Single-chain antibody-based gene therapy: inhibition of tumor growth by in situ production of phage-derived human antibody fragments blocking functionally active sites of cell-associated matrices.
Experimental evidence suggests that blocking the interactions between endothelial cells and extracellular matrix (ECM) components may provide a potent and general strategy to inhibit tumor neovascularization. Based on these considerations, we have focused our efforts on laminin, component of the vascular basement membrane of every tumor-associated vessel, which serves an essential role in tube formation. We screened anti-laminin single-chain antibody fragments (scFv) derived from a human phage-display library and identified one that blocks the formation of capillary-like structures in vitro. This scFv inhibits angiogenesis in vivo in the chick embryo chorioallantoic membrane assay and prevents the establishment and growth of subcutaneous tumors in mice, either when administered as bolus protein therapy or when produced locally by gene-modified tumor cells. Our work represents the first demonstration of a direct in vivo therapeutic effect of a single-chain antibody secreted by gene-modified mammalian cells. These results open the way for a new antibody-based gene therapy strategy of cancer.
Sanz
L
L
Department of Immunology, Hospital Universitario Clínica Puerta de Hierro, Madrid, Spain.
Kristensen
P
P
Blanco
B
B
Facteau
S
S
Russell
S J
SJ
Winter
G
G
Alvarez-Vallina
L
L
D000818:Animals; D002460:Cell Line; D002642:Chick Embryo; D046508:Culture Techniques; D004730:Endothelium, Vascular / Q000166:cytology; D005109:Extracellular Matrix; D005803:Genes, Immunoglobulin; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007128:Immunoglobulin Fragments / Q000235:genetics*; D007797:Laminin / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000098:blood supply / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*
D007128:Immunoglobulin Fragments; D007797:Laminin