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Holger Jensen - One of the best experts on this subject based on the ideXlab platform.
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towards elucidating the radiochemistry of astatine behavior in chloroform
Scientific Reports, 2019Co-Authors: Stig Palm, Holger Jensen, Emma Aneheim, Christian Ekberg, Per Albertsson, Sture LindegrenAbstract:Targeted alpha therapy of Disseminated Cancer is an emerging technique where astatine-211 is one of the most promising candidate nuclides. Although astatine has been known for over 70 years, its chemistry is still largely unexplored, mainly due to the lack of stable or long-lived isotopes. However, substantial amounts of astatine-211 can be produced in cyclotrons by the bombardment of natural bismuth. The astatine can be recovered from the resulting irradiated target material through either wet extraction or dry-distillation. Chloroform has become an important intermediate solvent for the recovery of astatine after production, especially following dry distillation. In this work, the radiochemistry of astatine in chloroform was investigated using evaporation, solvent extraction, chromatographic methods and molecular modeling. The extraction of astatine in chloroform led to the formation of multiple astatine species, allowing for evaporation of the solvent to dryness without any loss of activity. Radiolysis products of chloroform were shown to play an important role in the speciation of astatine forming both reactive and kinetically stable compounds. It was hypothesized that reactions with chlorine, as well as trichloromethyl hydroperoxide, forming polar astatine compounds are important reactions under the current experimental conditions.
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direct procedure for the production of 211at labeled antibodies with an e lysyl 3 trimethylstannyl benzamide immunoconjugate
The Journal of Nuclear Medicine, 2008Co-Authors: Sture Lindegren, Sofia Frost, Elin Haglund, Jorgen Elgqvist, Tom Bäck, Holger JensenAbstract:(211)At-labeled tumor-specific antibodies have long been considered for the treatment of Disseminated Cancer. However, the limited availability of the nuclide and the poor efficacy of labeling procedures at clinical activity levels present major obstacles to their use. This study evaluated a procedure for the direct astatination of antibodies for the production of clinical activity levels. METHODS: The monoclonal antibody trastuzumab was conjugated with the reagent N-succinimidyl-3-(trimethylstannyl)benzoate, and the immunoconjugate was labeled with astatine. Before astatination of the conjugated antibody, the nuclide was activated with N-iodosuccinimide. The labeling reaction was evaluated in terms of reaction time, volume of reaction solvent, immunoconjugate concentration, and applied activity. The quality of the astatinated antibodies was determined by in vitro analysis and biodistribution studies in nude mice. RESULTS: The reaction proceeded almost instantaneously, and the results indicated a low dependence on immunoconjugate concentration and applied activity. Radiochemical labeling yields were in the range of 68%-81%, and a specific radioactivity of up to 1 GBq/mg could be achieved. Stability and radiochemical purity were equal to or better than those attained with a conventional 2-step procedure. Dissociation constants for directly astatinated, conventionally astatinated, and radioiodinated trastuzumab were 1.0+/-0.06 (mean+/-SD), 0.44+/-0.06, and 0.29+/-0.02 nM, respectively. The tissue distribution in non-tumor-bearing nude mice revealed only minor differences in organ uptake relative to that obtained with the conventional method. CONCLUSION: The direct astatination procedure enables the high-yield production of astatinated antibodies with radioactivity in the amounts required for clinical applications.
