Commentary on "Humanization of an Anti-VEGF Monoclonal Antibody for the Therapy of Solid Tumors and Other Disorders".

See related article by Presta et al., Cancer Res 1997;57:4593–99. The highlighted article describes the engineering of a molecule that for the first time allowed testing the hypothesis that blocking VEGF-mediated angiogenesis may confer a benefit on human patients (1). Twenty years later, the reagent described in our study, known today as bevacizumab or Avastin, represents a standard of therapy for multiple malignancies (2). Also, VEGF inhibitors, including bevacizumab, have revolutionized the treatment of blinding neovascular disorders, such as age-related macular degeneration (AMD; ref. 2). Although the study was technological in nature (1), it was the culmination of several years of basic and preclinical investigation that established VEGF as a keymolecule in angiogenesis as well as a potential therapeutic target. Therefore, a brief overview of VEGF biology will be presented here, including some recent findings on molecular mechanisms underlying pathophysiologic changes in blood vessels after VEGF inhibition. The history of VEGF reflects independent efforts, which resulted in the discovery of apparently unrelated biological activities. In 1983, Senger and colleagues reported the identification of vascular permeability factor (VPF) as a protein that rapidly increased vascular permeability when injected in the skin (3). However, VPF was not fully purified or cloned at that time (3), and thus, very limited progress in elucidating the significance of this activity was possible during the next several years. In 1989, we described the purification and cloning of VEGF, a novel endothelial cell–specific mitogen (4). After our initial work was published, an independent group reported the cloning of VPF, which proved to be the same molecule as VEGF (reviewed in ref. 2). Since then, numerous studies have sought to dissect the contribution of these two activities to the pathophysiologic roles of VEGF and to the consequences of its blockade.