In vitro characterisation of [177Lu]Lu-DOTA-C595 as a novel radioimmunotherapy for MUC1-CE positive pancreatic cancer
Abstract Background Pancreatic ductal adenocarcinoma (PDAC) continues to be a malignancy with an unmet clinical demand. Development of radioimmunoconjugates which target cancer-specific receptors provides an opportunity for radioimmunotherapy of both metastatic and primary PDAC. In this study, we ch...
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| Format: | Article |
| Language: | English |
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SpringerOpen
2023-08-01
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| Series: | EJNMMI Radiopharmacy and Chemistry |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s41181-023-00204-4 |
| _version_ | 1797450957828653056 |
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| author | Ashleigh Hull William Hsieh William Tieu Dylan Bartholomeusz Yanrui Li Eva Bezak |
| author_facet | Ashleigh Hull William Hsieh William Tieu Dylan Bartholomeusz Yanrui Li Eva Bezak |
| author_sort | Ashleigh Hull |
| collection | DOAJ |
| description | Abstract Background Pancreatic ductal adenocarcinoma (PDAC) continues to be a malignancy with an unmet clinical demand. Development of radioimmunoconjugates which target cancer-specific receptors provides an opportunity for radioimmunotherapy of both metastatic and primary PDAC. In this study, we characterised the in vitro behaviour of a novel beta-emitting radioimmunoconjugate [177Lu]Lu-DOTA-C595 as a therapeutic agent against PDAC. [177Lu]Lu-DOTA-C595 is designed to target cancer-specific mucin 1 epitopes (MUC1-CE) overexpressed on most epithelial cancers, including PDAC. Results A series of in vitro experiments were performed on PDAC cell lines (PANC-1, CAPAN-1, BxPC-3 and AsPC-1) exhibiting strong to weak MUC1-CE expression. [177Lu]Lu-DOTA-C595 bound to all cell lines relative to their expression of MUC1-CE. [177Lu]Lu-DOTA-C595 was also rapidly internalised across all cell lines, with a maximum of 75.4% of activity internalised within the PANC-1 cell line at 48 h. The expression of γH2AX foci and clonogenic survival of PANC-1 and AsPC-1 cell lines after exposure to [177Lu]Lu-DOTA-C595 were used to quantify the in vitro cytotoxicity of [177Lu]Lu-DOTA-C595. At 1 h post treatment, the expression of γH2AX foci exceeded 97% in both cell lines. The expression of γH2AX foci continued to increase in PANC-1 cells at 24 h, although expression reduced in AsPC-1. Clonogenic assays showed a high level of cell kill induced by [177Lu]Lu-DOTA-C595. Conclusion [177Lu]Lu-DOTA-C595 has favourable in vitro characteristics to target and treat MUC1-CE positive PDAC. Further investigations to characterise the in vivo effects and potential value of [177Lu]Lu-DOTA-C595 in other MUC1-CE expressing malignancies such as lung, ovarian and colorectal adenocarcinoma are warranted. |
| first_indexed | 2024-03-09T14:48:01Z |
| format | Article |
| id | doaj.art-0e6a9c6427e044eca543f2af2fff269f |
| institution | Directory Open Access Journal |
| issn | 2365-421X |
| language | English |
| last_indexed | 2024-03-09T14:48:01Z |
| publishDate | 2023-08-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | EJNMMI Radiopharmacy and Chemistry |
