The carboxyl terminus of VEGF-A is a potential target for anti-angiogenic therapy

James G. Carter, Melissa V R Gammons, Gopinath Damodaran, Amanda J. Churchill, Steven J. Harper, David O. Bates*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)23-30
Number of pages8
JournalAngiogenesis
Volume18
Issue number1
Early online date2 Oct 2014
DOIs
Publication statusPublished - Jan 2015

Keywords

  • Bevacizumab
  • Splicing
  • VEGF
  • VEGF-Ab

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    Carter, J. G., Gammons, M. V. R., Damodaran, G., Churchill, A. J., Harper, S. J., & Bates, D. O. (2015). The carboxyl terminus of VEGF-A is a potential target for anti-angiogenic therapy. Angiogenesis, 18(1), 23-30. https://doi.org/10.1007/s10456-014-9444-3