Seminars in Oncology, 31(1), 9-20 (2004).

 

  1. K.E. Matheny, et al, Inhibition of epidermal growth factor receptor signaling decreases p63 expression in head and neck squamous carcinoma cells, Laryngoscope, 113(6), 936-939 (2003).

 

  1. D.S. Salomon, et al, Epidermal growth factor-related peptides and their receptors in human malignancies, Critical Reviews in Oncology/Hematology, 19(3), 183-232 (1995).

 

  1. M. Nouri, et al, Profile of epidermal growth factor receptor (EGFr) expression in human malignancies: effects of exposure to EGF and its biological influence on established human tumour cell lines, International Journal of Molecular Medicine, 6(4), 495-500 (2000).

 

  1. T. Sasaki, K. Hiroki, Y. Yamashita, Role of Epidermal Growth Factor Receptor in Cancer Metastasis and Microenvironment, BioMed Research International, 546318 (2013).

 

  1. J. Mendelsohn, J. Baselga, The EGF receptor family as targets for cancer therapy, Oncogene, 19, 6550–6565 (2000).

 

  1. J. Harding, B. Burtness, Cetuximab: An epidermal growth factor receptor chemeric human-murine monoclonal antibody, Drugs Today, 41, 107-127 (2005).

 

  1. G. Galizia, et al., Cetuximab, a chimeric human mouse antiepidermal growth factor receptor monoclonal antibody, in the treatment of human colorectal cancer, Oncogene, 26(25), 3654-3660 (2007).

 

  1. M. Fakih, M. Vincent, MD†Adverse events associated with anti-EGFR therapies for the treatment of metastatic colorectal cancer, Curr Oncol, 17(Suppl 1), S18–S30(2010).

 

  1. R.M. Sharkey, D.M. Goldenberg, Perspectives on cancer therapy with radiolabeled monoclonal antibodies, J. Nucl. Med, 46, 115-127 (2005).

 

  1. M.L. Steven, J.A. Carrasquillo, N.K.V. Cheung, Radioimmunotherapy of human tumours, Nature Reviews Cancer, 15(6), 347-360 (2015).

 

  1. M.W. Jordan, E.E. Freddy, T.V. Nerissa, Perspectives on metals-based radioimmunotherapy (RIT): moving forward, Theranostics, 11(13), 6293-6314 (2021).

 

  1. T.C. Karagiannis, Comparison of different classes of radionuclides for potential use in radioimmunotherapy, Journal of Nuclear Medicine, 10(2), 82-88 (2007).

 

  1. D. Zuzana, Production and chemical processing of 177Lu for nuclear medicine at the Munich research reactor FRM-II, Institute for Radiochemistry Technischen Universitat Munchen, (2007).

 

  1. A.H. Brouwers, et al., Optimization of radioimmunotherapy of renal cell carcinoma: labeling of monoclonal antibody cG250 with 131I, 90Y, 177Lu, or 186Re, Journal of Nuclear Medicine, 45(2), 327-337 (2004).

 

  1. G.J. Ehrhardt, A.R. Ketring, L.M. Ayers, Reactor-produced radionuclides at the University of Missouri Research Reactor, Applied Radiation and Isotopes, 49(4), 295-297 (1998).

 

  1. L.F. Mausner, S.C. Srivastava, Selection of radionuclides for radioimmunotherapy, Medical Physics, 20, 503–509 (1993).

 

  1. S. Lucas, et al, Monte Carlo Calculation of Radioimmunotherapy with 90Y-, 177Lu-, 131I-, 124I- and 188Re-Nanoobjects: Choice of the Best Radionuclide for Solid Tumour Treatment by Using TCP and NTCP Concepts, Computational and Mathematical Methods in Medicine Volume 2015, Article ID 284360, P 15.

 

  1. R. Osch, et al, A Handbook of Nuclear Chemistry: Radiochemistry and Radiopharmaceutical Chemistry in Life Sciences, Kluwer Academic Publishers, Amsterdam, 4 (2003).

