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dc.contributor.authorNettelbeck, Dirk M
dc.contributor.authorMiller, Daniel W
dc.contributor.authorJérôme, Valerie
dc.contributor.authorZuzarte, Marylou
dc.contributor.authorWatkins, Sarah J
dc.contributor.authorHawkins, Robert E
dc.contributor.authorMuller, Rolf
dc.contributor.authorKontermann, Roland E
dc.date.accessioned2009-11-10T09:37:32Z
dc.date.available2009-11-10T09:37:32Z
dc.date.issued2001-06
dc.identifier.citationTargeting of adenovirus to endothelial cells by a bispecific single-chain diabody directed against the adenovirus fiber knob domain and human endoglin (CD105). 2001, 3 (6):882-91 Mol. Ther.en
dc.identifier.issn1525-0016
dc.identifier.pmid11407902
dc.identifier.doi10.1006/mthe.2001.0342
dc.identifier.urihttp://hdl.handle.net/10541/85721
dc.description.abstractThe use of adenoviruses for antivascular cancer gene therapy is limited by their low transduction efficiency for endothelial cells. We have developed a recombinant bispecific antibody as a molecular bridge, linking the adenovirus capsid to the endothelial cell surface protein endoglin, for vascular targeting of adenoviruses. Endoglin (CD105), a component of the transforming growth factor beta receptor complex, represents a promising target for antivascular cancer therapy. Endoglin is expressed predominantly on endothelial cells and is upregulated in angiogenic areas of tumors. We isolated single-chain Fv fragments directed against human endoglin from a human semisynthetic antibody library. One of the isolated scFv fragments (scFv C4) bound specifically to various proliferating primary endothelial cells or cell lines including HUVEC, HDMEC, HMVEC, and HMEC. ScFv C4 was therefore used to construct a bispecific single-chain diabody directed against endoglin and the adenovirus fiber knob domain (scDb EDG-Ad). This bispecific molecule mediated enhanced and selective adenovirus transduction of HUVECs, which was independent from binding to the coxsackievirus and adenovirus receptor (CAR) and alpha(v)-integrins. Thus, adenovirus infection was redirected to a new cellular receptor (CD105) and cell entry pathway. These results demonstrate the utility of bispecific single-chain diabodies, which can be produced in large quantities in bacteria, for the retargeting of adenoviruses in cancer gene therapy.
dc.language.isoenen
dc.subject.meshAdenoviridae
dc.subject.meshAntibodies, Bispecific
dc.subject.meshAntibodies, Viral
dc.subject.meshAntigens, CD
dc.subject.meshBase Sequence
dc.subject.meshBlotting, Western
dc.subject.meshCells, Cultured
dc.subject.meshCloning, Molecular
dc.subject.meshEndothelium, Vascular
dc.subject.meshEnzyme-Linked Immunosorbent Assay
dc.subject.meshFlow Cytometry
dc.subject.meshGene Targeting
dc.subject.meshGene Therapy
dc.subject.meshGenetic Vectors
dc.subject.meshHumans
dc.subject.meshImmunoblotting
dc.subject.meshImmunoglobulin Fragments
dc.subject.meshImmunoglobulin Variable Region
dc.subject.meshMolecular Sequence Data
dc.subject.meshPeptide Library
dc.subject.meshPeptides, Cyclic
dc.subject.meshReceptors, Cell Surface
dc.subject.meshRecombinant Proteins
dc.subject.meshUmbilical Veins
dc.subject.meshVascular Cell Adhesion Molecule-1
dc.titleTargeting of adenovirus to endothelial cells by a bispecific single-chain diabody directed against the adenovirus fiber knob domain and human endoglin (CD105).en
dc.typeArticleen
dc.contributor.departmentInstitut für Molekularbiologie und Tumorforschung, Philipps-Universität Marburg, Emil-Mannkopff-Strabetae 2, Marburg, D-35033, Germany.en
dc.identifier.journalMolecular Therapyen
html.description.abstractThe use of adenoviruses for antivascular cancer gene therapy is limited by their low transduction efficiency for endothelial cells. We have developed a recombinant bispecific antibody as a molecular bridge, linking the adenovirus capsid to the endothelial cell surface protein endoglin, for vascular targeting of adenoviruses. Endoglin (CD105), a component of the transforming growth factor beta receptor complex, represents a promising target for antivascular cancer therapy. Endoglin is expressed predominantly on endothelial cells and is upregulated in angiogenic areas of tumors. We isolated single-chain Fv fragments directed against human endoglin from a human semisynthetic antibody library. One of the isolated scFv fragments (scFv C4) bound specifically to various proliferating primary endothelial cells or cell lines including HUVEC, HDMEC, HMVEC, and HMEC. ScFv C4 was therefore used to construct a bispecific single-chain diabody directed against endoglin and the adenovirus fiber knob domain (scDb EDG-Ad). This bispecific molecule mediated enhanced and selective adenovirus transduction of HUVECs, which was independent from binding to the coxsackievirus and adenovirus receptor (CAR) and alpha(v)-integrins. Thus, adenovirus infection was redirected to a new cellular receptor (CD105) and cell entry pathway. These results demonstrate the utility of bispecific single-chain diabodies, which can be produced in large quantities in bacteria, for the retargeting of adenoviruses in cancer gene therapy.


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