A truncated soluble epidermal growth factor receptor-Fc fusion ligand trap displays anti-tumour activityin vivo

Autor:	Timothy E. Adams, Eva J. Koziolek, Peter H. Hoyne, John D. Bentley, Louis Lu, George Lovrecz, Colin W. Ward, F. T. Lee, Andrew M. Scott, Andrew D. Nash, Julie Rothacker, Edouard C. Nice, Antony W. Burgess, Terrance G. Johns
Rok vydání:	2009
Předmět:	Cell Survival Recombinant Fusion Proteins Clinical Biochemistry Antineoplastic Agents chemistry.chemical_compound Endocrinology DU145 Epidermal growth factor Cell Line Tumor Humans Soluble Epidermal Growth Factor Receptor Epidermal growth factor receptor Phosphorylation Epidermal Growth Factor biology Tyrosine phosphorylation Cell Biology Xenograft Model Antitumor Assays Fusion protein Immunoglobulin Fc Fragments ErbB Receptors Epidermoid carcinoma Biochemistry chemistry Cancer research biology.protein Tyrosine Tyrosine kinase
Zdroj:	Growth Factors. 27:141-154
ISSN:	1029-2292 0897-7194
Popis:	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-alpha (TGF-alpha). 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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::805f618fe0bd19fbd50939206f55309c https://doi.org/10.1080/08977190902843565 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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