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CR 75 th Anniversary Commentary Commentary on Humanization of an Anti-VEGF Monoclonal Antibody for the Therapy of Solid Tumors and Other Disorders Napoleone Ferrara See related article by Presta et al., Cancer Res 1997;57:4593–99. The highlighted article describes the engineering of a mol- ecule that for the rst time allowed testing the hypothesis that blocking VEGF-mediated angiogenesis may confer a benet 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 key molecule in angiogenesis as well as a potential therapeutic target. Therefore, a brief overview of VEGF biology will be presented here, including some recent ndings on molecular mechanisms underlying pathophysiologic changes in blood vessels after VEGF inhibition. The history of VEGF reects independent efforts, which resulted in the discovery of apparently unrelated biological activities. In 1983, Senger and colleagues reported the identi- cation of vascular permeability factor (VPF) as a protein that rapidly increased vascular permeability when injected in the skin (3). However, VPF was not fully puried or cloned at that time (3), and thus, very limited progress in elucidating the signicance of this activity was possible during the next several years. In 1989, we described the purication and cloning of VEGF, a novel endothelial cell–specic 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 path- ophysiologic roles of VEGF and to the consequences of its blockade. VEGF as a Key Regulator of Angiogenesis Many studies have documented the crucial role of VEGF in the development of embryonic and postnatal blood vessels (2). Loss of even a single vegf allele resulted in defective vascular develop- ment and early embryonic lethality in mice. Additional studies revealed the role of VEGF-mediated angiogenesis in key postnatal physiologic processes, including skeletal growth and cyclical development of the ovarian corpus luteum (2). University of California San Diego Medical Center, La Jolla, California. Corresponding Author: Napoleone Ferrara, UC San Diego Moores Cancer Center, 3855 Health Sciences Dr, Room 3310, Mail Code 0819, La Jolla, CA 92093. Phone: 858-822-6822; Fax: 858-534-2157; E-mail: nferrara@ucsd.edu doi: 10.1158/0008-5472.CAN-16-1973 O2016 American Association for Cancer Research. www.aacrjournals.org A major milestone was the identication of the two VEGF tyrosine kinase receptors, VEGFR1 and VEGFR2. It is now well established that VEGFR2 is the main signaling receptor that mediates both angiogenic and permeability-enhancing effects of VEGF (2). Two major tyrosine residues in human VEGFR2, Y1175 (Y1173 in the mouse) and Y951 (Y949 in the mouse), have been shown to differentially regulate angiogenesis and vascular permeability. Mice homozygous for the single substi- tution tyrosine to phenylalanine in position 1173 showed defective vasculogenesis and angiogenesis and died in utero around day 8.5 to 9.5 (5). Phosphorylated Y949/951 interacts with an adaptor that triggers formation of complexes between Src and VE-cadherin, resulting in the opening of interendothe- lial junctions (6). Inactivating mutations in this pathway largely abolished the initially reported (3) permeability-enhancing effects of VEGF in mice (6). Mutant mice were normal and fertile, indicating that this function of VEGF does not play major physiologic roles (6). However, a transient reduction in tumor edema and a decrease in the number of metastases were observed in the mutants, although primary tumor growth and blood vessel density were the same as in wild-type controls (6). It is noteworthy that VEGF-induced chronic hyperpermeability is, to a large extent, indirect and reects growth of immature and structurally abnormal vessels that are inherently leaky due to a lack of pericytes and the development of microaneurysms (reviewed in ref. 2). Anti-VEGF Antibodies Inhibit Pathologic Angiogenesis in Animal Models To investigate the role of VEGF, we initially developed neu- tralizing mAbs (7). In 1993, we reported that the murine mAb A.4.6.1, which neutralized all bioactive forms of human VEGF, inhibited the growth of human tumor cell lines implanted in immunodecient mice (8). These ndings were unexpected at that time, as it was widely believed that blocking tumor angio- genesis required inhibition of multiple factors and also provided the rst direct evidence that tumor growth is dependent on angiogenesis. Further studies conrmed these ndings and extended them to a variety of tumor models, including orthotopic models (9). Imaging of the tumor vasculature by intravital microscopy strongly supported the hypothesis that inhibition of angiogenesis was the mechanism of tumor growth inhibition (10). However, because mAb A.4.6.1 does not block mouse VEGF, its use in human xenografts in mice resulted in underestimation of the contribution of VEGF to tumor angiogenesis, as several host stromal cell types produce VEGF (2). By the mid 1990s, strong correlative evidence implicated VEGF in retinal ischemia-related neovascular syndromes secondary to diabetes, prematurity, or retinal vein occlusion (2). Intravitreal injection of mAb A.4.6.1 resulted in a dramatic inhibition of neovascularization in a primate model of retinal vein occlusion,

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