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direct procedure for the production of 211at labeled antibodies with an e lysyl 3 trimethylstannyl benzamide immunoconjugate
The Journal of Nuclear Medicine, 2008Co-Authors: Sture Lindegren, Elin Haglund, Jorgen Elgqvist, Tom Bäck, Sofia H L Frost, Holger JensenAbstract:UNLABELLED (211)At-labeled tumor-specific antibodies have long been considered for the treatment of Disseminated Cancer. However, the limited availability of the nuclide and the poor efficacy of labeling procedures at clinical activity levels present major obstacles to their use. This study evaluated a procedure for the direct astatination of antibodies for the production of clinical activity levels. METHODS The monoclonal antibody trastuzumab was conjugated with the reagent N-succinimidyl-3-(trimethylstannyl)benzoate, and the immunoconjugate was labeled with astatine. Before astatination of the conjugated antibody, the nuclide was activated with N-iodosuccinimide. The labeling reaction was evaluated in terms of reaction time, volume of reaction solvent, immunoconjugate concentration, and applied activity. The quality of the astatinated antibodies was determined by in vitro analysis and biodistribution studies in nude mice. RESULTS The reaction proceeded almost instantaneously, and the results indicated a low dependence on immunoconjugate concentration and applied activity. Radiochemical labeling yields were in the range of 68%-81%, and a specific radioactivity of up to 1 GBq/mg could be achieved. Stability and radiochemical purity were equal to or better than those attained with a conventional 2-step procedure. Dissociation constants for directly astatinated, conventionally astatinated, and radioiodinated trastuzumab were 1.0+/-0.06 (mean+/-SD), 0.44+/-0.06, and 0.29+/-0.02 nM, respectively. The tissue distribution in non-tumor-bearing nude mice revealed only minor differences in organ uptake relative to that obtained with the conventional method. CONCLUSION The direct astatination procedure enables the high-yield production of astatinated antibodies with radioactivity in the amounts required for clinical applications.
Daniel H Palmer - One of the best experts on this subject based on the ideXlab platform.
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macrophage derived granulin drives resistance to immune checkpoint inhibition in metastatic pancreatic Cancer
Cancer Research, 2018Co-Authors: Valeria Quaranta, Sebastian R Nielsen, Carolyn Rainer, Dannielle D Engle, Meirion Raymant, Arthur Taylor, Trish Murray, Muhammad S Ahmed, Fiona Campbell, Daniel H PalmerAbstract:The ability of Disseminated Cancer cells to evade the immune response is a critical step for efficient metastatic progression. Protection against an immune attack is often provided by the tumor microenvironment that suppresses and excludes cytotoxic CD8+ T cells. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive metastatic disease with unmet needs, yet the immunoprotective role of the metastatic tumor microenvironment in pancreatic Cancer is not completely understood. In this study we find that macrophage-derived granulin contributes to cytotoxic CD8+ T cell exclusion in metastatic livers. Granulin expression by macrophages was induced in response to colony-stimulating factor-1. Genetic depletion of granulin reduced the formation of a fibrotic stroma, thereby allowing T cell entry at the metastatic site. While metastatic PDAC tumors are largely resistant to anti-PD-1 therapy, blockade of PD-1 in granulin-depleted tumors restored the anti-tumor immune defense and dramatically decreased metastatic tumor burden. These findings suggest that targeting granulin may serve as a potential therapeutic strategy to restore CD8+ T cell infiltration in metastatic PDAC, thereby converting PDAC metastatic tumors, which are refractory to immune checkpoint inhibitors, into tumors that respond to immune checkpoint inhibition therapies.
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macrophage derived granulin drives resistance to immune checkpoint inhibition in metastatic pancreatic Cancer
bioRxiv, 2017Co-Authors: Valeria Quaranta, Sebastian R Nielsen, Carolyn Rainer, Dannielle D Engle, Meirion Raymant, Arthur Taylor, Trish Murray, Muhammad S Ahmed, Fiona Campbell, Daniel H PalmerAbstract:The ability of Disseminated Cancer cells to evade the immune response is a critical step for efficient metastatic progression. Protection against an immune attack is often provided by the tumour microenvironment that suppresses and/or excludes cytotoxic CD8+ T cells. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive metastatic disease with unmet needs, yet the immuno-protective role of the metastatic tumour microenvironment in pancreatic Cancer is not completely understood. In this study we find that macrophage-derived granulin contributes to cytotoxic CD8+ T cell exclusion in metastatic livers. Mechanistically, we find that granulin expression by macrophages is induced in response to colony stimulating factor-1. Genetic depletion of granulin reduces the formation a fibrotic stroma, thereby allowing T cell entry at the metastatic site. While metastatic PDAC tumours are largely resistant to anti-PD-1 therapy, blockade of PD-1 in granulin depleted tumours restored the anti-tumour immune defence and dramatically decreased metastatic tumour burden. These findings suggest that targeting granulin may serve as a potential therapeutic strategy to restore CD8+ T cell infiltration in metastatic PDAC, thereby converting PDAC metastatic tumours, which are refractory to immune checkpoint inhibitors, into tumours that respond to immune checkpoint inhibition therapies.
