A strategy for antitumor vascular therapy by targeting the vascular endothelial growth factor: receptor complex.
Vascular endothelial growth factor (VEGF) is produced by cancer cells in response to hypoxia and is the primary stimulant of vascularization in solid tumors. Endothelial cells lining the blood vessels of these tumors have a high concentration of receptor-bound VEGF on their surface, providing a target for antibody- directed cancer therapy. To obtain a cloned antibody to this target when bound to its receptor on tumor endothelium, we used phage display technology to create a single-chain Fv (sFv) antibody library from mice immunized with the 165-amino acid isoform of human VEGF-A. We selected, purified, and characterized LL4, an anti-VEGF sFv that was shown to react with receptor-bound VEGF. LL4 bound selectively to blood vessel endothelium, as shown by immunohistochemistry on tissue sections of human tumors. Furthermore, using autoradiography and grain counting of histological sections, systemically administered LL4 was shown to localize selectively to the endothelial lining of tumor blood vessels in human colorectal carcinoma xenografts in vivo. This study demonstrates the feasibility of targeting tumor vasculature using recombinant antibodies to the VEGF:receptor complex.
Cooke
S P
SP
CRC Targeting and Imaging Group, Department of Oncology, Royal Free and University College Medical School, University College London, NW3 2PF, United Kingdom.
Boxer
G M
GM
Lawrence
L
L
Pedley
R B
RB
Spencer
D I
DI
Begent
R H
RH
Chester
K A
KA
D000818:Animals; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000276:immunology / Q000628:therapy; D016228:Endothelial Growth Factors / Q000276:immunology* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism; D007116:Immunization, Passive / Q000379:methods*; D007128:Immunoglobulin Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007150:Immunohistochemistry; D008222:Lymphokines / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D019151:Peptide Library; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000276:immunology* / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014018:Tissue Distribution; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D023041:Xenograft Model Antitumor Assays
D016228:Endothelial Growth Factors; D007128:Immunoglobulin Fragments; D007135:Immunoglobulin Variable Region; D008222:Lymphokines; D019151:Peptide Library; D017978:Receptors, Growth Factor; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor