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

Mol Cancer Ther. 2020 Sep;19(9):1833-1843. doi: 10.1158/1535-7163.MCT-19-1004. Epub 2020 Jul 15.


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.

MeSH terms

  • Ado-Trastuzumab Emtansine / pharmacology
  • Ado-Trastuzumab Emtansine / therapeutic use
  • Animals
  • Antibodies, Monoclonal / administration & dosage*
  • Antibodies, Monoclonal / pharmacokinetics
  • Antibodies, Monoclonal / pharmacology
  • Breast Neoplasms / blood
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Down-Regulation
  • Drug Resistance, Neoplasm / drug effects*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Mice
  • Oligopeptides / administration & dosage*
  • Oligopeptides / pharmacokinetics
  • Oligopeptides / pharmacology
  • Receptor, ErbB-2 / metabolism*
  • Stomach Neoplasms / blood
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / metabolism
  • Xenograft Model Antitumor Assays


  • ARX788
  • Antibodies, Monoclonal
  • Oligopeptides
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Ado-Trastuzumab Emtansine