Targeting TROP2, in Poorly Differentiated

Overview

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Key numbers

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• xenografts. A total of 78% (seven of nine) of the primary endometrial development of treatments when patients are resistant to other lines of
• patients developed a hyper-mutated microsatellite-unstable endometrial receptor (HR)–positive, HER2-negative breast cancer (objective response rate,
• cancer and have an intermediate prognosis, (iii) p53abn: protein 53 abnor- 29%; ref. 21) in TROPION-PanTumor01. Importantly, encouraging clinical
• stage I disease is 90%; refs. 7, 8). However, up to 35% of patients with clinical antitumor activity of Dato-DXd in vitro and in vivo against multiple
• year survival rate for stage IVA and IVB endometrial cancer is only 17% and
• 15%, respectively; refs. 8–11). The identification of novel treatment modal- Approval for this study was obtained through the Institutional Review
• linker. ADCs may therefore optimize tumor targeting in vivo while po- demographics (i.e., age and ethnicity) are described in Table 1. Tumors were
• TROP2 overexpression has been previously demonstrated to represent an FACSCalibur (RRID: SCR_000401). Mean fluorescence intensity (MFI)
• viable cells as a mean ± SEM relative to untreated cells as 100% viable
• L-Glutamine supplemented with 10% FBS, 1% penicillin/streptomycin, and different cell lines (END(K)254 and END(K)265, which were TROP2 3+, and
• 1% amphotericin. Cells were incubated at 37°C with 5% CO2 for 24 hours. END(K)34, which was TROP2 negative) were first plated and incubated for
• then treated with Dato-DXd and the control ADC at concentrations of 0.1, done in 200 μL of fixative buffer (4% paraformaldehyde in PBS 1�) and
• (2 μL of 500 μg/mL stock solution in PBS). Viable cell percentage was then a solution of PBS with 0.5% saponin and 1% BSA. The PE mouse anti-H2AX
• quantified using flow cytometry as a mean ± SEM relative to untreated cells antibody was added to the cells, 5 μL per sample, followed by incubation on
• as 100% viable controls. A minimum of three independent experiments per ice for 30 minutes. The cells were washed twice with 2 mL of a solution of
• cell line were performed to determine the IC50 of Dato-DXd versus CTL- PBS with 0.5% of BSA and then analyzed for phosphorylated H2AX as a
• sured as evidence of tumor cell lysis. As a positive control condition, 0.1%
• drug was calculated by the following formula: % cytotoxicity ¼ 100 � (E � TROP2 protein expression by flow cytometry. Seven of nine (78%) were
• S)/(T � S), in which E is the experimental release, S is the spontaneous found to express TROP2, with four of the nine (44%) cell lines demon-
• release by target cells, and T is the maximum release by target cells lysed with strating moderate to strong (i.e., 2+/3+) TROP2 expression (Table 1). Sup-
• 0.1% SDS. A minimum of three replicates were performed. Results are re- plementary Figure S1 shows representative flow cytometric analysis of
• ported as mean ± SEM. END(K)254 and END(K)265 cell lines, both showing high TROP2 expres-
• mice were randomized into four groups: Dato-DXd (10 mg/kg), CTL-ADC DXd and CTL-ADC with an incubation period of 72 hours. As demonstrated
• (10 mg/kg), datopotamab (10 mg/kg), and control vehicle, with four animals in Fig. 1, Dato-DXd was significantly more potent against TROP2-positive
• or tumor volume of 1.0 cm3) were analyzed and plotted using Kaplan–Meier treated with CTL-ADC (i.e., 94.7% live cells; Fig. 2).
• FIGURE 1 Flow cytometry–based cytotoxicity assay. Determination of Dato-DXd and control ADC IC50 (mean SEM) in the tested cell lines. A, Cell
• datopotamab, and control vehicle were performed using END(K)265 xeno- DXd was not reached at day 60 as all mice were alive. In contrast, median
• Significant ADCC was detectable only against the TROP2-positive cell lines (B and C; *, P < 0.05)
• CTRL vehicle vs. CTL-ADC 0.0462 Median survival
• Dato-DXd (10 mg/kg) caused a statistically significant difference in END(K) tiple solid tumors resistant to chemotherapy including advanced endometrial
• breast cancer. Heliyon 2024;10:e28385. 34. FDA. FDA approves datopotamab deruxtecan-dlnk for unresectable or met-

Methods (brief)

• fresh tumor biopsy samples, determined to be free of Mycoplasma and with
• tumor cells with highly potent anticancer agents linked via a chemical Cell sample characteristics (i.e., histology, stage, and grade) and patient
• and 2 mL of tissue culture media were added to each culture well. Cells were for 72 hours. The cells were then harvested and collected. Resuspension was
• quantified using flow cytometry as a mean ± SEM relative to untreated cells antibody was added to the cells, 5 μL per sample, followed by incubation on

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• Chromium

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