First-generation antibody–drug conjugates (ADC) are heterogeneous mixtures that have shown clinical benefit, but generally exhibited safety issues and a narrow therapeutic window due, in part, to off-target toxicity caused by ADC instability. ARX788 is a next-generation, site-specific anti-HER2 ADC that utilizes a unique nonnatural amino acid–enabled conjugation technology and a noncleavable Amberstatin (AS269) drug-linker to generate a homogeneous ADC with a drug-to-antibody ratio of 1.9. ARX788 exhibits high serum stability in mice and a relatively long ADC half-life of 12.5 days. When compared in vitro against T-DM1 across a panel of cancer cell lines, ARX788 showed superior activity in the lower HER2-expressing cell lines and no activity in normal cardiomyocyte cells. Similarly, ARX788 significantly inhibited tumor growth, and generally outperformed T-DM1 in HER2-high and HER2-low expression xenograft models. Breast and gastric cancer patient-derived xenograft studies confirmed strong antitumor activity of ARX788 in HER2-positive and HER2-low expression tumors, as well as in a T-DM1-resistant model. The encouraging preclinical data support the further development of ARX788 for treatment of patients with HER2-positive breast and gastric cancer, including those who have developed T-DM1 resistance, and patients with HER2-low expression tumors who are currently ineligible to receive HER2-targeted therapy.

中文翻译：

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ARX788 是一种位点特异性抗 HER2 抗体药物偶联物，在 HER2 低和 T-DM1 耐药的乳腺癌和胃癌中显示出有效的选择性活性

第一代抗体-药物偶联物 (ADC) 是异质混合物，已显示出临床益处，但通常表现出安全问题和狭窄的治疗窗口，部分原因是 ADC 不稳定性引起的脱靶毒性。ARX788 是下一代位点特异性抗 HER2 ADC，它利用独特的非天然氨基酸结合技术和不可切割的 Amberstatin (AS269) 药物接头来生成药物抗体比为 1.9 的均质 ADC . ARX788 在小鼠中表现出高血清稳定性和 12.5 天的相对较长的 ADC 半衰期。在体外与一组癌细胞系中的 T-DM1 进行比较时，ARX788 在低表达 HER2 的细胞系中显示出优异的活性，而在正常心肌细胞中没有活性。同样，ARX788 显着抑制肿瘤生长，并且在 HER2 高表达和 HER2 低表达异种移植模型中通常优于 T-DM1。源自乳腺癌和胃癌患者的异种移植研究证实 ARX788 在 HER2 阳性和 HER2 低表达肿瘤以及 T-DM1 耐药模型中具有很强的抗肿瘤活性。令人鼓舞的临床前数据支持进一步开发 ARX788 用于治疗 HER2 阳性乳腺癌和胃癌患者，包括那些已经产生 T-DM1 耐药的患者，以及目前不符合接受 HER2 靶向治疗的 HER2 低表达肿瘤患者治疗。