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EV016/#559  Preclinical activity of datopotamab deruxtecan, a novel trophoblast cell-surface antigen 2 (TROP2) directed antibody-drug conjugate targeting TROP2 in high grade serous ovarian carcinoma
  1. Blair Mcnamara,
  2. Michelle Greenman,
  3. Stefania Bellone,
  4. Cem Demirkiran,
  5. Levent Mutlu,
  6. Tobias Hartwich,
  7. Yang Yang-Hartwich,
  8. Elena Ratner,
  9. Peter Schwartz and
  10. Alessandro Santin
  1. Yale University, Obstetrics and Gynecology, New Haven, USA

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).

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