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The carboxyl terminus of VEGF-A is a potential target for anti-angiogenic therapy
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-A(xxx) and the partial agonist VEGF-A...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Netherlands
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4280485/ https://www.ncbi.nlm.nih.gov/pubmed/25274272 http://dx.doi.org/10.1007/s10456-014-9444-3 |
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author | Carter, James G. Gammons, Melissa V. R. Damodaran, Gopinath Churchill, Amanda J. Harper, Steven J. Bates, David O. |
author_facet | Carter, James G. Gammons, Melissa V. R. Damodaran, Gopinath Churchill, Amanda J. Harper, Steven J. Bates, David O. |
author_sort | Carter, James G. |
collection | PubMed |
description | 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-A(xxx) and the partial agonist VEGF-A(xxx)b 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-A(165) and tested it in vitro and in vivo. The exon8a polyclonal antibody (Exon8apab) did not bind VEGF-A(165)b even at greater than 100-fold excess concentration, and dose dependently inhibited VEGF-A(165) 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-A(xxx) levels specifically that were upregulated in plasma from patients with proliferative diabetic retinopathy. These results suggest that VEGF-A(165)-specific antibodies can be therapeutically useful. |
format | Online Article Text |
id | pubmed-4280485 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Springer Netherlands |
record_format | MEDLINE/PubMed |
spelling | pubmed-42804852015-01-02 The carboxyl terminus of VEGF-A is a potential target for anti-angiogenic therapy Carter, James G. Gammons, Melissa V. R. Damodaran, Gopinath Churchill, Amanda J. Harper, Steven J. Bates, David O. Angiogenesis Original Paper 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-A(xxx) and the partial agonist VEGF-A(xxx)b 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-A(165) and tested it in vitro and in vivo. The exon8a polyclonal antibody (Exon8apab) did not bind VEGF-A(165)b even at greater than 100-fold excess concentration, and dose dependently inhibited VEGF-A(165) 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-A(xxx) levels specifically that were upregulated in plasma from patients with proliferative diabetic retinopathy. These results suggest that VEGF-A(165)-specific antibodies can be therapeutically useful. Springer Netherlands 2014-10-02 2015 /pmc/articles/PMC4280485/ /pubmed/25274272 http://dx.doi.org/10.1007/s10456-014-9444-3 Text en © The Author(s) 2014 https://creativecommons.org/licenses/by/4.0/ Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. |
spellingShingle | Original Paper Carter, James G. Gammons, Melissa V. R. Damodaran, Gopinath Churchill, Amanda J. Harper, Steven J. Bates, David O. The carboxyl terminus of VEGF-A is a potential target for anti-angiogenic therapy |
title | The carboxyl terminus of VEGF-A is a potential target for anti-angiogenic therapy |
title_full | The carboxyl terminus of VEGF-A is a potential target for anti-angiogenic therapy |
title_fullStr | The carboxyl terminus of VEGF-A is a potential target for anti-angiogenic therapy |
title_full_unstemmed | The carboxyl terminus of VEGF-A is a potential target for anti-angiogenic therapy |
title_short | The carboxyl terminus of VEGF-A is a potential target for anti-angiogenic therapy |
title_sort | carboxyl terminus of vegf-a is a potential target for anti-angiogenic therapy |
topic | Original Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4280485/ https://www.ncbi.nlm.nih.gov/pubmed/25274272 http://dx.doi.org/10.1007/s10456-014-9444-3 |
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