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A high-affinity ErbB4Fc fusion protein is a potent antagonist of heregulin-mediated receptor activation

icecream 添加于 2012-10-26 19:25 | 965 次阅读 | 0 个评论

作者
Koziolek EJ, Donoghue JF, Bentley JD, Lovrecz G, Dolezal O, Ward CW, Rothacker J, Nice EC, Burgess AW, Hafner M, Johns TG, Adams TE
摘要
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-beta1 (HRG-beta1) 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-beta1 activation of the IKB/MAP/JNK/AKT signalling pathways. sErbB4.497.Fc inhibited HRG-beta1-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.
详细资料
- 文献种类: Journal Article
- 期刊名称: Growth Factors (Chur, Switzerland)
- 期刊缩写: Growth Factors
- 期卷页: 2012年第30卷第5期 310-319页
- 地址: CSIRO Division of Materials Science and Engineering , 343 Royal Parade, Parkville, VIC 3052 , Australia
- ISBN: 0897-7194
学科领域生物医药 » 预防卫生学
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