Sture Lindegren - One of the best experts on this subject based on the ideXlab platform.
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towards elucidating the radiochemistry of astatine behavior in chloroform
Scientific Reports, 2019Co-Authors: Stig Palm, Holger Jensen, Emma Aneheim, Christian Ekberg, Per Albertsson, Sture LindegrenAbstract:Targeted alpha therapy of Disseminated Cancer is an emerging technique where astatine-211 is one of the most promising candidate nuclides. Although astatine has been known for over 70 years, its chemistry is still largely unexplored, mainly due to the lack of stable or long-lived isotopes. However, substantial amounts of astatine-211 can be produced in cyclotrons by the bombardment of natural bismuth. The astatine can be recovered from the resulting irradiated target material through either wet extraction or dry-distillation. Chloroform has become an important intermediate solvent for the recovery of astatine after production, especially following dry distillation. In this work, the radiochemistry of astatine in chloroform was investigated using evaporation, solvent extraction, chromatographic methods and molecular modeling. The extraction of astatine in chloroform led to the formation of multiple astatine species, allowing for evaporation of the solvent to dryness without any loss of activity. Radiolysis products of chloroform were shown to play an important role in the speciation of astatine forming both reactive and kinetically stable compounds. It was hypothesized that reactions with chlorine, as well as trichloromethyl hydroperoxide, forming polar astatine compounds are important reactions under the current experimental conditions.
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direct procedure for the production of 211at labeled antibodies with an e lysyl 3 trimethylstannyl benzamide immunoconjugate
The Journal of Nuclear Medicine, 2008Co-Authors: Sture Lindegren, Sofia Frost, Elin Haglund, Jorgen Elgqvist, Tom Bäck, Holger JensenAbstract:(211)At-labeled tumor-specific antibodies have long been considered for the treatment of Disseminated Cancer. However, the limited availability of the nuclide and the poor efficacy of labeling procedures at clinical activity levels present major obstacles to their use. This study evaluated a procedure for the direct astatination of antibodies for the production of clinical activity levels. METHODS: The monoclonal antibody trastuzumab was conjugated with the reagent N-succinimidyl-3-(trimethylstannyl)benzoate, and the immunoconjugate was labeled with astatine. Before astatination of the conjugated antibody, the nuclide was activated with N-iodosuccinimide. The labeling reaction was evaluated in terms of reaction time, volume of reaction solvent, immunoconjugate concentration, and applied activity. The quality of the astatinated antibodies was determined by in vitro analysis and biodistribution studies in nude mice. RESULTS: The reaction proceeded almost instantaneously, and the results indicated a low dependence on immunoconjugate concentration and applied activity. Radiochemical labeling yields were in the range of 68%-81%, and a specific radioactivity of up to 1 GBq/mg could be achieved. Stability and radiochemical purity were equal to or better than those attained with a conventional 2-step procedure. Dissociation constants for directly astatinated, conventionally astatinated, and radioiodinated trastuzumab were 1.0+/-0.06 (mean+/-SD), 0.44+/-0.06, and 0.29+/-0.02 nM, respectively. The tissue distribution in non-tumor-bearing nude mice revealed only minor differences in organ uptake relative to that obtained with the conventional method. CONCLUSION: The direct astatination procedure enables the high-yield production of astatinated antibodies with radioactivity in the amounts required for clinical applications.
