Antitumor Activity of a Novel Bispecific Antibody That Targets the ErbB2/ErbB3 Oncogenic Unit and Inhibits Heregulin-Induced Activation of ErbB3
Antitumor Activity of a Novel Bispecific Antibody That Targets the ErbB2/ErbB3 Oncogenic Unit and Inhibits Heregulin-Induced Activation of ErbB3
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DOI：
10.1158/1535-7163.mct-11-0820
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发表时间：
2012-03-01
影响因子：
5.7
通讯作者：
Nielsen, Ulrik B.
中科院分区：
文献类型：
--
作者：
McDonagh, Charlotte F.;Huhalov, Alexandra;Nielsen, Ulrik B.
乳腺癌中ErbB2扩增的普遍存在导致了对ErbB2作为治疗靶点的大量追求。尽管ErbB2单克隆抗体曲妥珠单抗和ErbB1/ErbB2双激酶抑制剂拉帕替尼在临床上都取得了成功，但许多患者未能从中受益。此外，不幸的是，大多数最初有反应的患者最终将在这些治疗中取得进展。ErbB2的首选二聚化伙伴ErbB3的激活在驱动ErbB2扩增的肿瘤生长中起着关键作用，但我们发现目前的ErbB2定向治疗是配体诱导激活的不良抑制剂。通过在ErbB2/ErbB3受体信号传导的计算模型中模拟ErbB3的抑制作用，我们预测了一种双特异性抗体，该抗体与ErbB2对接，随后与ErbB3结合并阻断配体诱导的受体激活，在ErbB2扩增的肿瘤中非常有效，具有优于单特异性ErbB3抑制剂的活性。我们已经开发出一种适合大规模生产和全身治疗的双特异性抗体，通过产生与修饰的人血清白蛋白连接的两种人scFv抗体的单一多肽融合蛋白。得到的分子MM-111与ErbB2和ErbB3形成三聚体复合物，有效抑制ErbB3信号传导，并在依赖ErbB2过表达的临床前模型中显示出抗肿瘤活性。MM-111可以合理地与曲妥珠单抗或拉帕替尼联合使用，以提高抗肿瘤活性，并可能在未来补充现有的erbb2靶向治疗，以治疗耐药肿瘤或阻止复发。巨蟹座；11 (3);582 - 93。(c) 2012年aacr。
The prevalence of ErbB2 amplification in breast cancer has resulted in the heavy pursuit of ErbB2 as a therapeutic target. Although both the ErbB2 monoclonal antibody trastuzumab and ErbB1/ErbB2 dual kinase inhibitor lapatinib have met with success in the clinic, many patients fail to benefit. In addition, the majority of patients who initially respond will unfortunately ultimately progress on these therapies. Activation of ErbB3, the preferred dimerization partner of ErbB2, plays a key role in driving ErbB2-amplified tumor growth, but we have found that current ErbB2-directed therapies are poor inhibitors of ligand-induced activation. By simulating ErbB3 inhibition in a computational model of ErbB2/ErbB3 receptor signaling, we predicted that a bispecific antibody that docks onto ErbB2 and subsequently binds to ErbB3 and blocks ligand-induced receptor activation would be highly effective in ErbB2-amplified tumors, with superior activity to a mono-specific ErbB3 inhibitor. We have developed a bispecific antibody suitable for both large scale production and systemic therapy by generating a single polypeptide fusion protein of two human scFv antibodies linked to modified human serum albumin. The resulting molecule, MM-111, forms a trimeric complex with ErbB2 and ErbB3, effectively inhibiting ErbB3 signaling and showing antitumor activity in preclinical models that is dependent on ErbB2 overexpression. MM-111 can be rationally combined with trastuzumab or lapatinib for increased antitumor activity and may in the future complement existing ErbB2-directed therapies to treat resistant tumors or deter relapse. Mol Cancer Ther; 11(3); 582-93. (C) 2012 AACR.