ARX788, a Site-specific Anti-HER2 Antibody–Drug Conjugate, Demonstrates Potent and Selective Activity in HER2-low and T-DM1–resistant Breast and Gastric Cancers

抗体-药物偶联物 癌症 抗体 癌症研究 结合 医学 药品 体外 药理学 乳腺癌 单克隆抗体 内科学 化学 免疫学 生物化学 数学 数学分析
作者
Lillian Skidmore,Sukumar Sakamuri,Nick Knudsen,Amha Gebre Hewet,Snezana Milutinovic,Wisam Barkho,Sandra L. Biroc,Jessica Kirtley,Robin Marsden,Kristine Storey,Ianina Lopez,Wayne Yu,Shiao-Yan Fang,Sulan Yao,Yi Gu,Feng Tian
出处
期刊:Molecular Cancer Therapeutics [American Association for Cancer Research]
卷期号:19 (9): 1833-1843 被引量:127
标识
DOI:10.1158/1535-7163.mct-19-1004
摘要

Abstract 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.
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