| spelling | doaj.art-0e6a9c6427e044eca543f2af2fff269f2023-11-26T14:37:33ZengSpringerOpenEJNMMI Radiopharmacy and Chemistry2365-421X2023-08-018111610.1186/s41181-023-00204-4In vitro characterisation of [177Lu]Lu-DOTA-C595 as a novel radioimmunotherapy for MUC1-CE positive pancreatic cancerAshleigh Hull0William Hsieh1William Tieu2Dylan Bartholomeusz3Yanrui Li4Eva Bezak5Allied Health and Human Performance Academic Unit, University of South AustraliaAllied Health and Human Performance Academic Unit, University of South AustraliaSchool of Physical Sciences, The University of AdelaideDepartment of PET, Nuclear Medicine and Bone Densitometry, Royal Adelaide Hospital, SA Medical ImagingAllied Health and Human Performance Academic Unit, University of South AustraliaAllied Health and Human Performance Academic Unit, University of South AustraliaAbstract Background Pancreatic ductal adenocarcinoma (PDAC) continues to be a malignancy with an unmet clinical demand. Development of radioimmunoconjugates which target cancer-specific receptors provides an opportunity for radioimmunotherapy of both metastatic and primary PDAC. In this study, we characterised the in vitro behaviour of a novel beta-emitting radioimmunoconjugate [177Lu]Lu-DOTA-C595 as a therapeutic agent against PDAC. [177Lu]Lu-DOTA-C595 is designed to target cancer-specific mucin 1 epitopes (MUC1-CE) overexpressed on most epithelial cancers, including PDAC. Results A series of in vitro experiments were performed on PDAC cell lines (PANC-1, CAPAN-1, BxPC-3 and AsPC-1) exhibiting strong to weak MUC1-CE expression. [177Lu]Lu-DOTA-C595 bound to all cell lines relative to their expression of MUC1-CE. [177Lu]Lu-DOTA-C595 was also rapidly internalised across all cell lines, with a maximum of 75.4% of activity internalised within the PANC-1 cell line at 48 h. The expression of γH2AX foci and clonogenic survival of PANC-1 and AsPC-1 cell lines after exposure to [177Lu]Lu-DOTA-C595 were used to quantify the in vitro cytotoxicity of [177Lu]Lu-DOTA-C595. At 1 h post treatment, the expression of γH2AX foci exceeded 97% in both cell lines. The expression of γH2AX foci continued to increase in PANC-1 cells at 24 h, although expression reduced in AsPC-1. Clonogenic assays showed a high level of cell kill induced by [177Lu]Lu-DOTA-C595. Conclusion [177Lu]Lu-DOTA-C595 has favourable in vitro characteristics to target and treat MUC1-CE positive PDAC. Further investigations to characterise the in vivo effects and potential value of [177Lu]Lu-DOTA-C595 in other MUC1-CE expressing malignancies such as lung, ovarian and colorectal adenocarcinoma are warranted.https://doi.org/10.1186/s41181-023-00204-4Lutetium-177RadioimmunotherapyPancreatic cancerMUC1C595 |
| spellingShingle | Ashleigh Hull William Hsieh William Tieu Dylan Bartholomeusz Yanrui Li Eva Bezak In vitro characterisation of [177Lu]Lu-DOTA-C595 as a novel radioimmunotherapy for MUC1-CE positive pancreatic cancer EJNMMI Radiopharmacy and Chemistry Lutetium-177 Radioimmunotherapy Pancreatic cancer MUC1 C595 |
| title | In vitro characterisation of [177Lu]Lu-DOTA-C595 as a novel radioimmunotherapy for MUC1-CE positive pancreatic cancer |
| title_full | In vitro characterisation of [177Lu]Lu-DOTA-C595 as a novel radioimmunotherapy for MUC1-CE positive pancreatic cancer |
| title_fullStr | In vitro characterisation of [177Lu]Lu-DOTA-C595 as a novel radioimmunotherapy for MUC1-CE positive pancreatic cancer |
| title_full_unstemmed | In vitro characterisation of [177Lu]Lu-DOTA-C595 as a novel radioimmunotherapy for MUC1-CE positive pancreatic cancer |
| title_short | In vitro characterisation of [177Lu]Lu-DOTA-C595 as a novel radioimmunotherapy for MUC1-CE positive pancreatic cancer |
| title_sort | in vitro characterisation of 177lu lu dota c595 as a novel radioimmunotherapy for muc1 ce positive pancreatic cancer |
| topic | Lutetium-177 Radioimmunotherapy Pancreatic cancer MUC1 C595 |
| url | https://doi.org/10.1186/s41181-023-00204-4 |
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