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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 ( HER 2)‐targeting antibody–drug conjugate prepared using a novel linker‐payload system with a potent topoisomerase I inhibitor, exatecan derivative ( DX ‐8951 derivative,  DX d). It was effective against trastuzumab emtansine (T‐ DM 1)‐insensitive patient‐derived xenograft models with both high and low  HER 2 expression. In this study, the bystander killing effect of  DS ‐8201a was evaluated and compared with that of T‐ DM 1. We confirmed that the payload of  DS ‐8201a,  DX d (1), was highly membrane‐permeable whereas that of T‐ DM 1, Lys‐ SMCC ‐ DM 1, had a low level of permeability. Under a coculture condition of  HER 2‐positive  KPL ‐4 cells and negative  MDA ‐ MB ‐468 cells  in vitro ,  DS ‐8201a killed both cells, whereas T‐ DM 1 and an antibody–drug conjugate with a low permeable payload, anti‐ HER 2‐ DX d (2), did not.  In vivo  evaluation was carried out using mice inoculated with a mixture of  HER 2‐positive  NCI ‐N87 cells and  HER 2‐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‐ DM 1 and anti‐ HER 2‐ DX d (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  HER 2‐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  HER 2 heterogeneity that are unresponsive to T‐ DM 1.

cancer science

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