The majority of HER2-positive breast or gastric cancers treated with T-DM1 eventually show resistance to this agent. We compared the effects of T-DM1 and ARX788, a novel anti-HER2 antibody-drug conjugate, on cell growth and apoptosis in HER2-positive breast cancer and gastric cancer cell lines sensitive to T-DM1, gastric cancer cell lines resistant to T-DM1, HER2-negative breast cancer cell lines, and T-DM1-resistant xenograft models. ARX788 was effective in T-DM1-resistant in vitro and in vivo models of HER2-positive breast cancer and gastric cancer. ARX788 showed a pronounced growth inhibitory effect on all five HER2-positive cell lines tested, of which two gastric cancer cell lines had acquired resistance to T-DM1. ARX788 evoked more apoptotic events compared to T-DM1. While JIMT-1 and RN-87 xenograft tumors progressed on T-DM1 treatment, all such tumors responded to ARX788, and four out of the six JIMT-1 tumors and nine out of the twelve RN-87 tumors disappeared during the ARX788 treatment. Mice treated with ARX788 survived longer than those treated with T-DM1. The data support evaluation of ARX788 in patients with HER2-positive breast cancer or gastric cancer including cancers that progress during T-DM1 therapy.

中文翻译：

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ARX788是一种新型的抗HER2抗体-药物偶联物，在曲妥珠单抗耐美登素的HER2阳性乳腺癌和胃癌的临床前模型中显示出抗肿瘤作用。

用T-DM1治疗的大多数HER2阳性乳腺癌或胃癌最终都显示出对该药的耐药性。我们比较了新型抗HER2抗体-药物偶联物T-DM1和ARX788对HER2阳性乳腺癌和对T-DM1敏感的胃癌细胞系，对T耐药的胃癌细胞系的细胞生长和凋亡的影响-DM1，HER2阴性乳腺癌细胞系和T-DM1耐药异种移植模型。ARX788在抗T-DM1的HER2阳性乳腺癌和胃癌的体外和体内模型中有效。ARX788对测试的所有五个HER2阳性细胞系均表现出明显的生长抑制作用，其中两个胃癌细胞系已获得对T-DM1的抗性。与T-DM1相比，ARX788引发了更多的凋亡事件。尽管JIMT-1和RN-87异种移植瘤在T-DM1治疗中进展，所有这些肿瘤均对ARX788产生反应，在ARX788治疗期间，六种JIMT-1肿瘤中的四种和十二种RN-87肿瘤中的九种消失。用ARX788治疗的小鼠存活时间比用T-DM1治疗的小鼠更长。数据支持对HER2阳性乳腺癌或胃癌（包括在T-DM1治疗期间进展的癌症）患者进行ARX788评估。