Comparison of antibody-scTRAIL Fc fusion proteins with varying valency for EGFR and TRAIL receptors
Abstract Fusion proteins combining TNF-related apoptosis inducing ligand (TRAIL) and antibody building blocks have emerged as a strategy for the targeted treatment of cancer cells. Using a single-chain derivative of homotrimeric TRAIL (scTRAIL), several targeted and non-targeted scTRAIL fusion prote...
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Nature Portfolio
2025-05-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-025-00476-7 |
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| author | Dennis Michler Oliver Seifert Klaus Pfizenmaier Roland E. Kontermann |
| author_facet | Dennis Michler Oliver Seifert Klaus Pfizenmaier Roland E. Kontermann |
| author_sort | Dennis Michler |
| collection | DOAJ |
| description | Abstract Fusion proteins combining TNF-related apoptosis inducing ligand (TRAIL) and antibody building blocks have emerged as a strategy for the targeted treatment of cancer cells. Using a single-chain derivative of homotrimeric TRAIL (scTRAIL), several targeted and non-targeted scTRAIL fusion proteins of varying geometries and valencies for TRAIL receptors and target antigens, all comprising an Fc region, were generated. These fusion proteins comprised either 1 or 2 scTRAIL units, i.e. are tri- or hexavalent for TRAIL receptors and in the targeted versions, 1 or 2 binding sites for EGFR. These fusion proteins were analyzed for cell binding and cell death induction using the EGFR-expressing colorectal cancer cell lines Colo205 and HCT116. In line with previous findings, all fusion proteins that were hexavalent for TRAIL receptors exhibited a strongly increased cell killing activity compared to the trivalent ones. Interestingly, the fusion proteins comprising one scTRAIL unit, did not benefit from targeting to EGFR. In contrast, the hexavalent scTRAIL fusion proteins further benefited from EGFR targeting, resulting in an approximately 6- to 30-fold increase in cell killing. In summary, this study shed further light on the influence of geometry and valency of TRAIL fusion proteins and confirmed IgG-scTRAIL fusion proteins as highly potent cell death inducers. |
| format | Article |
| id | doaj-art-361e15ecada94dcaa9ff7fdcfd0ec0ef |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-361e15ecada94dcaa9ff7fdcfd0ec0ef2025-08-20T03:09:35ZengNature PortfolioScientific Reports2045-23222025-05-0115111010.1038/s41598-025-00476-7Comparison of antibody-scTRAIL Fc fusion proteins with varying valency for EGFR and TRAIL receptorsDennis Michler0Oliver Seifert1Klaus Pfizenmaier2Roland E. Kontermann3Institute of Cell Biology and Immunology, University of StuttgartInstitute of Cell Biology and Immunology, University of StuttgartInstitute of Cell Biology and Immunology, University of StuttgartInstitute of Cell Biology and Immunology, University of StuttgartAbstract Fusion proteins combining TNF-related apoptosis inducing ligand (TRAIL) and antibody building blocks have emerged as a strategy for the targeted treatment of cancer cells. Using a single-chain derivative of homotrimeric TRAIL (scTRAIL), several targeted and non-targeted scTRAIL fusion proteins of varying geometries and valencies for TRAIL receptors and target antigens, all comprising an Fc region, were generated. These fusion proteins comprised either 1 or 2 scTRAIL units, i.e. are tri- or hexavalent for TRAIL receptors and in the targeted versions, 1 or 2 binding sites for EGFR. These fusion proteins were analyzed for cell binding and cell death induction using the EGFR-expressing colorectal cancer cell lines Colo205 and HCT116. In line with previous findings, all fusion proteins that were hexavalent for TRAIL receptors exhibited a strongly increased cell killing activity compared to the trivalent ones. Interestingly, the fusion proteins comprising one scTRAIL unit, did not benefit from targeting to EGFR. In contrast, the hexavalent scTRAIL fusion proteins further benefited from EGFR targeting, resulting in an approximately 6- to 30-fold increase in cell killing. In summary, this study shed further light on the influence of geometry and valency of TRAIL fusion proteins and confirmed IgG-scTRAIL fusion proteins as highly potent cell death inducers.https://doi.org/10.1038/s41598-025-00476-7TNF-related apoptosis-inducing factorTRAILScTRAILAntibody fusion proteinTargetingCancer |
| spellingShingle | Dennis Michler Oliver Seifert Klaus Pfizenmaier Roland E. Kontermann Comparison of antibody-scTRAIL Fc fusion proteins with varying valency for EGFR and TRAIL receptors Scientific Reports TNF-related apoptosis-inducing factor TRAIL ScTRAIL Antibody fusion protein Targeting Cancer |
| title | Comparison of antibody-scTRAIL Fc fusion proteins with varying valency for EGFR and TRAIL receptors |
| title_full | Comparison of antibody-scTRAIL Fc fusion proteins with varying valency for EGFR and TRAIL receptors |
| title_fullStr | Comparison of antibody-scTRAIL Fc fusion proteins with varying valency for EGFR and TRAIL receptors |
| title_full_unstemmed | Comparison of antibody-scTRAIL Fc fusion proteins with varying valency for EGFR and TRAIL receptors |
| title_short | Comparison of antibody-scTRAIL Fc fusion proteins with varying valency for EGFR and TRAIL receptors |
| title_sort | comparison of antibody sctrail fc fusion proteins with varying valency for egfr and trail receptors |
| topic | TNF-related apoptosis-inducing factor TRAIL ScTRAIL Antibody fusion protein Targeting Cancer |
| url | https://doi.org/10.1038/s41598-025-00476-7 |
| work_keys_str_mv | AT dennismichler comparisonofantibodysctrailfcfusionproteinswithvaryingvalencyforegfrandtrailreceptors AT oliverseifert comparisonofantibodysctrailfcfusionproteinswithvaryingvalencyforegfrandtrailreceptors AT klauspfizenmaier comparisonofantibodysctrailfcfusionproteinswithvaryingvalencyforegfrandtrailreceptors AT rolandekontermann comparisonofantibodysctrailfcfusionproteinswithvaryingvalencyforegfrandtrailreceptors |