Selective targeting of oncogenic hotspot mutations of the HER2 extracellular domain

IF 12.9 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Injin Bang, Takamitsu Hattori, Nadia Leloup, Alexis Corrado, Atekana Nyamaa, Akiko Koide, Ken Geles, Elizabeth Buck, Shohei Koide
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引用次数: 0

Abstract

Oncogenic mutations in the extracellular domain (ECD) of cell-surface receptors could serve as tumor-specific antigens that are accessible to antibody therapeutics. Such mutations have been identified in receptor tyrosine kinases including HER2. However, it is challenging to selectively target a point mutant, while sparing the wild-type protein. Here we developed antibodies selective to HER2 S310F and S310Y, the two most common oncogenic mutations in the HER2 ECD, via combinatorial library screening and structure-guided design. Cryogenic-electron microscopy structures of the HER2 S310F homodimer and an antibody bound to HER2 S310F revealed that these antibodies recognize the mutations in a manner that mimics the dimerization arm of HER2 and thus inhibit HER2 dimerization. These antibodies as T cell engagers selectively killed a HER2 S310F-driven cancer cell line in vitro, and in vivo as a xenograft. These results validate HER2 ECD mutations as actionable therapeutic targets and offer promising candidates toward clinical development.

Abstract Image

选择性靶向 HER2 细胞外结构域的致癌热点突变
细胞表面受体胞外结构域(ECD)中的致癌突变可作为肿瘤特异性抗原,供抗体疗法使用。在包括 HER2 在内的受体酪氨酸激酶中已经发现了此类突变。然而,要选择性地靶向点突变体,同时不损伤野生型蛋白是一项挑战。在这里,我们通过组合库筛选和结构引导设计,开发出了针对 HER2 S310F 和 S310Y(HER2 ECD 中最常见的两种致癌突变)的选择性抗体。HER2 S310F同源二聚体和与HER2 S310F结合的抗体的低温电子显微镜结构显示,这些抗体能以模拟HER2二聚化臂的方式识别突变,从而抑制HER2二聚化。这些抗体作为T细胞吞噬因子,在体外和体内异种移植中选择性地杀死了HER2 S310F驱动的癌细胞系。这些结果验证了 HER2 ECD 突变是可行的治疗靶点,并为临床开发提供了有希望的候选药物。
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来源期刊
Nature chemical biology
Nature chemical biology 生物-生化与分子生物学
CiteScore
23.90
自引率
1.40%
发文量
238
审稿时长
12 months
期刊介绍: Nature Chemical Biology stands as an esteemed international monthly journal, offering a prominent platform for the chemical biology community to showcase top-tier original research and commentary. Operating at the crossroads of chemistry, biology, and related disciplines, chemical biology utilizes scientific ideas and approaches to comprehend and manipulate biological systems with molecular precision. The journal embraces contributions from the growing community of chemical biologists, encompassing insights from chemists applying principles and tools to biological inquiries and biologists striving to comprehend and control molecular-level biological processes. We prioritize studies unveiling significant conceptual or practical advancements in areas where chemistry and biology intersect, emphasizing basic research, especially those reporting novel chemical or biological tools and offering profound molecular-level insights into underlying biological mechanisms. Nature Chemical Biology also welcomes manuscripts describing applied molecular studies at the chemistry-biology interface due to the broad utility of chemical biology approaches in manipulating or engineering biological systems. Irrespective of scientific focus, we actively seek submissions that creatively blend chemistry and biology, particularly those providing substantial conceptual or methodological breakthroughs with the potential to open innovative research avenues. The journal maintains a robust and impartial review process, emphasizing thorough chemical and biological characterization.
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