Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity

Cancer Sci. 2016 Jul;107(7):1039-46. doi: 10.1111/cas.12966. Epub 2016 Jun 22.


Antibody-drug conjugates deliver anticancer agents selectively and efficiently to tumor tissue and have significant antitumor efficacy with a wide therapeutic window. DS-8201a is a human epidermal growth factor receptor 2 (HER2)-targeting antibody-drug conjugate prepared using a novel linker-payload system with a potent topoisomerase I inhibitor, exatecan derivative (DX-8951 derivative, DXd). It was effective against trastuzumab emtansine (T-DM1)-insensitive patient-derived xenograft models with both high and low HER2 expression. In this study, the bystander killing effect of DS-8201a was evaluated and compared with that of T-DM1. We confirmed that the payload of DS-8201a, DXd (1), was highly membrane-permeable whereas that of T-DM1, Lys-SMCC-DM1, had a low level of permeability. Under a coculture condition of HER2-positive KPL-4 cells and negative MDA-MB-468 cells in vitro, DS-8201a killed both cells, whereas T-DM1 and an antibody-drug conjugate with a low permeable payload, anti-HER2-DXd (2), did not. In vivo evaluation was carried out using mice inoculated with a mixture of HER2-positive NCI-N87 cells and HER2-negative MDA-MB-468-Luc cells by using an in vivo imaging system. In vivo, DS-8201a reduced the luciferase signal of the mice, indicating suppression of the MDA-MB-468-Luc population; however, T-DM1 and anti-HER2-DXd (2) did not. Furthermore, it was confirmed that DS-8201a was not effective against MDA-MB-468-Luc tumors inoculated at the opposite side of the NCI-N87 tumor, suggesting that the bystander killing effect of DS-8201a is observed only in cells neighboring HER2-positive cells, indicating low concern in terms of systemic toxicity. These results indicated that DS-8201a has a potent bystander effect due to a highly membrane-permeable payload and is beneficial in treating tumors with HER2 heterogeneity that are unresponsive to T-DM1.

Keywords: Antibody-drug conjugate; HER2; T-DM; bystander killing; topoisomerase I inhibitor.

MeSH terms

  • Ado-Trastuzumab Emtansine
  • Animals
  • Antibodies, Monoclonal, Humanized / immunology*
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / immunology
  • Breast Neoplasms / pathology
  • Bystander Effect / drug effects*
  • Camptothecin / analogs & derivatives*
  • Camptothecin / immunology
  • Camptothecin / pharmacology
  • Cell Line, Tumor
  • Cell Membrane Permeability / drug effects
  • Cell Proliferation / drug effects
  • Female
  • Humans
  • Immunoconjugates / immunology*
  • Immunoconjugates / pharmacology*
  • Maytansine / analogs & derivatives
  • Maytansine / immunology
  • Maytansine / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasms / enzymology
  • Neoplasms / genetics*
  • Neoplasms / immunology
  • Neoplasms / pathology*
  • Receptor, ErbB-2 / genetics*
  • Receptor, ErbB-2 / immunology*
  • Stomach Neoplasms / enzymology
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / immunology
  • Stomach Neoplasms / pathology
  • Topoisomerase I Inhibitors / pharmacology
  • Trastuzumab


  • Antibodies, Monoclonal, Humanized
  • Immunoconjugates
  • Topoisomerase I Inhibitors
  • Maytansine
  • trastuzumab deruxtecan
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Trastuzumab
  • Ado-Trastuzumab Emtansine
  • Camptothecin