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.

First generation antibody drug conjugates (ADCs) 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 non-natural amino acid enabled conjugation technology and a non-cleavable 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 PDX studies confirmed strong anti-tumor 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 HER2 positive breast and gastric cancer patients, including those who have developed T-DM1 resistance, and patients with HER2 low expression tumors who are currently ineligible to receive HER2 targeted therapy.