Conjugate

Antibody-drug conjugate

Molecular biology

Biotechnology

Biology

Cancer research

Drug

Immunology

Genetics

In vivo

Monoclonal antibody

Mathematics

Pharmacology

Mathematical analysis

Medicine

Topoisomerase

Antibody

Topoisomerase inhibitor

Journal of Clinical Oncology

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

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