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Title: Targeting a unique EGFR epitope with monoclonal antibody 806 activates NF-kappaB and initiates tumour vascular normalization.
Austin Authors: Gan, Hui K ;Lappas, Martha;Cao, Diana;Cvrljevdic, Anna;Scott, Andrew M ;Johns, Terrance G
Affiliation: Oncogenic Signalling Laboratory, Ludwig Institute for Cancer Research, Austin Health, Heidelberg, Victoria, Australia
Issue Date: 11-May-2009
Publication information: Journal of Cellular and Molecular Medicine 2009; 13(9B): 3993-4001
Abstract: 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-kappaB and normalizes tumour vasculature. Pharmacological inhibition of NF-kappaB completely abrogated mAb 806 activity, demonstrating that NF-kappaB 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.
Gov't Doc #: 19432811
DOI: 10.1111/j.1582-4934.2009.00783.x
Type: Journal Article
Subjects: Animals
Antibodies, Monoclonal.therapeutic use
Cell Line, Tumor
Mice, Nude
NF-kappa B.metabolism
Neoplasm Transplantation
Neovascularization, Pathologic
Receptor, Epidermal Growth Factor.chemistry.immunology.metabolism
Vascular Endothelial Growth Factor A.metabolism
Appears in Collections:Journal articles

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