Targeting immune effector molecules to human tumor cells through genetic delivery of 5T4-specific scFv fusion proteins.
AuthorsMyers, Kevin A
Ryan, Matthew G
Stern, Peter L
Shaw, David M
Kingsman, Susan M
Carroll, Miles W
AffiliationOxford BioMedica (UK) Ltd., Medawar Centre, Oxford Science Park, UK.
MetadataShow full item record
AbstractAlthough several clinical trials have shown beneficial effects by targeting tumor-associated antigens (TAAs) with monoclonal antibodies, a number of issues, including poor penetration of the tumor mass and human antimouse antibody responses, remain. The use of recombinant single-chain Fv (scFv) fragments has the potential to address these and other issues while allowing the addition of different effector functions. To develop therapeutic strategies that recruit both humoral and cellular arms of the immune response, we have constructed chimeric proteins linking either the human IgG1 Fc domain or the extracellular domain of murine B7.1 to a scFv specific for the oncofetal glycoprotein, 5T4. This TAA is expressed by a wide variety of carcinomas and is associated with metastasis and poorer clinical outcome. We have engineered retroviral constructs that produce fusion proteins able to interact simultaneously with both 5T4-positive cells and with the receptor/ligands of the immune effector moieties. Genetic delivery through a murine leukemia virus vector to 5T4-positive tumor cells results in the secreted scFv fusion protein binding to the cell surface. Furthermore, the scFv-HIgG1 fusion protein is able to direct lysis of 5T4-expressing human tumor cell lines through antibody-dependent cell cytotoxicity, indicating its potential as a gene therapy for human cancers.
CitationTargeting immune effector molecules to human tumor cells through genetic delivery of 5T4-specific scFv fusion proteins. 2002, 9 (11):884-96 Cancer Gene Ther.
JournalCancer Gene Therapy
- Chimeric anti-ganglioside GM2 antibody with antitumor activity.
- Authors: Nakamura K, Koike M, Shitara K, Kuwana Y, Kiuragi K, Igarashi S, Hasegawa M, Hanai N
- Issue date: 1994 Mar 15
- Binding activities and antitumor properties of a new mouse/human chimeric antibody specific for GD2 ganglioside antigen.
- Authors: Alvarez-Rueda N, Leprieur S, Clémenceau B, Supiot S, Sébille-Rivain V, Faivre-Chauvet A, Davodeau F, Paris F, Barbet J, Aubry J, Birklé S
- Issue date: 2007 Sep 15
- Transfer of chimeric receptor gene made of variable regions of tumor-specific antibody confers anticarbohydrate specificity on T cells.
- Authors: Mezzanzanica D, Canevari S, Mazzoni A, Figini M, Colnaghi MI, Waks T, Schindler DG, Eshhar Z
- Issue date: 1998 Nov-Dec
- Fucose removal from complex-type oligosaccharide enhances the antibody-dependent cellular cytotoxicity of single-gene-encoded antibody comprising a single-chain antibody linked the antibody constant region.
- Authors: Natsume A, Wakitani M, Yamane-Ohnuki N, Shoji-Hosaka E, Niwa R, Uchida K, Satoh M, Shitara K
- Issue date: 2005 Nov 30
- In vitro and in vivo antitumor activity of a mouse CTL hybridoma expressing chimeric receptors bearing the single chain Fv from HER-2/neu- specific antibody and the gamma-chain from Fc(epsilon) RI.
- Authors: Mamalaki A, Gritzapis AD, Kretsovali A, Belimezi M, Papamatheakis J, Perez SA, Papamichail M, Baxevanis CN
- Issue date: 2003 Aug