Cargando…

Anti-Vascular Endothelial Growth Factor C Antibodies Efficiently Inhibit the Growth of Experimental Clear Cell Renal Cell Carcinomas

Despite improvement during the last ten years in the longevity of patients with metastatic clear cell renal cell carcinoma (mccRCC) the disease remains incurable. Hence, new therapeutic strategies are urgently needed. Relapse following anti-angiogenic treatment depends on the over-expression of vasc...

Descripción completa

Detalles Bibliográficos
Autores principales: Dumond, Aurore, Montemagno, Christopher, Vial, Valérie, Grépin, Renaud, Pagès, Gilles
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157203/
https://www.ncbi.nlm.nih.gov/pubmed/34067671
http://dx.doi.org/10.3390/cells10051222
_version_ 1783699628890259456
author Dumond, Aurore
Montemagno, Christopher
Vial, Valérie
Grépin, Renaud
Pagès, Gilles
author_facet Dumond, Aurore
Montemagno, Christopher
Vial, Valérie
Grépin, Renaud
Pagès, Gilles
author_sort Dumond, Aurore
collection PubMed
description Despite improvement during the last ten years in the longevity of patients with metastatic clear cell renal cell carcinoma (mccRCC) the disease remains incurable. Hence, new therapeutic strategies are urgently needed. Relapse following anti-angiogenic treatment depends on the over-expression of vascular endothelial growth factor C (VEGFC), one of the main drivers of lymphangiogenesis. Therefore, we developed specific mouse monoclonal antibodies and evaluated their therapeutic efficacy in vitro and in vivo. Immunization of mice with the domain of VEGFC that stimulates the VEGF receptor 3 (VEGFR3) led to the selection of one hybridoma producing specific anti-VEGFC monoclonal antibodies. The selected 1E9 antibodies were sequenced, and the corresponding variable light and heavy chains were subcloned into expression vectors in frame with sequences encoding the human IgG1 constant heavy and light chains. CHO cells were stably transfected and cloned to produce chimeric antibodies. These antibodies inhibited the activation of VEGFR3 signaling, and therefore the proliferation and migration of VEGFC-stimulated endothelial cells. Moreover, they inhibited the proliferation of VEGFC-expressing renal cancer cells through NRP2 signaling. 1E9 antibodies inhibited the growth of experimental RCC, and their therapeutic efficacy was enhanced by the anti-VEGF antibody bevacizumab. Hence, our results suggest that targeting VEGFC could have a relevant therapeutic impact on mccRCC that relapse following anti-angiogenic treatment.
format Online
Article
Text
id pubmed-8157203
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-81572032021-05-28 Anti-Vascular Endothelial Growth Factor C Antibodies Efficiently Inhibit the Growth of Experimental Clear Cell Renal Cell Carcinomas Dumond, Aurore Montemagno, Christopher Vial, Valérie Grépin, Renaud Pagès, Gilles Cells Article Despite improvement during the last ten years in the longevity of patients with metastatic clear cell renal cell carcinoma (mccRCC) the disease remains incurable. Hence, new therapeutic strategies are urgently needed. Relapse following anti-angiogenic treatment depends on the over-expression of vascular endothelial growth factor C (VEGFC), one of the main drivers of lymphangiogenesis. Therefore, we developed specific mouse monoclonal antibodies and evaluated their therapeutic efficacy in vitro and in vivo. Immunization of mice with the domain of VEGFC that stimulates the VEGF receptor 3 (VEGFR3) led to the selection of one hybridoma producing specific anti-VEGFC monoclonal antibodies. The selected 1E9 antibodies were sequenced, and the corresponding variable light and heavy chains were subcloned into expression vectors in frame with sequences encoding the human IgG1 constant heavy and light chains. CHO cells were stably transfected and cloned to produce chimeric antibodies. These antibodies inhibited the activation of VEGFR3 signaling, and therefore the proliferation and migration of VEGFC-stimulated endothelial cells. Moreover, they inhibited the proliferation of VEGFC-expressing renal cancer cells through NRP2 signaling. 1E9 antibodies inhibited the growth of experimental RCC, and their therapeutic efficacy was enhanced by the anti-VEGF antibody bevacizumab. Hence, our results suggest that targeting VEGFC could have a relevant therapeutic impact on mccRCC that relapse following anti-angiogenic treatment. MDPI 2021-05-17 /pmc/articles/PMC8157203/ /pubmed/34067671 http://dx.doi.org/10.3390/cells10051222 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Dumond, Aurore
Montemagno, Christopher
Vial, Valérie
Grépin, Renaud
Pagès, Gilles
Anti-Vascular Endothelial Growth Factor C Antibodies Efficiently Inhibit the Growth of Experimental Clear Cell Renal Cell Carcinomas
title Anti-Vascular Endothelial Growth Factor C Antibodies Efficiently Inhibit the Growth of Experimental Clear Cell Renal Cell Carcinomas
title_full Anti-Vascular Endothelial Growth Factor C Antibodies Efficiently Inhibit the Growth of Experimental Clear Cell Renal Cell Carcinomas
title_fullStr Anti-Vascular Endothelial Growth Factor C Antibodies Efficiently Inhibit the Growth of Experimental Clear Cell Renal Cell Carcinomas
title_full_unstemmed Anti-Vascular Endothelial Growth Factor C Antibodies Efficiently Inhibit the Growth of Experimental Clear Cell Renal Cell Carcinomas
title_short Anti-Vascular Endothelial Growth Factor C Antibodies Efficiently Inhibit the Growth of Experimental Clear Cell Renal Cell Carcinomas
title_sort anti-vascular endothelial growth factor c antibodies efficiently inhibit the growth of experimental clear cell renal cell carcinomas
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157203/
https://www.ncbi.nlm.nih.gov/pubmed/34067671
http://dx.doi.org/10.3390/cells10051222
work_keys_str_mv AT dumondaurore antivascularendothelialgrowthfactorcantibodiesefficientlyinhibitthegrowthofexperimentalclearcellrenalcellcarcinomas
AT montemagnochristopher antivascularendothelialgrowthfactorcantibodiesefficientlyinhibitthegrowthofexperimentalclearcellrenalcellcarcinomas
AT vialvalerie antivascularendothelialgrowthfactorcantibodiesefficientlyinhibitthegrowthofexperimentalclearcellrenalcellcarcinomas
AT grepinrenaud antivascularendothelialgrowthfactorcantibodiesefficientlyinhibitthegrowthofexperimentalclearcellrenalcellcarcinomas
AT pagesgilles antivascularendothelialgrowthfactorcantibodiesefficientlyinhibitthegrowthofexperimentalclearcellrenalcellcarcinomas