Abstract C026: DS-1062a, a novel TROP2-targeting antibody-drug conjugate with a novel DNA topoisomerase I inhibitor DXd, demonstrates potent antitumor activity in preclinical models
Authors: Okajima Daisuke , Yamaguchi Junko , Kitamura Michiko , Kamei Reiko , Maejima Takanori , Shibutani Tomoko , Yasuda Satoru , Toki Tadashi , Karibe Tsuyoshi , Fujitani Tomomichi , Nakada Takashi , Goto Riki , Noguchi Yutaka , Abe Yuki , Agatsuma Toshinori 
Published: March 2020

Abstract
Background: A trophoblast cell surface antigen 2 (TROP2) is a 36-kDa single-pass transmembrane protein overexpressed in various epithelial tumors including non-small cell lung cancer (NSCLC) with relatively low and restricted expression in normal tissues, and is associated with aggressive tumor behavior. Therefore, TROP2 could be an attractive target for cancer therapy. We created DS-1062a, TROP2-targeting antibody-drug conjugate (ADC) with Daiichi Sankyo DXd technology using a novel DNA topoisomerase I inhibitor DXd. In this study, the pharmacological activity and the mechanism of action of DS-1062a were evaluated in preclinical in vitro and in vivo models. Methods: In vitro cell growth inhibitory and in vivo antitumor activities of DS-1062a were evaluated using TROP2-high and -low tumor cell lines and xenograft mouse models. Internalization and intracellular trafficking of DS-1062a in tumor cells were analyzed by immunofluorescence microscopy. Induction of DNA damage and apoptosis to tumor cells by DXd payload released from DS-1062a were assessed by western blot and immunohistochemistry. Pharmacokinetic profiles of DS-1062a were also analyzed in xenograft mouse model. Results: DS-1062a showed in vitro cell growth inhibitory activity to TROP2-high tumor cells, but not to TROP2-low tumor cells. It was observed with confocal microscopy that DS-1062a was co-localized with a lysosomal marker LAMP-2 after internalizing into TROP2-high tumor cells. The amount of DXd payload released from TROP2-high tumor cells after the in vitro treatment with DS-1062a was higher than that of TROP2-low tumor cells. DNA damage and apoptosis were induced in TROP2-high tumor cells after the in vitro treatment with DXd and DS-1062a, but not with isotype control IgG ADC. Similarly, DS-1062a exhibited strong antitumor activity with tumor regression in several TROP2-high tumors including NSCLC and DXd accumulation and DNA damage in TROP2-high tumors were observed in DS-1062a-treated tumors, but not in isotype control IgG ADC-treated tumors. Pharmacokinetic profiles of DS-1062a in xenograft mouse model were preferable. Conclusion: Based on these preclinical results, DS-1062a could provide a valuable therapy with a potential benefit in TROP2-expressing cancers in the clinical setting. A first-in-human phase 1 study in patients with advanced solid tumors is in progress (NCT03401385).
Citation Format: Daisuke Okajima, Junko Yamaguchi, Michiko Kitamura, Reiko Kamei, Takanori Maejima, Tomoko Shibutani, Satoru Yasuda, Tadashi Toki, Tsuyoshi Karibe, Tomomichi Fujitani, Takashi Nakada, Riki Goto, Yutaka Noguchi, Yuki Abe, Toshinori Agatsuma. DS-1062a, a novel TROP2-targeting antibody-drug conjugate with a novel DNA topoisomerase I inhibitor DXd, demonstrates potent antitumor activity in preclinical models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C026. doi:10.1158/1535-7163.TARG-19-C026