Author: Adams Timothy Koziolek Eva Hoyne Peter Bentley John Lu Louis Lovrecz George Ward Colin Lee F. T. Scott Andrew Nash Andrew Rothacker Julie Nice Edouard Burgess Antony Johns Terrance
Publisher: Informa Healthcare
ISSN: 0897-7194
Source: Growth Factors, Vol.27, Iss.3, 2009-03, pp. : 141-154
Disclaimer: Any content in publications that violate the sovereignty, the constitution or regulations of the PRC is not accepted or approved by CNPIEC.
Abstract
A number of therapeutic strategies including small molecule tyrosine kinase inhibitors and monoclonal antibodies have been developed to target the epidermal growth factor receptor (EGFR) signalling axis for the treatment of cancer. To date, the focus of therapeutic intervention has been the EGFR itself. In the current study, we have assembled and expressed in mammalian cells a soluble, EGFR ligand trap comprising the first 501 amino acids of the mature EGFR sequence fused in-frame with a human IgG Fc domain. The fusion protein, designated sEGFR501.Fc, was secreted as a 220 kDa disulphide-linked homodimer that exhibited high affinity (0.4-8 nM) in competition assays for a number of EGFR ligands including EGF and transforming growth factor-α (TGF-α). sEGFR501.Fc inhibited EGF-stimulated tyrosine phosphorylation of the EGFR of the lung cancer cell lines A549 and H1437, and inhibited and blocked the proliferation of H1437 cells. Administration of sEGFR501.Fc to mice bearing human tumour xenografts derived from A431 (epidermoid carcinoma) and DU145 (androgen-independent prostate cancer) tumour cell lines resulted in modest retardation of tumour growth. These results provide proof-in-principle that using high affinity soluble receptors is a viable method for inhibiting multi-ligand systems, and the impetus to optimize this approach and develop reagents with greater affinity and broader specificity.
Related content
Ligand binding induces a conformational change in epidermal growth factor receptor dimers
By Walker Francesca Rothacker Julie Henderson Christine Nice Edouard C. Catimel Bruno Zhang Hui-Hua Scott Andrew M. Bailey Michael F. Orchard Suzanne G. Adams Timothy E. Liu Zhanqi Garrett Thomas P.J. Clayton Andrew H.A. Burgess Antony W.
Growth Factors, Vol. 30, Iss. 6, 2012-12 ,pp. :
By Zhu Hong-Jian Iaria Josephine Orchard Suzanne Walker Francesca Burgess Antony W.
Growth Factors, Vol. 21, Iss. 1, 2003-03 ,pp. :
By Souriau Christelle Rothacker Julie Hoogenboom Hennie R. Nice Edouard
Growth Factors, Vol. 22, Iss. 3, 2004-09 ,pp. :