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

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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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Skidmore, L., Sakamuri, S., Knudsen, N. A., Hewet, A. G., Milutinovic, S., Barkho, W., … Tian, F. (2020). 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. Molecular Cancer Therapeutics, 19(9), 1833–1843. https://doi.org/10.1158/1535-7163.MCT-19-1004

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