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direct procedure for the production of 211at labeled antibodies with an e lysyl 3 trimethylstannyl benzamide immunoconjugate
The Journal of Nuclear Medicine, 2008Co-Authors: Sture Lindegren, Elin Haglund, Jorgen Elgqvist, Tom Bäck, Sofia H L Frost, Holger JensenAbstract:UNLABELLED (211)At-labeled tumor-specific antibodies have long been considered for the treatment of Disseminated Cancer. However, the limited availability of the nuclide and the poor efficacy of labeling procedures at clinical activity levels present major obstacles to their use. This study evaluated a procedure for the direct astatination of antibodies for the production of clinical activity levels. METHODS The monoclonal antibody trastuzumab was conjugated with the reagent N-succinimidyl-3-(trimethylstannyl)benzoate, and the immunoconjugate was labeled with astatine. Before astatination of the conjugated antibody, the nuclide was activated with N-iodosuccinimide. The labeling reaction was evaluated in terms of reaction time, volume of reaction solvent, immunoconjugate concentration, and applied activity. The quality of the astatinated antibodies was determined by in vitro analysis and biodistribution studies in nude mice. RESULTS The reaction proceeded almost instantaneously, and the results indicated a low dependence on immunoconjugate concentration and applied activity. Radiochemical labeling yields were in the range of 68%-81%, and a specific radioactivity of up to 1 GBq/mg could be achieved. Stability and radiochemical purity were equal to or better than those attained with a conventional 2-step procedure. Dissociation constants for directly astatinated, conventionally astatinated, and radioiodinated trastuzumab were 1.0+/-0.06 (mean+/-SD), 0.44+/-0.06, and 0.29+/-0.02 nM, respectively. The tissue distribution in non-tumor-bearing nude mice revealed only minor differences in organ uptake relative to that obtained with the conventional method. CONCLUSION The direct astatination procedure enables the high-yield production of astatinated antibodies with radioactivity in the amounts required for clinical applications.
John A Foekens - One of the best experts on this subject based on the ideXlab platform.
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latent bone metastasis in breast Cancer tied to src dependent survival signals
Cancer Cell, 2009Co-Authors: Xiang Zhang, Qiongqing Wang, William L Gerald, Clifford A Hudis, Larry Norton, Marcel Smid, John A FoekensAbstract:Metastasis may arise years after removal of a primary tumor. The mechanisms allowing latent Disseminated Cancer cells to survive are unknown. We report that a gene expression signature of Src activation is associated with late-onset bone metastasis in breast Cancer. This link is independent of hormone receptor status or breast Cancer subtype. In breast Cancer cells, Src is dispensable for homing to the bones or lungs but is critical for the survival and outgrowth of these cells in the bone marrow. Src mediates AKT regulation and Cancer cell survival responses to CXCL12 and TNF-related apoptosis-inducing ligand (TRAIL), factors that are distinctively expressed in the bone metastasis microenvironment. Breast Cancer cells that lodge in the bone marrow succumb in this environment when deprived of Src activity.
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genes that mediate breast Cancer metastasis to the brain
Nature, 2009Co-Authors: Paula D Bos, Xiang Zhang, William L Gerald, Cristina Nadal, Weiping Shu, R Gomis, Don X Nguyen, Andy J Minn, Marc J Van De Vijver, John A FoekensAbstract:The molecular basis for breast Cancer metastasis to the brain is largely unknown. Brain relapse typically occurs years after the removal of a breast tumour, suggesting that Disseminated Cancer cells must acquire specialized functions to take over this organ. Here we show that breast Cancer metastasis to the brain involves mediators of extravasation through non-fenestrated capillaries, complemented by specific enhancers of blood-brain barrier crossing and brain colonization. We isolated cells that preferentially infiltrate the brain from patients with advanced disease. Gene expression analysis of these cells and of clinical samples, coupled with functional analysis, identified the cyclooxygenase COX2 (also known as PTGS2), the epidermal growth factor receptor (EGFR) ligand HBEGF, and the alpha2,6-sialyltransferase ST6GALNAC5 as mediators of Cancer cell passage through the blood-brain barrier. EGFR ligands and COX2 were previously linked to breast Cancer infiltration of the lungs, but not the bones or liver, suggesting a sharing of these mediators in cerebral and pulmonary metastases. In contrast, ST6GALNAC5 specifically mediates brain metastasis. Normally restricted to the brain, the expression of ST6GALNAC5 in breast Cancer cells enhances their adhesion to brain endothelial cells and their passage through the blood-brain barrier. This co-option of a brain sialyltransferase highlights the role of cell-surface glycosylation in organ-specific metastatic interactions.
