Nature Communications ( IF 14.7 ) Pub Date : 2023-03-13 , DOI: 10.1038/s41467-023-37029-3
Nina E Weisser 1 , Mario Sanches 1 , Eric Escobar-Cabrera 1 , Jason O'Toole 1 , Elizabeth Whalen 1 , Peter W Y Chan 1 , Grant Wickman 1 , Libin Abraham 2 , Kate Choi 2 , Bryant Harbourne 1 , Antonios Samiotakis 1 , Andrea Hernández Rojas 1 , Gesa Volkers 1 , Jodi Wong 1 , Claire E Atkinson 3, 4, 5 , Jason Baardsnes 6 , Liam J Worrall 3, 4, 5 , Duncan Browman 1 , Emma E Smith 6 , Priya Baichoo 1 , Chi Wing Cheng 1 , Joy Guedia 1 , Sohyeong Kang 1 , Abhishek Mukhopadhyay 1 , Lisa Newhook 1 , Anders Ohrn 1 , Prajwal Raghunatha 1 , Matteo Zago-Schmitt 1 , Joseph D Schrag 6 , Joel Smith 1 , Patricia Zwierzchowski 1 , Joshua M Scurll 7, 8 , Vincent Fung 1 , Sonia Black 1 , Natalie C J Strynadka 3, 4, 5 , Michael R Gold 2 , Leonard G Presta 1 , Gordon Ng 9 , Surjit Dixit 1
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Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase that plays an oncogenic role in breast, gastric and other solid tumors. However, anti-HER2 therapies are only currently approved for the treatment of breast and gastric/gastric esophageal junction cancers and treatment resistance remains a problem. Here, we engineer an anti-HER2 IgG1 bispecific, biparatopic antibody (Ab), zanidatamab, with unique and enhanced functionalities compared to both trastuzumab and the combination of trastuzumab plus pertuzumab (tras + pert). Zanidatamab binds adjacent HER2 molecules in trans and initiates distinct HER2 reorganization, as shown by polarized cell surface HER2 caps and large HER2 clusters, not observed with trastuzumab or tras + pert. Moreover, zanidatamab, but not trastuzumab nor tras + pert, elicit potent complement-dependent cytotoxicity (CDC) against high HER2-expressing tumor cells in vitro. Zanidatamab also mediates HER2 internalization and downregulation, inhibition of both cell signaling and tumor growth, antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP), and also shows superior in vivo antitumor activity compared to tras + pert in a HER2-expressing xenograft model. Collectively, we show that zanidatamab has multiple and distinct mechanisms of action derived from the structural effects of biparatopic HER2 engagement.
中文翻译:
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一种抗 HER2 双互补位抗体,可诱导独特的 HER2 聚集和补体依赖性细胞毒性
人表皮生长因子受体 2 (HER2) 是一种受体酪氨酸激酶,在乳腺癌、胃癌和其他实体瘤中起致癌作用。然而,抗 HER2 疗法目前仅被批准用于治疗乳腺癌和胃/胃食管交界处癌症,治疗耐药性仍然是一个问题。在这里,我们设计了一种抗 HER2 IgG1 双特异性双互补位抗体 (Ab),zanidatamab,与曲妥珠单抗和曲妥珠单抗加帕妥珠单抗 (tras + pert) 的组合相比,具有独特和增强的功能。Zanidatamab反式结合相邻的 HER2 分子并启动不同的 HER2 重组,如极化细胞表面 HER2 帽和大 HER2 簇所示,而曲妥珠单抗或 tras + pert 未观察到。此外,zanidatamab,而不是曲妥珠单抗或 tras + pert,在体外对高 HER2 表达肿瘤细胞产生有效的补体依赖性细胞毒性 (CDC)。Zanidatamab 还介导 HER2 内化和下调、细胞信号传导和肿瘤生长的抑制、抗体依赖性细胞毒性 (ADCC) 和吞噬作用 (ADCP),并且在表达 HER2 的异种移植物中显示出优于 tras + pert 的体内抗肿瘤活性模型。总的来说,我们表明 zanidatamab 具有多种不同的作用机制,这些作用机制源自双互补位 HER2 结合的结构效应。