VEGF and Other Targets for Antiangiogenic Treatment

An important player in tumor angiogenesis, VEGF-A is targeted by a humanized anti-VEGF-A mAb (bevacizumab, AvastinĀ®) (119), which has been approved by the FDA as a treatment for metastatic colorectal (120), metastatic breast (121), and nonsquamous, non-small-cell lung cancer in combination with chemotherapy (122). Discrepancies between in vitro and in vivo data among various affinity-matured anti-VEGF-A Abs have revealed important factors contributing to this apparent lack of correlation (123). Contributions of both

36 Boswell et al.

tumor- and stromal cell-derived VEGF-A to vascularization of human tumors grown in immunodeficient mice hinder the direct comparison between the pharmacological effects of anti-VEGF Abs having different binding affinities (123). Even though in vitro studies demonstrated a correlation between Ab binding affinity and potency in assays measuring inhibition of VEGF-stimulated endothelial cell proliferation, various affinity-matured anti-VEGF-A Abs did not show a clearly increased potency and efficacy to block tumor growth in most in vivo models when compared with their lower-affinity counterparts (123). Several factors may help explain the failure of potency to increase with anti-VEGF-A binding affinity. For instance, in contrast to Abs that directly target antigens in the tumor cells, anti-VEGF-A Abs may not need to penetrate the tumor mass to induce pharmacological effects because they interfere with angiogenesis primarily by preventing VEGF-A from binding its receptors within tumor vascu-lature; this opens the possibility that inhibition of VEGF-A binding to VEGF receptors may be saturated in vivo even when lower-affinity anti-VEGF-A Abs are used (123).

In addition to oncological applications, VEGF-A is also an exciting target in ocular disorders, where IVIVCs play critical roles in the study of its mechanism of action. Neovascular age-related macular degeneration (AMD) is the leading cause of blindness in older adults in the Western world, and ranibizu-mab (LucentisĀ®, anti-VEGF-A), a humanized Ab fragment directed against VEGF-A, is FDA approved for the treatment of neovascular AMD. PK studies of ranibizumab (rhuFabV2) revealed a favorable three-day terminal half-life following intravitreal administration to monkeys (124). In subsequent studies, Lowe et al. related the in vitro binding and HUVEC proliferation effects of ranibizumab to its effects on VEGF-A vascular permeability (125).

0 0

Post a comment