Abstract 4893: Evaluation of bystander antitumor effect of Dato-DXd in TROP2 (+) and TROP2 (-) lung cell lines admixed tumor xenograft mouse models

Abstract

Abstract Background: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate (ADC) consisting of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a highly potent topoisomerase I inhibitor payload (DXd) via a stable, tumor-selective, tetrapeptide-based cleavable linker (Nakada T. et al. Bioorg Med Chem Lett., 2016). Dato-DXd demonstrated encouraging efficacy in clinical studies in TROP2 expressing tumors, including NSCLC and TNBC (NCT03401385). Clinical efficacy of Dato-DXd in heterogeneous tumors is hypothesized to be derived not only via effective selective delivery of DXd to TROP2 (+) tumor cells but also DXd diffusion from TROP2 (+) tumor cells to nearby TROP2 (-) tumor cells due to high membrane permeability of the DXd payload, an effect called the bystander antitumor effect. In this preclinical study, the bystander antitumor effect was tested by establishing tumor xenograft mouse models containing admixed TROP2 (+) and TROP2 (-) lung cell lines. The antitumor activity of Dato-DXd was tested in these models to demonstrate the bystander antitumor effect of Dato-DXd. Materials and Methods: EBC-1 cells and NCI-H526 cells or Calu-6 cells were used as models of TROP2 (+) cells and TROP2 (-) cells, respectively. TROP2 (+) cells and TROP2 (-) cells were mixed in various ratios and inoculated subcutaneously in mice to establish heterogeneous xenograft tumor models with various levels of TROP2 expression. Tumor growth inhibition in each model was evaluated by tumor volume after Dato-DXd or control-ADC administration. Immunohistochemistry (IHC) of DXd and TROP2 were performed in Dato-DXd treated tumors to analyze distribution in TROP2 (+) and (-) tumor cells. Tumor cells that responded to Dato-DXd treatment were identified by IHC assay of γH2AX (an indicator of DNA damage). Results: TROP2 expression analysis showed that various TROP2 positivity tumor models were established by inoculating various ratios of admixed EBC-1 cells with NCI-H526 cells or Calu-6 cells. Dato-DXd did not inhibit growth of tumors consisting of only TROP2 (-) cells, as expected. In contrast, Dato-DXd showed strong tumor growth inhibition effect on all tumors in which TROP2 (+) cells were inoculated in various levels with TROP2 (-) cells. DXd-IHC analysis showed that Dato-DXd distributed to only TROP2 (+) tumor cells in admixed tumors, however, an increase of γH2AX was observed not only in TROP2 (+) tumor cells but also TROP2 (-) tumor cells, suggesting TROP2 (-) tumor cells responded to DXd generated and distributed from Dato-DXd bound to TROP2 (+) tumor cells. Conclusion: Dato-DXd is effective not only in TROP2 (+) tumor cells but also TROP2 (-) tumor cells adjacent to TROP2 (+) tumor cells, thereby demonstrating the bystander antitumor effect of Dato-DXd. This property suggests Dato-DXd should be active in the clinical setting even given potential heterogeneity of TROP2 expression. Citation Format: Satoru Yasuda, Takanori Maejima, Tadashi Toki, Tsuyoshi Karibe, Daisuke Okajima, Penny Phillips. Evaluation of bystander antitumor effect of Dato-DXd in TROP2 (+) and TROP2 (-) lung cell lines admixed tumor xenograft mouse models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4893.