Targeting of adenovirus to endothelial cells by a bispecific single-chain diabody directed against the adenovirus fiber knob domain and human endoglin (CD105).
AuthorsNettelbeck, Dirk M
Miller, Daniel W
Watkins, Sarah J
Hawkins, Robert E
Kontermann, Roland E
AffiliationInstitut für Molekularbiologie und Tumorforschung, Philipps-Universität Marburg, Emil-Mannkopff-Strabetae 2, Marburg, D-35033, Germany.
MetadataShow full item record
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.
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.
- Targeting of adenoviral vectors through a bispecific single-chain antibody.
- Authors: Haisma HJ, Grill J, Curiel DT, Hoogeland S, van Beusechem VW, Pinedo HM, Gerritsen WR
- Issue date: 2000 Jun
- Bispecific single-chain diabody-mediated killing of endoglin-positive endothelial cells by cytotoxic T lymphocytes.
- Authors: Korn T, Müller R, Kontermann RE
- Issue date: 2004 Mar-Apr
- Bispecific single-chain diabody-immunoliposomes targeting endoglin (CD105) and fibroblast activation protein (FAP) simultaneously.
- Authors: Rabenhold M, Steiniger F, Fahr A, Kontermann RE, Rüger R
- Issue date: 2015 Mar 10
- Targeting of immunoliposomes to endothelial cells using a single-chain Fv fragment directed against human endoglin (CD105).
- Authors: Völkel T, Hölig P, Merdan T, Müller R, Kontermann RE
- Issue date: 2004 May 27
- Recombinant bispecific antibodies for the targeting of adenoviruses to CEA-expressing tumour cells: a comparative analysis of bacterially expressed single-chain diabody and tandem scFv.
- Authors: Korn T, Nettelbeck DM, Völkel T, Müller R, Kontermann RE
- Issue date: 2004 Jun