title: A high-affinity ErbB4Fc fusion protein is a potent antagonist of heregulin-mediated receptor activation.
abstract: Ligand-mediated activation of ErbB3 and ErbB4 is implicated in the pathogenesis of several human malignancies including cancer of the ovary and melanoma. We have used the broad ErbB ligand specificity of ErbB4 to assemble and express an ErbB4 fusion protein comprising the first 497 amino acids of the mature ErbB4 ectodomain fused to the human IgG Fc constant region. The purified fusion protein, designated sErbB4.497.Fc, binds the ErbB receptor ligands betacellulin and heregulin-β1 (HRG-β1) with high affinity (K(D) = 130 pM), an increase in affinity of 10- to 20-fold, respectively, compared with sErbB4.615.Fc. sErbB4.497.Fc inhibited ligand-stimulated phosphorylation of epidermal growth factor receptor and ErbB2, and blocked HRG-β1 activation of the IKB/MAP/JNK/AKT signalling pathways. sErbB4.497.Fc inhibited HRG-β1-stimulated proliferation in MCF7 cells. In a mouse tumour xenograft model, sErbB4.497.Fc as a monotherapy modestly inhibited the growth of MDA-MB-231 breast cancer cells. sErbB4.497.Fc may be useful in an adjuvant setting in combination with conventional therapeutic agents.
authors.affiliation: CSIRO Division of Materials Science and Engineering, 343 Royal Parade, Parkville, VIC 3052, Australia.
authors.forename: Eva J
authors.initials: EJ
authors.lastname: Koziolek
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Donoghue
authors.forename: John D
authors.initials: JD
authors.lastname: Bentley
authors.forename: George
authors.initials: G
authors.lastname: Lovrecz
authors.forename: Olan
authors.initials: O
authors.lastname: Dolezal
authors.forename: Colin W
authors.initials: CW
authors.lastname: Ward
authors.forename: Julie
authors.initials: J
authors.lastname: Rothacker
authors.forename: Edouard C
authors.initials: EC
authors.lastname: Nice
authors.forename: Antony W
authors.initials: AW
authors.lastname: Burgess
authors.forename: M
authors.initials: M
authors.lastname: Hafner
authors.forename: Terrance G
authors.initials: TG
authors.lastname: Johns
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Adams
mesh_terms: D000818:Animals; D066259:Betacellulin; D001943:Breast Neoplasms / Q000188:drug therapy; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D061986:MCF-7 Cells; D008545:Melanoma / Q000473:pathology; D051379:Mice; D020890:Neuregulin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000473:pathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D066247:Receptor, ErbB-4; D011961:Receptors, Fc / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: C587851:BTC protein, human; D066259:Betacellulin; C587852:Btc protein, mouse; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D007074:Immunoglobulin G; D036341:Intercellular Signaling Peptides and Proteins; D020890:Neuregulin-1; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; C087230:heregulin beta1; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases