Novel anti-ErbB3 monoclonal antibodies show therapeutic efficacy in xenografted and spontaneous mouse tumors
Novel anti-ErbB3 monoclonal antibodies show therapeutic efficacy in xenografted and spontaneous mouse tumors
复制标题
DOI：
10.1002/jcp.24037
复制
发表时间：
2012-10-01
影响因子：
5.6
通讯作者：
Ciliberto, Gennaro
中科院分区：
文献类型：
--
作者：
Aurisicchio, Luigi;Marra, Emanuele;Ciliberto, Gennaro
ErbB 3受体在信号转导中的作用是通过激活PI 3 K/AKT途径来增加活性异源二聚体ErbB受体复合物的信号库，这反过来促进存活和增殖。ErbB 3最近被提出参与对酪氨酸激酶抑制剂（TKI）的获得性耐药性，因此是一个有前途的新药物癌症靶点。由于ErbB 3是一种激酶缺陷型受体，它不能被小分子抑制剂靶向，而单克隆抗体可能提供一种可行的药物干预策略。在这项研究中，我们利用DNA电穿孔（DNA-EP）产生一组新的杂交瘤针对人类ErbB 3，其特征在于其生化和功能特性，并选择其负调控ErbB 3介导的信号通路的能力。在体外，抗ErbB 3抗体调节不同来源的癌细胞的生长速率。在体内，它们在人胰腺肿瘤异种移植模型和ErbB 2驱动的致癌基因工程小鼠模型（GEMM）乳腺肿瘤模型（Balb/neuT）中显示出抗肿瘤特性。我们的数据证实，使用抗ErbB 3单克隆抗体下调ErbB 3介导的信号对于治疗目的是可行的和相关的，并且为用于癌症治疗的新型抗ErbB 3组合策略提供了新的机会。J.细胞。227：33813388，2012。(C)2011 Wiley Periodicals，Inc.
The role of the ErbB3 receptor in signal transduction is to augment the signaling repertoire of active heterodimeric ErbB receptor complexes through activating the PI3K/AKT pathway, which in turn promotes survival and proliferation. ErbB3 has recently been proposed to be involved in acquired resistance to tyrosine kinase inhibitors (TKIs), and is therefore a promising new drug cancer target. Since ErbB3 is a kinase defective receptor, it cannot be targeted by small molecule inhibitors, whereas monoclonal antibodies may offer a viable strategy for pharmacological intervention. In this study, we have utilized DNA electroporation (DNA-EP) to generate a set of novel hybridomas directed against human ErbB3, which have been characterized for their biochemical and functional properties and selected for their ability to negatively regulate the ErbB3-mediated signaling pathway. In vitro, the anti-ErbB3 antibodies modulate the growth rate of cancer cells of different origins. In vivo they show antitumoral properties in a xenograft model of human pancreatic tumor and in the ErbB2-driven carcinogenesis genetically engineered mouse model (GEMM) for mammary tumor, the BALB/neuT. Our data confirm that downregulating the ErbB3-mediated signals with the use of anti-ErbB3 monoclonal antibodies is both feasible and relevant for therapeutic purposes and provides new opportunities for novel anti-ErbB3 combinatory strategies for cancer treatment. J. Cell. Physiol. 227: 33813388, 2012. (C) 2011 Wiley Periodicals, Inc.