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Novel Ubiquitin-derived High Affinity Binding Proteins with Tumor Targeting Properties

Targeting effector molecules to tumor cells is a promising mode of action for cancer therapy and diagnostics. Binding proteins with high affinity and specificity for a tumor target that carry effector molecules such as toxins, cytokines, or radiolabels to their intended site of action are required f...

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Autores principales: Lorey, Susan, Fiedler, Erik, Kunert, Anja, Nerkamp, Jörg, Lange, Christian, Fiedler, Markus, Bosse-Doenecke, Eva, Meysing, Maren, Gloser, Manja, Rundfeldt, Chris, Rauchhaus, Una, Hänssgen, Ilka, Göttler, Thomas, Steuernagel, Arnd, Fiedler, Ulrike, Haupts, Ulrich
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961674/
https://www.ncbi.nlm.nih.gov/pubmed/24474690
http://dx.doi.org/10.1074/jbc.M113.519884
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author Lorey, Susan
Fiedler, Erik
Kunert, Anja
Nerkamp, Jörg
Lange, Christian
Fiedler, Markus
Bosse-Doenecke, Eva
Meysing, Maren
Gloser, Manja
Rundfeldt, Chris
Rauchhaus, Una
Hänssgen, Ilka
Göttler, Thomas
Steuernagel, Arnd
Fiedler, Ulrike
Haupts, Ulrich
author_facet Lorey, Susan
Fiedler, Erik
Kunert, Anja
Nerkamp, Jörg
Lange, Christian
Fiedler, Markus
Bosse-Doenecke, Eva
Meysing, Maren
Gloser, Manja
Rundfeldt, Chris
Rauchhaus, Una
Hänssgen, Ilka
Göttler, Thomas
Steuernagel, Arnd
Fiedler, Ulrike
Haupts, Ulrich
author_sort Lorey, Susan
collection PubMed
description Targeting effector molecules to tumor cells is a promising mode of action for cancer therapy and diagnostics. Binding proteins with high affinity and specificity for a tumor target that carry effector molecules such as toxins, cytokines, or radiolabels to their intended site of action are required for these applications. In order to yield high tumor accumulation while maintaining low levels in healthy tissues and blood, the half-life of such conjugates needs to be in an optimal range. Scaffold-based binding molecules are small proteins with high affinity and short systemic circulation. Due to their low molecular complexity, they are well suited for combination with effector molecules as well as half-life extension technologies yielding therapeutics with half-lives adapted to the specific therapy. We have identified ubiquitin as an ideal scaffold protein due to its outstanding biophysical and biochemical properties. Based on a dimeric ubiquitin library, high affinity and specific binding molecules, so-called Affilin® molecules, have been selected against the extradomain B of fibronectin, a target almost exclusively expressed in tumor tissues. Extradomain B-binding molecules feature high thermal and serum stability as well as strong in vitro target binding and in vivo tumor accumulation. Application of several half-life extension technologies results in molecules of largely unaffected affinity but significantly prolonged in vivo half-life and tumor retention. Our results demonstrate the utility of ubiquitin as a scaffold for the generation of high affinity binders in a modular fashion, which can be combined with effector molecules and half-life extension technologies.
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spelling pubmed-39616742014-03-25 Novel Ubiquitin-derived High Affinity Binding Proteins with Tumor Targeting Properties Lorey, Susan Fiedler, Erik Kunert, Anja Nerkamp, Jörg Lange, Christian Fiedler, Markus Bosse-Doenecke, Eva Meysing, Maren Gloser, Manja Rundfeldt, Chris Rauchhaus, Una Hänssgen, Ilka Göttler, Thomas Steuernagel, Arnd Fiedler, Ulrike Haupts, Ulrich J Biol Chem Genomics and Proteomics Targeting effector molecules to tumor cells is a promising mode of action for cancer therapy and diagnostics. Binding proteins with high affinity and specificity for a tumor target that carry effector molecules such as toxins, cytokines, or radiolabels to their intended site of action are required for these applications. In order to yield high tumor accumulation while maintaining low levels in healthy tissues and blood, the half-life of such conjugates needs to be in an optimal range. Scaffold-based binding molecules are small proteins with high affinity and short systemic circulation. Due to their low molecular complexity, they are well suited for combination with effector molecules as well as half-life extension technologies yielding therapeutics with half-lives adapted to the specific therapy. We have identified ubiquitin as an ideal scaffold protein due to its outstanding biophysical and biochemical properties. Based on a dimeric ubiquitin library, high affinity and specific binding molecules, so-called Affilin® molecules, have been selected against the extradomain B of fibronectin, a target almost exclusively expressed in tumor tissues. Extradomain B-binding molecules feature high thermal and serum stability as well as strong in vitro target binding and in vivo tumor accumulation. Application of several half-life extension technologies results in molecules of largely unaffected affinity but significantly prolonged in vivo half-life and tumor retention. Our results demonstrate the utility of ubiquitin as a scaffold for the generation of high affinity binders in a modular fashion, which can be combined with effector molecules and half-life extension technologies. American Society for Biochemistry and Molecular Biology 2014-03-21 2014-01-28 /pmc/articles/PMC3961674/ /pubmed/24474690 http://dx.doi.org/10.1074/jbc.M113.519884 Text en © 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Unported License (http://creativecommons.org/licenses/by/3.0/) applies to Author Choice Articles
spellingShingle Genomics and Proteomics
Lorey, Susan
Fiedler, Erik
Kunert, Anja
Nerkamp, Jörg
Lange, Christian
Fiedler, Markus
Bosse-Doenecke, Eva
Meysing, Maren
Gloser, Manja
Rundfeldt, Chris
Rauchhaus, Una
Hänssgen, Ilka
Göttler, Thomas
Steuernagel, Arnd
Fiedler, Ulrike
Haupts, Ulrich
Novel Ubiquitin-derived High Affinity Binding Proteins with Tumor Targeting Properties
title Novel Ubiquitin-derived High Affinity Binding Proteins with Tumor Targeting Properties
title_full Novel Ubiquitin-derived High Affinity Binding Proteins with Tumor Targeting Properties
title_fullStr Novel Ubiquitin-derived High Affinity Binding Proteins with Tumor Targeting Properties
title_full_unstemmed Novel Ubiquitin-derived High Affinity Binding Proteins with Tumor Targeting Properties
title_short Novel Ubiquitin-derived High Affinity Binding Proteins with Tumor Targeting Properties
title_sort novel ubiquitin-derived high affinity binding proteins with tumor targeting properties
topic Genomics and Proteomics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961674/
https://www.ncbi.nlm.nih.gov/pubmed/24474690
http://dx.doi.org/10.1074/jbc.M113.519884
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