Valeria Quaranta - One of the best experts on this subject based on the ideXlab platform.
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macrophage derived granulin drives resistance to immune checkpoint inhibition in metastatic pancreatic Cancer
Cancer Research, 2018Co-Authors: Valeria Quaranta, Sebastian R Nielsen, Carolyn Rainer, Dannielle D Engle, Meirion Raymant, Arthur Taylor, Trish Murray, Muhammad S Ahmed, Fiona Campbell, Daniel H PalmerAbstract:The ability of Disseminated Cancer cells to evade the immune response is a critical step for efficient metastatic progression. Protection against an immune attack is often provided by the tumor microenvironment that suppresses and excludes cytotoxic CD8+ T cells. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive metastatic disease with unmet needs, yet the immunoprotective role of the metastatic tumor microenvironment in pancreatic Cancer is not completely understood. In this study we find that macrophage-derived granulin contributes to cytotoxic CD8+ T cell exclusion in metastatic livers. Granulin expression by macrophages was induced in response to colony-stimulating factor-1. Genetic depletion of granulin reduced the formation of a fibrotic stroma, thereby allowing T cell entry at the metastatic site. While metastatic PDAC tumors are largely resistant to anti-PD-1 therapy, blockade of PD-1 in granulin-depleted tumors restored the anti-tumor immune defense and dramatically decreased metastatic tumor burden. These findings suggest that targeting granulin may serve as a potential therapeutic strategy to restore CD8+ T cell infiltration in metastatic PDAC, thereby converting PDAC metastatic tumors, which are refractory to immune checkpoint inhibitors, into tumors that respond to immune checkpoint inhibition therapies.
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macrophage derived granulin drives resistance to immune checkpoint inhibition in metastatic pancreatic Cancer
bioRxiv, 2017Co-Authors: Valeria Quaranta, Sebastian R Nielsen, Carolyn Rainer, Dannielle D Engle, Meirion Raymant, Arthur Taylor, Trish Murray, Muhammad S Ahmed, Fiona Campbell, Daniel H PalmerAbstract:The ability of Disseminated Cancer cells to evade the immune response is a critical step for efficient metastatic progression. Protection against an immune attack is often provided by the tumour microenvironment that suppresses and/or excludes cytotoxic CD8+ T cells. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive metastatic disease with unmet needs, yet the immuno-protective role of the metastatic tumour microenvironment in pancreatic Cancer is not completely understood. In this study we find that macrophage-derived granulin contributes to cytotoxic CD8+ T cell exclusion in metastatic livers. Mechanistically, we find that granulin expression by macrophages is induced in response to colony stimulating factor-1. Genetic depletion of granulin reduces the formation a fibrotic stroma, thereby allowing T cell entry at the metastatic site. While metastatic PDAC tumours are largely resistant to anti-PD-1 therapy, blockade of PD-1 in granulin depleted tumours restored the anti-tumour immune defence and dramatically decreased metastatic tumour burden. These findings suggest that targeting granulin may serve as a potential therapeutic strategy to restore CD8+ T cell infiltration in metastatic PDAC, thereby converting PDAC metastatic tumours, which are refractory to immune checkpoint inhibitors, into tumours that respond to immune checkpoint inhibition therapies.