Low-Level Endothelial TRAIL-Receptor Expression Obstructs the CNS-Delivery of Angiopep-2 Functionalised TRAIL-Receptor Agonists for the Treatment of Glioblastoma
Glioblastoma (GBM) is the most malignant and aggressive form of glioma and is associated with a poor survival rate. Latest generation Tumour Necrosis Factor Related Apoptosis-Inducing Ligand (TRAIL)-based therapeutics potently induce apoptosis in cancer cells, including GBM cells, by binding to deat...
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| Format: | Article |
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MDPI AG
2021-12-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/24/7582 |
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| author | Nivetha Krishna Moorthy Oliver Seifert Stephan Eisler Sara Weirich Roland E. Kontermann Markus Rehm Gavin Fullstone |
| author_facet | Nivetha Krishna Moorthy Oliver Seifert Stephan Eisler Sara Weirich Roland E. Kontermann Markus Rehm Gavin Fullstone |
| author_sort | Nivetha Krishna Moorthy |
| collection | DOAJ |
| description | Glioblastoma (GBM) is the most malignant and aggressive form of glioma and is associated with a poor survival rate. Latest generation Tumour Necrosis Factor Related Apoptosis-Inducing Ligand (TRAIL)-based therapeutics potently induce apoptosis in cancer cells, including GBM cells, by binding to death receptors. However, the blood–brain barrier (BBB) is a major obstacle for these biologics to enter the central nervous system (CNS). We therefore investigated if antibody-based fusion proteins that combine hexavalent TRAIL and angiopep-2 (ANG2) moieties can be developed, with ANG2 promoting receptor-mediated transcytosis (RMT) across the BBB. We demonstrate that these fusion proteins retain the potent apoptosis induction of hexavalent TRAIL-receptor agonists. Importantly, blood–brain barrier cells instead remained highly resistant to this fusion protein. Binding studies indicated that ANG2 is active in these constructs but that TRAIL-ANG2 fusion proteins bind preferentially to BBB endothelial cells via the TRAIL moiety. Consequently, transport studies indicated that TRAIL-ANG2 fusion proteins can, in principle, be shuttled across BBB endothelial cells, but that low TRAIL receptor expression on BBB endothelial cells interferes with efficient transport. Our work therefore demonstrates that TRAIL-ANG2 fusion proteins remain highly potent in inducing apoptosis, but that therapeutic avenues will require combinatorial strategies, such as TRAIL-R masking, to achieve effective CNS transport. |
| first_indexed | 2024-03-10T03:28:11Z |
| format | Article |
| id | doaj.art-4ed2b32cb0be4d78a5ca22734b51a25f |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T03:28:11Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-4ed2b32cb0be4d78a5ca22734b51a25f2023-11-23T09:46:17ZengMDPI AGMolecules1420-30492021-12-012624758210.3390/molecules26247582Low-Level Endothelial TRAIL-Receptor Expression Obstructs the CNS-Delivery of Angiopep-2 Functionalised TRAIL-Receptor Agonists for the Treatment of GlioblastomaNivetha Krishna Moorthy0Oliver Seifert1Stephan Eisler2Sara Weirich3Roland E. Kontermann4Markus Rehm5Gavin Fullstone6Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569 Stuttgart, GermanyInstitute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569 Stuttgart, GermanyInstitute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569 Stuttgart, GermanyInstitute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569 Stuttgart, GermanyInstitute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569 Stuttgart, GermanyInstitute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569 Stuttgart, GermanyInstitute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569 Stuttgart, GermanyGlioblastoma (GBM) is the most malignant and aggressive form of glioma and is associated with a poor survival rate. Latest generation Tumour Necrosis Factor Related Apoptosis-Inducing Ligand (TRAIL)-based therapeutics potently induce apoptosis in cancer cells, including GBM cells, by binding to death receptors. However, the blood–brain barrier (BBB) is a major obstacle for these biologics to enter the central nervous system (CNS). We therefore investigated if antibody-based fusion proteins that combine hexavalent TRAIL and angiopep-2 (ANG2) moieties can be developed, with ANG2 promoting receptor-mediated transcytosis (RMT) across the BBB. We demonstrate that these fusion proteins retain the potent apoptosis induction of hexavalent TRAIL-receptor agonists. Importantly, blood–brain barrier cells instead remained highly resistant to this fusion protein. Binding studies indicated that ANG2 is active in these constructs but that TRAIL-ANG2 fusion proteins bind preferentially to BBB endothelial cells via the TRAIL moiety. Consequently, transport studies indicated that TRAIL-ANG2 fusion proteins can, in principle, be shuttled across BBB endothelial cells, but that low TRAIL receptor expression on BBB endothelial cells interferes with efficient transport. Our work therefore demonstrates that TRAIL-ANG2 fusion proteins remain highly potent in inducing apoptosis, but that therapeutic avenues will require combinatorial strategies, such as TRAIL-R masking, to achieve effective CNS transport.https://www.mdpi.com/1420-3049/26/24/7582glioblastomaTRAILangiopep-2CNS deliveryreceptor-mediated transcytosisblood–brain barrier |
| spellingShingle | Nivetha Krishna Moorthy Oliver Seifert Stephan Eisler Sara Weirich Roland E. Kontermann Markus Rehm Gavin Fullstone Low-Level Endothelial TRAIL-Receptor Expression Obstructs the CNS-Delivery of Angiopep-2 Functionalised TRAIL-Receptor Agonists for the Treatment of Glioblastoma Molecules glioblastoma TRAIL angiopep-2 CNS delivery receptor-mediated transcytosis blood–brain barrier |
| title | Low-Level Endothelial TRAIL-Receptor Expression Obstructs the CNS-Delivery of Angiopep-2 Functionalised TRAIL-Receptor Agonists for the Treatment of Glioblastoma |
| title_full | Low-Level Endothelial TRAIL-Receptor Expression Obstructs the CNS-Delivery of Angiopep-2 Functionalised TRAIL-Receptor Agonists for the Treatment of Glioblastoma |
| title_fullStr | Low-Level Endothelial TRAIL-Receptor Expression Obstructs the CNS-Delivery of Angiopep-2 Functionalised TRAIL-Receptor Agonists for the Treatment of Glioblastoma |
| title_full_unstemmed | Low-Level Endothelial TRAIL-Receptor Expression Obstructs the CNS-Delivery of Angiopep-2 Functionalised TRAIL-Receptor Agonists for the Treatment of Glioblastoma |
| title_short | Low-Level Endothelial TRAIL-Receptor Expression Obstructs the CNS-Delivery of Angiopep-2 Functionalised TRAIL-Receptor Agonists for the Treatment of Glioblastoma |
| title_sort | low level endothelial trail receptor expression obstructs the cns delivery of angiopep 2 functionalised trail receptor agonists for the treatment of glioblastoma |
| topic | glioblastoma TRAIL angiopep-2 CNS delivery receptor-mediated transcytosis blood–brain barrier |
| url | https://www.mdpi.com/1420-3049/26/24/7582 |
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