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Tumor-targeting properties of antibody-vascular endothelial growth factor fusion proteins

TitleTumor-targeting properties of antibody-vascular endothelial growth factor fusion proteins
Publication TypeArticolo su Rivista peer-reviewed
Year of Publication2002
AuthorsHalin, C., Niesner U., Villani Maria Elena, Zardi L., and Neri D.
JournalInternational Journal of Cancer
Keywordsacute granulocytic leukemia, angiogenesis, animal cell, animal model, Animals, Antibodies, Antineoplastic Agents, article, binding kinetics, blood vessel permeability, cancer immunology, cancer immunotherapy, Cloning, drug approval, drug targeting, Endothelial Growth Factors, Experimental, Female, fibronectin, food and drug administration, gemtuzumab ozogamicin, gene sequence, human, human cell, hybrid protein, ibritumomab tiuxetan, Immunoconjugates, Intercellular Signaling Peptides and Proteins, isotope labeling, Lymphokines, Mice, Molecular, molecular cloning, Monoclonal, Monoclonal antibody, mouse, Neoplasms, nonhodgkin lymphoma, nonhuman, priority journal, radioiodination, Recombinant Fusion Proteins, recombinant vasculotropin, solid tumor, Tissue Distribution, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors

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 VEGF120 or VEGF164 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)-VEGF120 but not scFv(L19)-VEGF164 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)-VEGF120-prior to administration of radiolabeled fusion protein led to increased accumulation of radiolabeled scFv(L19)-VEGF120 in the tumor but only at very high concentrations (20 μg/mouse). © 2002 Wiley-Liss, Inc.


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Citation KeyHalin2002109