Targeted antireceptor therapy with monoclonal antibodies leads to the formation of inactivated tetrameric forms of ErbB receptors
Targeted antireceptor therapy with monoclonal antibodies leads to the formation of inactivated tetrameric forms of ErbB receptors
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DOI：
10.4049/jimmunol.178.2.1021
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发表时间：
2007-01-15
影响因子：
4.4
通讯作者：
Greene, Mark I.
中科院分区：
文献类型：
--
作者：
Furuuchi, Keiji;Berezov, Alan;Greene, Mark I.
能够禁用表皮生长因子受体(EGFR)和人EGFR 2型/neu的异二聚体激酶复合体的单抗对各种人类癌症具有治疗意义。在这项研究中，我们证明除了二聚体外，EGFR和人EGFR类型2还可以作为同源和异源四聚体。EGF诱导的四聚体的磷酸化水平明显低于二聚体，表明四聚体受体复合体的信号活性受损。单抗靶向v-erb-b2红细胞性白血病病毒癌基因同源受体促进了erbB四聚体的组装，提示抗肿瘤活性的一部分可能是通过单抗将平衡从活跃的二聚体转移到受损的四聚体受体复合体状态来实现的。这项研究提出了一种新的治疗方法，通过能够诱导受体四聚化的生物制剂来禁用肿瘤中erb B和潜在的其他受体的信号。
mAbs capable of disabling heterodimeric kinase complexes of the epidermal growth factor receptor (EGFR) and human EGFR type 2/neu have therapeutic relevance to various human cancers. In this study, we demonstrate that in addition to the dimer, EGFR and human EGFR type 2 can associate as homo- and heterotetramers. EGF-induced phosphorylation of the tetramers was significantly lower than that of the dimers, indicating that the tetrameric receptor complexes have impaired signaling activity. Targeting v-erb-b2 erythroblastic leukemia viral oncogene homolog (erbB) receptors with mAbs promoted erbB tetrameric assembly, suggesting that a component of the antitumor activity may be mediated by the ability of Abs to shift the equilibrium from active dimeric to impaired tetrameric receptor complex states. This study suggests a novel therapeutic approach to disable signaling of erbB and potentially other receptors in tumors by biologic agents capable of inducing receptor tetramerization.