Targeted delivery of tissue factor to the ED-B domain of fibronectin, a marker of angiogenesis, mediates the infarction of solid tumors in mice.
The selective thrombosis of tumor blood vessels, leading to the starvation and subsequent death of tumor cells, is an attractive anticancer strategy. Here we report that a fusion protein, consisting of an antibody fragment specific for the oncofoetal ED-B domain of fibronectin fused to the extracellular domain of tissue factor, selectively targets tumor blood vessels in vivo. Furthermore, this fusion protein mediates the complete and selective infarction of three different types of solid tumors in mice. At the highest doses administered, complete tumor eradication was observed in 30% of the mice treated without apparent side effects. These results are of therapeutic relevance because the ED-B domain of fibronectin, a naturally occurring marker of angiogenesis identical in mouse and man, is expressed in the majority of aggressive solid tumors but is undetectable in normal vessels and tissues.
Nilsson
F
F
Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich.
Kosmehl
H
H
Zardi
L
L
Neri
D
D
D000818:Animals; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D003001:Cloning, Molecular; D016503:Drug Delivery Systems; D005260:Female; D005353:Fibronectins / Q000737:chemistry / Q000276:immunology*; D018796:Immunoconjugates / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D007128:Immunoglobulin Fragments / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000276:immunology* / Q000517:prevention & control; D009389:Neovascularization, Pathologic / Q000276:immunology* / Q000517:prevention & control; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D013925:Thromboplastin / Q000235:genetics / Q000276:immunology*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D005353:Fibronectins; D018796:Immunoconjugates; D007128:Immunoglobulin Fragments; D011993:Recombinant Fusion Proteins; D013925:Thromboplastin