Tumor-targeting properties of antibody-vascular endothelial growth factor fusion proteins.
A major problem of antibody-based targeting of solid tumors is the poor penetration of antibodies into tumor tissue. Vasoactive immunoconjugates have been proposed as a means of increasing antibody uptake in tumors. In principle, VEGF (also known as vascular permeability factor) could selectively alter vascular permeability, leading to improved tumor targeting. A possible role for VEGF in the targeting of tumor neovasculature has been postulated, based on the overexpression of VEGF receptors in tumor endothelial cells. However, quantitative biodistribution studies on this topic are not available. In this report, we describe the cloning, expression, characterization and biodistribution in tumor-bearing mice of antibodies fused to either VEGF(120) or VEGF(164) The MAb fragments chosen for analysis were scFv(L19), specific for the ED-B domain of fibronectin, a marker of angiogenesis, and scFv(HyHEL-10), a negative control antibody of irrelevant specificity in mice. Neither unconjugated VEGF nor scFv(HyHEL-10)-VEGF fusion proteins showed accumulation in the tumor (tumor:blood ratios approx. 1 at 4 hr and 24 hr postinjection). By contrast, scFv(L19)-VEGF(120) but not scFv(L19)-VEGF(164) showed significant accumulation in tumors (tumor:blood ratio = 9.3 at 24 hr) but was not superior to unconjugated scFv(L19). Preinjection of unlabeled scFv(L19)-VEGF(120) prior to administration of radiolabeled fusion protein led to increased accumulation of radiolabeled scFv(L19)-VEGF(120) in the tumor but only at very high concentrations (20 microg/mouse).
Halin
Cornelia
C
Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology-Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Niesner
Uwe
U
Villani
Maria Elena
ME
Zardi
Luciano
L
Neri
Dario
D
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003001:Cloning, Molecular; D016228:Endothelial Growth Factors / Q000627:therapeutic use*; D005260:Female; D018796:Immunoconjugates / Q000627:therapeutic use*; D036341:Intercellular Signaling Peptides and Proteins / Q000627:therapeutic use*; D008222:Lymphokines / Q000627:therapeutic use*; D051379:Mice; D009374:Neoplasms, Experimental / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D016228:Endothelial Growth Factors; D018796:Immunoconjugates; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors