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- Evans Axelsson, Susan, et al.
(författare)
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Targeting free prostate-specific antigen for in vivo imaging of prostate cancer using a monoclonal antibody specific for unique epitopes accessible on free prostate-specific antigen alone
- 2012
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Ingår i: Cancer Biotherapy and Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 27:4, s. 243-251
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Tidskriftsartikel (refereegranskat)abstract
- This study investigated the feasibility of targeting the free, unbound forms of prostate-specific antigen (fPSA) for in vivo imaging of prostate adenocarcinomas (PCa), as PSA is produced and secreted at abundance during every clinical stage and grade of PCa, including castration-resistant disease. We injected 125I-labeled monoclonal antibody PSA30 (specific for an epitope uniquely accessible on fPSA alone) intravenously in male nude mice carrying subcutaneous xenografts of LNCaP tumors (n=36). Mice were sacrificed over a time course from 4 hours to 13 days after injecting 125I-labeled PSA30. Tissue uptake of 125I-PSA30 at 48 and 168 hours after intravenous injection was compared with two clinically used positron emission tomography radiopharmaceuticals, 18F-fluoro-deoxy-glucose (18F-FDG) or 18F-choline, in cryosections using Digital AutoRadiography (DAR) and also compared with immunohistochemical staining of PSA and histopathology. On DAR, the areas with high 125I-PSA30 uptake corresponded mainly to morphologically intact and PSA-producing LNCaP cells, but did not associate with the areas of high uptake of either 18F-FDG or 18F-choline. Biodistribution of 125I-PSA30 measured in dissected organs ex vivo during 4 to 312 hours after intravenous injection demonstrated maximum selective tumor uptake 24–48 hours after antibody injection. Our data showed selective uptake in vivo of a monoclonal antibody highly specific for fPSA in LNCaP cells. Hence, in vivo imaging of fPSA may be feasible with putative usefulness in disseminated PCa.
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| 2. |
- Evans Axelsson, Susan, et al.
(författare)
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Preclinical evaluation of (111)In-DTPA-INCA-X anti-Ku70/Ku80 monoclonal antibody in prostate cancer.
- 2014
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Ingår i: American journal of nuclear medicine and molecular imaging. - 2160-8407. ; 4:4, s. 311-323
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this investigation was to assess the Ku70/Ku80 complex as a potential target for antibody imaging of prostate cancer. We evaluated the in vivo and ex vivo tumor targeting and biodistribution of the (111)In-labeled human internalizing antibody, INCA-X ((111)In-DTPA-INCA-X antibody), in NMRI-nude mice bearing human PC-3, PC-3M-Lu2 or DU145 xenografts. DTPA-conjugated, non-labeled antibody was pre-administered at different time-points followed by a single intravenous injection of (111)In-DTPA-INCA-X. At 48, 72 and 96 h post-injection, tissues were harvested, and the antibody distribution was determined by measuring radioactivity. Preclinical SPECT/CT imaging of mice with and without the predose was performed at 48 hours post-injection of labeled DTPA-INCA-X. Biodistribution of the labeled antibody showed enriched activity in tumor, spleen and liver. Animals pre-administered with DTPA-INCA-X showed increased tumor uptake and blood content of (111)In-DTPA-INCA-X with reduced splenic and liver uptake. The in vitro and in vivo data presented show that the (111)In-labeled INCA-X antibody is internalized into prostate cancer cells and by pre-administering non-labeled DTPA-INCA-X, we were able to significantly reduce the off target binding and increase the (111)In-DTPA-INCA-X mAb uptake in PC-3, PC-3M-Lu2 and DU145 xenografts. The results are encouraging and identifying the Ku70/Ku80 antigen as a target is worth further investigation for functional imaging of prostate cancer.
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| 3. |
- Evans Axelsson, Susan, et al.
(författare)
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Radioimmunotherapy for Prostate Cancer-Current Status and Future Possibilities.
- 2016
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Ingår i: Seminars in Nuclear Medicine. - : Elsevier BV. - 0001-2998. ; 46:2, s. 165-179
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Forskningsöversikt (refereegranskat)abstract
- Prostate cancer (PCa) is one of the most common cancers in men and is the second leading cause of cancer-related deaths in the USA. In the United States, it is the second most frequently diagnosed cancer after skin cancer, and in Europe it is number one. According to the American Cancer Society, approximately 221,000 men in the United States would be diagnosed with PCa during 2015, and approximately 28,000 would die of the disease. According to the International Agency for Research on Cancer, approximately 345,000 men were diagnosed with PCa in Europe during 2012, and despite more emphasis placed on early detection through routine screening, 72,000 men died of the disease. Hence, the need for improved therapy modalities is of utmost importance. And targeted therapies based on radiolabeled specific antibodies or peptides are a very interesting and promising alternative to increase the therapeutic efficacy and overall chance of survival of these patients. There are currently several preclinical and some clinical studies that have been conducted, or are ongoing, to investigate the therapeutic efficacy and toxicity of radioimmunotherapy (RIT) against PCa. One thing that is lacking in a lot of these published studies is the dosimetry data, which are needed to compare results between the studies and the study locations. Given the complicated tumor microenvironment and overall complexity of RIT to PCa, old and new targets and targeting strategies like combination RIT and pretargeting RIT are being improved and assessed along with various therapeutic radionuclides candidates. Given alone or in combination with other therapies, these new and improved strategies and RIT tools further enhance the clinical response to RIT drugs in PCa, making RIT for PCa an increasingly practical clinical tool.
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| 4. |
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| 5. |
- Vilhelmsson Timmermand, Oskar, et al.
(författare)
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Preclinical imaging of kallikrein-related peptidase 2 (hK2) in prostate cancer with a In-111-radiolabelled monoclonal antibody, 11B6
- 2014
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Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Prostate cancer is a leading cause of death in the male population of the western world. Human kallikrein-related peptidase 2 (hK2) is abundantly expressed in malignant prostatic tissue, and its gene, KLK2, is regulated by the androgen receptor. 11B6 is a murine IgG(1) monoclonal antibody directed against free human hK2. In this study, we performed a preclinical evaluation of In-111-labelled 11B6 in mouse xenografts to investigate its potential in the clinical staging and assessment of metastatic prostate cancer. Methods: 11B6 was radiolabelled with In-111 through CHX-A"-DTPA chelation. In vivo biodistribution and uptake of In-111-DTPA-11B6 were measured until 168 h post-injection in NMRI nude mice bearing subcutaneous LNCaP xenografts. The binding specificity to hK2 was evaluated by both in vivo competitive binding assays with excess non-labelled 11B6 and hK2-negative DU145 xenografts. SPECT/CT imaging of subcutaneous and intra-tibial LNCaP xenografts was used to visualize the tumours. Results: Tumour uptake of In-111-DTPA-11B6 in LNCaP xenografts was 19% +/- 0.78% IA/g at 48 h, giving a tumour-to-blood ratio of 1.6, which increases to 2.4 at 1 week post-injection. Accumulation was low in other organs except for the salivary glands, which is probably the result of cross-reactivity with mouse kallikreins. Significantly lower tumour accumulation was observed in competitive assays and DU145 xenografts. SPECT/CT imaging could clearly visualize the subcutaneous and intra-tibial LNCaP xenografts. Conclusions: Our study demonstrates the potential of In-111-DTPA-11B6 for the detection of metastatic prostate cancer and monitoring anti-androgen therapy, as it exhibits an increased uptake and accumulation in viable tumour when compared to normal tissue. A humanised version of the 11B6 monoclonal antibody is currently under evaluation.
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| 6. |
- Vilhelmsson Timmermand, Oskar, et al.
(författare)
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Radiolabeled antibodies in prostate cancer: A case study showing the effect of host immunity on antibody bio-distribution.
- 2015
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Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 1872-9614 .- 0969-8051. ; 42:4, s. 375-380
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Tidskriftsartikel (refereegranskat)abstract
- Human tumors xenografted in immunodeficient mice are crucial models in nuclear medicine to evaluate the effectiveness of candidate diagnostic and therapeutic compounds. However, little attention has been focused on the biological profile of the host model and its potential effects on the bio-distribution and tumor targeting of the tracer compound under study. We specifically investigated the dissimilarity in bio-distribution of (111)In-DTPA-5A10, which targets free prostate specific antigen (fPSA), in two animal models.
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| 7. |
- Örbom, Anders, et al.
(författare)
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Multi-radionuclide digital autoradiography of the intra-aortic atherosclerotic plaques using a monoclonal antibody targeting oxidized low-density lipoprotein.
- 2014
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Ingår i: American journal of nuclear medicine and molecular imaging. - 2160-8407. ; 4:2, s. 172-180
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to use multi-radionuclide autoradiography to compare the different distributions of three radiolabelled tracers in an atherosclerotic mouse model. This method, along with immunohistochemistry, was applied to investigate the intra-aortic distribution of 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG), (131)I/(125)I labeled anti-oxidized Low Density Lipoprotein (oxLDL), and non-binding control antibodies. Aortas were isolated from a total of 12 apoB-100/LDL receptor deficient mice 73 h post injection of radioiodine-labeled anti-oxLDL and control antibody and 1 h post injection of (18)F-FDG. A solid-state real-time digital autoradiography system was used to image the slide mounted aortas. Contributions from each radionuclide were separated by half-life and emission energy and the aortas were subsequently stained with Oil Red O for plaque to aorta contrast ratios. Immunohistochemical staining was performed to detect anti-oxLDL and control antibody localization. Radiolabeled anti-oxLDL showed increased total activity uptake in the aorta over control antibody and immunohistochemical analysis of plaques indicated increased binding of the specific antibody compared to control. The intra-aortic activity distribution of the anti-oxLDL antibody was however very similar to that of the control antibody although both had higher atherosclerotic plaques to aorta wall ratios than (18)F-FDG. Given the right choice of radionuclides, multi-radionuclide digital autoradiography can be employed to compare several tracers ex vivo in the same animal. The distribution of anti-oxLDL antibodies did not significantly differ from the control antibody but it did appear to have a better plaque to aorta contrast at 73 h post injection than (18)F-FDG at 1 h post injection.
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