title: The carboxyl terminus of VEGF-A is a potential target for anti-angiogenic therapy.
abstract: Anti-VEGF-A therapy has become a mainstay of treatment for ocular neovascularisation and in cancer; however, their effectiveness is not universal, in some cases only benefiting a minority of patients. Anti-VEGF-A therapies bind and block both pro-angiogenic VEGF-Axxx and the partial agonist VEGF-Axxxb isoforms, but their anti-angiogenic benefit only comes about from targeting the pro-angiogenic isoforms. Therefore, antibodies that exclusively target the pro-angiogenic isoforms may be more effective. To determine whether C-terminal-targeted antibodies could inhibit angiogenesis, we generated a polyclonal antibody to the last nine amino acids of VEGF-A165 and tested it in vitro and in vivo. The exon8a polyclonal antibody (Exon8apab) did not bind VEGF-A165b even at greater than 100-fold excess concentration, and dose dependently inhibited VEGF-A165 induced endothelial migration in vitro at concentrations similar to the VEGF-A antibody fragment ranibizumab. Exon8apab can inhibit tumour growth of LS174t cells implanted in vivo and blood vessel growth in the eye in models of age-related macular degeneration, with equal efficacy to non-selective anti-VEGF-A antibodies. It also showed that it was the VEGF-Axxx levels specifically that were upregulated in plasma from patients with proliferative diabetic retinopathy. These results suggest that VEGF-A165-specific antibodies can be therapeutically useful.
authors.affiliation: Microvascular Research Laboratories, School of Physiology and Pharmacology, University of Bristol, Preclinical Veterinary Sciences Building, Southwell Street, Bristol, BS2 8EJ, UK.
authors.forename: James G
authors.initials: JG
authors.lastname: Carter
authors.forename: Melissa V R
authors.initials: MV
authors.lastname: Gammons
authors.forename: Gopinath
authors.initials: G
authors.lastname: Damodaran
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Churchill
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Harper
authors.forename: David O
authors.initials: DO
authors.lastname: Bates
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000906:Antibodies / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000906:Antibodies; D020033:Protein Isoforms; D042461:Vascular Endothelial Growth Factor A