Preclinical efficacy studies of DS-1062a, a novel TROP2-targeting antibody-drug conjugate with a novel DNA topoisomerase I inhibitor DXd.

• DOI: 10.1200/jco.2018.36.15_suppl.e24206
• Publication Date: 2018-09-05T14:54:16Z
• Authors: Daisuke Okajima; Satoru Yasuda; Yusuke Yokouchi; Tomomichi Fujitani; Ken Sakurai; Junko Yamaguchi; Michiko Kitamura; Tomoko Terauchi; Tomoko Shibutani; Tetsuo Aida; Takashi Nakada; Shinya Tokuhiro; Tadashi Toki; Yutaka Noguchi; Yuki Abe; Toshinori Agatsuma
• Keywords: Antibody-drug conjugate

e24206 Background: DS-1062a is a trophoblast cell surface protein 2 (TROP2)-targeting antibody-drug conjugate (ADC) comprised of humanized anti-TROP2 monoclonal antibody, enzymatically cleavable peptide-linker, and novel topoisomerase I inhibitor DXd which derivative Exatecan (DX-8951). TROP2 36-kDa single-pass transmembrane overexpressed in various epithelial tumors including non-small lung cancer (NSCLC) with relatively low restricted expression normal tissues, associated aggressive tumor behavior. Therefore, could be an attractive target for therapy. Methods: In vitro growth inhibitory vivo anti-tumor activities were evaluated using TROP2-positive negative lines xenograft mice models. Pharmacokinetic safety profiles also assessed cynomolgus monkeys. Results: showed activity to cells (CFPAC-1, BxPC-3 (pancreas adenocarcinoma)) IC50 values 706 ng/mL 74.6 ng/mL, respectively, but not TROP2-negative (Calu-6 (anaplastic carcinoma)) value > 20000 ng/mL. induced dose-dependent inhibition regression at more than 1 mg/kg single dosing the CFPAC-1 model contrast isotype control IgG-ADC antibody no efficacy. exhibited stronger higher concentrations TROP2-high compared TROP2-low or several addition, favorable pharmacokinetic acceptable Conclusions: Based on these preclinical results, provide valuable therapy potential benefit cancers clinical setting. A first-in-human phase study patients advanced solid progress (NCT03401385).