Article Text
Abstract
Introduction Datopotamab deruxtecan (Dato-DXd) is a TROP2 directed antibody drug conjugate (ADC) composed of the humanized anti-TROP2 IgG1 monoclonal antibody, a cleavable tetrapeptide linker, and a topoisomerase I inhibitor payload. We evaluated the preclinical activity of Dato-DXd in high grade serous ovarian cancer (HGSOC).
Methods In vitro cell viability with Dato-DXd was assessed using flow-cytometry assays against primary HGSOC cell lines with variable TROP2 expression. The TROP2 overexpressing HGSOC (TROP2 3+) were co-cultured with a TROP2 non-expressing cell line (TROP2 0) and treated with Dato-DXd to evaluate potential bystander effect. Mouse xenograft models were established from a TROP2 overexpressing platinum resistant HGSOC cell line. Animals were randomized to treatment groups: control PDS (n=5), Datopotomab (n=5), Dato-Dxd (n=5), or CTL ADC (n=5).
Results TROP2 3+ HGSOC cell lines demonstrated higher sensitivity to Dato-DXd compared to TROP2 0 (IC50: 0.49µM vs. 5.1µM, p<0.0001). While negligible activity was detected against TROP2 0 cells, Dato-DXd demonstrated significant bystander killing against TROP2 0 tumor when admixed with TROP2 3+ cells in vitro (p=0.009). Dato-DXd showed tumor growth suppression in in vivo HGSOC PDX models after single retro-orbital injection of Dato-Dxd (p<0.0001). Survival of Dato-DXd-treated mice was significantly longer than other arms (p<0.0001). Toxicity was minimal.
Conclusion/Implications This study shows promising in vitro and in vivo preclinical efficacy of Dato-DXd in HGSOC. This preclinical data supports evaluation of Dato-DXd in patients with advanced or recurrent HGSOC. A Phase 2 trial of Dato-DXd as monotherapy and in combination with other anticancer agents in patients with advanced solid tumors is ongoing (Tropion-Pantumor03).