 

  1. B.C. Ketcetu, et al., Development of radioimmunotherapeutic and diagnostic dntibodies: An inside-out view, Nuclear Medicine and Biology, 34(7), 757-778 (2007).

 

  1. Ada H. V. Repetto-Llamazares, et al, Advantage of Lutetium-177 versus Radioiodine Immunoconjugate in Targeted Radionuclide Therapy of B-cell Tumors, Anticancer Research July, 34(7), 3263-3269 (2014).

 

  1. K. Yavari, M. Ghannadi, Lutetium 177-Labeled Cetuximab Evaluation for Radioimmunotherapeutic Applications, Journal of Ardabil University Medical Sciences, 12(2), 204-212 (2012).

 

  1. C.G. Pippin, et al, Spectrophotometric method for the determination of a bifuctional DTPA ligand in DTPA-monoclonal antibody conjugates, Bioconjugate Chemistry, 3(4), 342-345 (1992).

 

  1. T. Lindmo, et al, Determination of the immunoreactive fraction of radiolabeled monoclonal antibodies by linear extrapolation to binding at infinite antigen excess, The Journal of Immunological Methods, 372(1), 77-89 (1984).

 

  1. J.B. Vermorken, et al, Platinum-based chemotherapy plus cetuximab in head and neck cancer, N. Engl. J. Med, 359, 1116-27 (2008).

 

  1. R. Pirker, et al, Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial, Lancet, 373, 1525-31 (2009).

 

  1. E. Van Cutsem, et al, Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer, N. Engl. J. Med, 360, 1408-17 (2009).

 

  1. J. Mendelsohn, Z. Fan, Epidermal growth factor receptor family and chemosensitization, J. Natl. Cancer Inst, 89, 341-3 (1997).

 

  1. L. Milas, et al, In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody, Clin Cancer Res, 6, 701-8 (2000).

 

  1. M. Krause, et al, Heterogeneity of tumour response to combined radiotherapy and EGFR inhibitors: differences between antibodies and TK inhibitors, Int. J. Radiat. Biol, 85, 934-54 (2009).

 

  1. G. Niu, et al, Cetuximab-based immunotherapy and radioimmunotherapy of head and neck squamous cell carcinoma, Clin Cancer Res, 16, 2095-105 (2010).

 

  1. Z. Liu Z, et al, 177Lu-labeled antibodies for EGFR-targeted SPECT/CT imaging and radioimmunotherapy in a preclinical head and neck carcinoma model, Mol Pharm, 11, 800-7 (2014).

 

  1. R. Benedetto, et al, Development of radioimmunoconjugate for diagnosis and management of head-and-neck subclinical cancer and colorectal carcinoma Braz, J. Pharm Sci, 53, e170039 (2017).

 

  1. R. Chakravarty, et al, 90Y/177Lu-labelled Cetuximab immunoconjugates: radiochemistry optimization to clinical dose formulation, J. Label Compd Radiopharm, 59(9), 354-63 (2016).

 

  1. W. Sihver, et al, Radiolabeled cetuximab conjugates for EGFR targeted cancer diagnostics and therapy, Pharmaceuticals, 7, 311-338 (2014).

 

  1. E. May, M. Thoennessen, Discovery of Samarium, Europium, Gadolinium, and Terbium Isotopes, Atomic Data and Nuclear Data Tables, (June 13, 2011).

 

  1. I.H. Song, T.S. Lee, Y.S. Park, Immuno-PET Imaging and Radioimmunotherapy of 64Cu-/ 177 Lu-Labeled Anti-EGFR Antibody in Esophageal Squamous Cell Carcinoma Model, J. Nucl. Med, 57, 1105-1111 ( 2016).

 

  1. R. Shabbir, et al., EGFR targeting of [177 Lu] gold nanoparticles to colorectal and breast tumour cells: Affinity, duration of binding and growth inhibition of Cetuximab-resistant cells, Science, 33(7), 101573 (2021)
Journal of Nuclear Science, Engineering and Technology (JONSAT)
Volume 44, Issue 3 - Serial Number 105
October 2023
Pages 171-179
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