Targeted beta therapy of prostate cancer with 177Lu-labelled Miltuximab® antibody against glypican-1 (GPC-1)
Abstract Purpose Chimeric antibody Miltuximab®, a human IgG1 engineered from the parent antibody MIL-38, is in clinical development for solid tumour therapy. Miltuximab® targets glypican-1 (GPC-1), a cell surface protein involved in tumour growth, which is overexpressed in solid tumours, including p...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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SpringerOpen
2020-05-01
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| Series: | EJNMMI Research |
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| Online Access: | http://link.springer.com/article/10.1186/s13550-020-00637-x |
| _version_ | 1828532583592361984 |
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| author | Mei-Chun Yeh Brian W. C. Tse Nicholas L. Fletcher Zachary H. Houston Maria Lund Marianna Volpert Chelsea Stewart Kamil A. Sokolowski Varinder Jeet Kristofer J. Thurecht Douglas H. Campbell Bradley J. Walsh Colleen C. Nelson Pamela J. Russell |
| author_facet | Mei-Chun Yeh Brian W. C. Tse Nicholas L. Fletcher Zachary H. Houston Maria Lund Marianna Volpert Chelsea Stewart Kamil A. Sokolowski Varinder Jeet Kristofer J. Thurecht Douglas H. Campbell Bradley J. Walsh Colleen C. Nelson Pamela J. Russell |
| author_sort | Mei-Chun Yeh |
| collection | DOAJ |
| description | Abstract Purpose Chimeric antibody Miltuximab®, a human IgG1 engineered from the parent antibody MIL-38, is in clinical development for solid tumour therapy. Miltuximab® targets glypican-1 (GPC-1), a cell surface protein involved in tumour growth, which is overexpressed in solid tumours, including prostate cancer (PCa). This study investigated the potential of 89Zr-labelled Miltuximab® as an imaging agent, and 177Lu-labelled Miltuximab® as a targeted beta therapy, in a mouse xenograft model of human prostate cancer. Methods Male BALB/c nude mice were inoculated subcutaneously with GPC-1-positive DU-145 PCa cells. In imaging and biodistribution studies, mice bearing palpable tumours received (a) 2.62 MBq [89Zr]Zr-DFO-Miltuximab® followed by PET-CT imaging, or (b) 6 MBq [177Lu]Lu-DOTA-Miltuximab® by Cerenkov imaging, and ex vivo assessment of biodistribution. In an initial tumour efficacy study, mice bearing DU-145 tumours were administered intravenously with 6 MBq [177Lu]Lu-DOTA-Miltuximab® or control DOTA-Miltuximab® then euthanised after 27 days. In a subsequent survival efficacy study, tumour-bearing mice were given 3 or 10 MBq of [177Lu]Lu-DOTA-Miltuximab®, or control, and followed up to 120 days. Results Antibody accumulation in DU-145 xenografts was detected by PET-CT imaging using [89Zr]Zr-DFO-Miltuximab® and confirmed by Cerenkov luminescence imaging post injection of [177Lu]Lu-DOTA-Miltuximab®. Antibody accumulation was higher (% IA/g) in tumours than other organs across multiple time points. A single injection with 6 MBq of [177Lu]Lu-DOTA-Miltuximab® significantly inhibited tumour growth as compared with DOTA-Miltuximab® (control). In the survival study, mice treated with 10 MBq [177Lu]Lu-DOTA-Miltuximab® had significantly prolonged survival (mean 85 days) versus control (45 days), an effect associated with increased cancer cell apoptosis. Tissue histopathology assessment showed no abnormalities associated with [177Lu]Lu-DOTA-Miltuximab®, in line with other observations of tolerability, including body weight stability. Conclusion These findings demonstrate the potential utility of Miltuximab® as a PET imaging agent ([89Zr]Zr-DFO-Miltuximab®) and a beta therapy ([177Lu]Lu-DOTA-Miltuximab®) in patients with PCa or other GPC-1 expressing tumours. |
| first_indexed | 2024-12-11T22:55:09Z |
| format | Article |
| id | doaj.art-2ef2c8e3d8664d7a8617ef5010ba309f |
| institution | Directory Open Access Journal |
| issn | 2191-219X |
| language | English |
| last_indexed | 2024-12-11T22:55:09Z |
| publishDate | 2020-05-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | EJNMMI Research |
| spelling | doaj.art-2ef2c8e3d8664d7a8617ef5010ba309f2022-12-22T00:47:16ZengSpringerOpenEJNMMI Research2191-219X2020-05-0110111310.1186/s13550-020-00637-xTargeted beta therapy of prostate cancer with 177Lu-labelled Miltuximab® antibody against glypican-1 (GPC-1)Mei-Chun Yeh0Brian W. C. Tse1Nicholas L. Fletcher2Zachary H. Houston3Maria Lund4Marianna Volpert5Chelsea Stewart6Kamil A. Sokolowski7Varinder Jeet8Kristofer J. Thurecht9Douglas H. Campbell10Bradley J. Walsh11Colleen C. Nelson12Pamela J. Russell13Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Princess Alexandra Hospital, Translational Research InstitutePreclinical Imaging Facility, Translational Research InstituteCentre for Advanced Imaging, Australian Institute for Bioengineering and Nanotechnology, ARC Centre of Excellence in Convergent Bio-Nano Science and Technology and ARC Training Centre in Biomedical Imaging Technology, University of QueenslandCentre for Advanced