title: 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.
abstract: 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.
authors.affiliation: Biologics & Immuno-Oncology Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ogitani
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Katsunobu
authors.initials: K
authors.lastname: Hagihara
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Oitate
authors.affiliation: Oncology Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Naito
authors.affiliation: Biologics & Immuno-Oncology Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Agatsuma
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D024201:Bystander Effect / Q000187:drug effects*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000276:immunology* / Q000494:pharmacology*; D008453:Maytansine / Q000031:analogs & derivatives / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000276:immunology*; D013274:Stomach Neoplasms / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology; D000068878:Trastuzumab
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D002166:Camptothecin; D018796:Immunoconjugates; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D059004:Topoisomerase I Inhibitors; D000068878:Trastuzumab; C000614160:trastuzumab deruxtecan; C508053:ERBB2 protein, human
keywords: Antibody-drug conjugate; HER2; T-DM; bystander killing; topoisomerase I inhibitor