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Targeting a unique EGFR epitope with monoclonal antibody 806 activates NF-κB and initiates tumour vascular normalization

Monoclonal antibodies (mAbs) and tyrosine kinase inhibitors targeting the epidermal growth factor receptor (EGFR), which is often pathogenetically overexpressed or mutated in epithelial malignancies and glioma, have been modestly successful, with some approved for human use. MAb 806 was raised again...

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Autores principales: Gan, Hui K, Lappas, Martha, Cao, Diana X, Cvrljevdic, Anna, Scott, Andrew M, Johns, Terrance G
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Ltd 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516546/
https://www.ncbi.nlm.nih.gov/pubmed/19432811
http://dx.doi.org/10.1111/j.1582-4934.2009.00783.x
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author Gan, Hui K
Lappas, Martha
Cao, Diana X
Cvrljevdic, Anna
Scott, Andrew M
Johns, Terrance G
author_facet Gan, Hui K
Lappas, Martha
Cao, Diana X
Cvrljevdic, Anna
Scott, Andrew M
Johns, Terrance G
author_sort Gan, Hui K
collection PubMed
description Monoclonal antibodies (mAbs) and tyrosine kinase inhibitors targeting the epidermal growth factor receptor (EGFR), which is often pathogenetically overexpressed or mutated in epithelial malignancies and glioma, have been modestly successful, with some approved for human use. MAb 806 was raised against de2–7EGFR (or EGFRvIII), a constitutively active mutation expressed in gliomas, but also recognizes a subset (<10%) of wild-type (wt) EGFR when it is activated by autocrine loop, overexpression or mutation. It does not bind inactive EGFR in normal tissues like liver. Glioma xenografts expressing the de2–7EGFR treated with mAb 806 show reduced receptor autophosphorylation, increased p27(KIP1) and reduced cell proliferation. Xenografts expressing the wtEGFR activated by overexpression or autocrine ligand are also inhibited by mAb 806, but the mechanism of inhibition has been difficult to elucidate, especially because mAb 806 does not prevent wtEGFR phosphorylation or downstream signalling in vitro. Thus, we examined the effects of mAb 806 on A431 xenograft angiogenesis. MAb 806 increases vascular endothelial growth factor (VEGF) and interleukin-8 production by activating NF-κB and normalizes tumour vasculature. Pharmacological inhibition of NF-κB completely abrogated mAb 806 activity, demonstrating that NF-κB activation is necessary for its anti-tumour function in xenografts. Given the increase in VEGF, we combined mAb 806 with bevacizumab in vivo, resulting in additive activity.
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spelling pubmed-45165462015-08-03 Targeting a unique EGFR epitope with monoclonal antibody 806 activates NF-κB and initiates tumour vascular normalization Gan, Hui K Lappas, Martha Cao, Diana X Cvrljevdic, Anna Scott, Andrew M Johns, Terrance G J Cell Mol Med Molecular Oncology Monoclonal antibodies (mAbs) and tyrosine kinase inhibitors targeting the epidermal growth factor receptor (EGFR), which is often pathogenetically overexpressed or mutated in epithelial malignancies and glioma, have been modestly successful, with some approved for human use. MAb 806 was raised against de2–7EGFR (or EGFRvIII), a constitutively active mutation expressed in gliomas, but also recognizes a subset (<10%) of wild-type (wt) EGFR when it is activated by autocrine loop, overexpression or mutation. It does not bind inactive EGFR in normal tissues like liver. Glioma xenografts expressing the de2–7EGFR treated with mAb 806 show reduced receptor autophosphorylation, increased p27(KIP1) and reduced cell proliferation. Xenografts expressing the wtEGFR activated by overexpression or autocrine ligand are also inhibited by mAb 806, but the mechanism of inhibition has been difficult to elucidate, especially because mAb 806 does not prevent wtEGFR phosphorylation or downstream signalling in vitro. Thus, we examined the effects of mAb 806 on A431 xenograft angiogenesis. MAb 806 increases vascular endothelial growth factor (VEGF) and interleukin-8 production by activating NF-κB and normalizes tumour vasculature. Pharmacological inhibition of NF-κB completely abrogated mAb 806 activity, demonstrating that NF-κB activation is necessary for its anti-tumour function in xenografts. Given the increase in VEGF, we combined mAb 806 with bevacizumab in vivo, resulting in additive activity. John Wiley & Sons, Ltd 2009-09 2009-05-11 /pmc/articles/PMC4516546/ /pubmed/19432811 http://dx.doi.org/10.1111/j.1582-4934.2009.00783.x Text en © 2009 The Authors Journal compilation © 2009 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
spellingShingle Molecular Oncology
Gan, Hui K
Lappas, Martha
Cao, Diana X
Cvrljevdic, Anna
Scott, Andrew M
Johns, Terrance G
Targeting a unique EGFR epitope with monoclonal antibody 806 activates NF-κB and initiates tumour vascular normalization
title Targeting a unique EGFR epitope with monoclonal antibody 806 activates NF-κB and initiates tumour vascular normalization
title_full Targeting a unique EGFR epitope with monoclonal antibody 806 activates NF-κB and initiates tumour vascular normalization
title_fullStr Targeting a unique EGFR epitope with monoclonal antibody 806 activates NF-κB and initiates tumour vascular normalization
title_full_unstemmed Targeting a unique EGFR epitope with monoclonal antibody 806 activates NF-κB and initiates tumour vascular normalization
title_short Targeting a unique EGFR epitope with monoclonal antibody 806 activates NF-κB and initiates tumour vascular normalization
title_sort targeting a unique egfr epitope with monoclonal antibody 806 activates nf-κb and initiates tumour vascular normalization
topic Molecular Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516546/
https://www.ncbi.nlm.nih.gov/pubmed/19432811
http://dx.doi.org/10.1111/j.1582-4934.2009.00783.x
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