Imaging, Australian Institute for Bioengineering and Nanotechnology, ARC Centre of Excellence in Convergent Bio-Nano Science and Technology and ARC Training Centre in Biomedical Imaging Technology, University of QueenslandGlytherix LtdAustralian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Princess Alexandra Hospital, Translational Research InstituteAustralian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Princess Alexandra Hospital, Translational Research InstitutePreclinical Imaging Facility, Translational Research InstituteAustralian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Princess Alexandra Hospital, Translational Research InstituteCentre for Advanced Imaging, Australian Institute for Bioengineering and Nanotechnology, ARC Centre of Excellence in Convergent Bio-Nano Science and Technology and ARC Training Centre in Biomedical Imaging Technology, University of QueenslandGlytherix LtdGlytherix LtdAustralian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Princess Alexandra Hospital, Translational Research InstituteAustralian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Princess Alexandra Hospital, Translational Research InstituteAbstract Purpose Chimeric antibody Miltuximab®, a human IgG1 engineered from the parent antibody MIL-38, is in clinical development for solid tumour therapy. Miltuximab® targets glypican-1 (GPC-1), a cell surface protein involved in tumour growth, which is overexpressed in solid tumours, including prostate cancer (PCa). This study investigated the potential of 89Zr-labelled Miltuximab® as an imaging agent, and 177Lu-labelled Miltuximab® as a targeted beta therapy, in a mouse xenograft model of human prostate cancer. Methods Male BALB/c nude mice were inoculated subcutaneously with GPC-1-positive DU-145 PCa cells. In imaging and biodistribution studies, mice bearing palpable tumours received (a) 2.62 MBq [89Zr]Zr-DFO-Miltuximab® followed by PET-CT imaging, or (b) 6 MBq [177Lu]Lu-DOTA-Miltuximab® by Cerenkov imaging, and ex vivo assessment of biodistribution. In an initial tumour efficacy study, mice bearing DU-145 tumours were administered intravenously with 6 MBq [177Lu]Lu-DOTA-Miltuximab® or control DOTA-Miltuximab® then euthanised after 27 days. In a subsequent survival efficacy study, tumour-bearing mice were given 3 or 10 MBq of [177Lu]Lu-DOTA-Miltuximab®, or control, and followed up to 120 days. Results Antibody accumulation in DU-145 xenografts was detected by PET-CT imaging using [89Zr]Zr-DFO-Miltuximab® and confirmed by Cerenkov luminescence imaging post injection of [177Lu]Lu-DOTA-Miltuximab®. Antibody accumulation was higher (% IA/g) in tumours than other organs across multiple time points. A single injection with 6 MBq of [177Lu]Lu-DOTA-Miltuximab® significantly inhibited tumour growth as compared with DOTA-Miltuximab® (control). In the survival study, mice treated with 10 MBq [177Lu]Lu-DOTA-Miltuximab® had significantly prolonged survival (mean 85 days) versus control (45 days), an effect associated with increased cancer cell apoptosis. Tissue histopathology assessment showed no abnormalities associated with [177Lu]Lu-DOTA-Miltuximab®, in line with other observations of tolerability, including body weight stability. Conclusion These findings demonstrate the potential utility of Miltuximab® as a PET imaging agent ([89Zr]Zr-DFO-Miltuximab®) and a beta therapy ([177Lu]Lu-DOTA-Miltuximab®) in patients with PCa or other GPC-1 expressing tumours.http://link.springer.com/article/10.1186/s13550-020-00637-xProstate cancerRadionuclide therapyMiltuximab®Glypican-1MIL-38 |
| spellingShingle | Mei-Chun Yeh Brian W. C. Tse Nicholas L. Fletcher Zachary H. Houston Maria Lund Marianna Volpert Chelsea Stewart Kamil A. Sokolowski Varinder Jeet Kristofer J. Thurecht Douglas H. Campbell Bradley J. Walsh Colleen C. Nelson Pamela J. Russell Targeted beta therapy of prostate cancer with 177Lu-labelled Miltuximab® antibody against glypican-1 (GPC-1) EJNMMI Research Prostate cancer Radionuclide therapy Miltuximab® Glypican-1 MIL-38 |
| title | Targeted beta therapy of prostate cancer with 177Lu-labelled Miltuximab® antibody against glypican-1 (GPC-1) |
| title_full | Targeted beta therapy of prostate cancer with 177Lu-labelled Miltuximab® antibody against glypican-1 (GPC-1) |
| title_fullStr | Targeted beta therapy of prostate cancer with 177Lu-labelled Miltuximab® antibody against glypican-1 (GPC-1) |
| title_full_unstemmed | Targeted beta therapy of prostate cancer with 177Lu-labelled Miltuximab® antibody against glypican-1 (GPC-1) |
| title_short | Targeted beta therapy of prostate cancer with 177Lu-labelled Miltuximab® antibody against glypican-1 (GPC-1) |
| title_sort | targeted beta therapy of prostate cancer with 177lu labelled miltuximab r antibody against glypican 1 gpc 1 |
| topic | Prostate cancer Radionuclide therapy Miltuximab® Glypican-1 MIL-38 |
| url | http://link.springer.com/article/10.1186/s13550-020-00637-x |
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