Deruxtecan is an ADC drug-linker conjugate composed of a derivative of DX-8951 (DXd) and a maleimide-GGFG peptide linker used in the synthesis of DS-8201 and U3-1402.

METHODS: Trastuzumab Deruxtecan (DS-8201a) was administered at scalar concentrations of 0.005 μg/mL, 0.05 μg/mL, 0.2 μg/mL, 0.5 μg/mL, and 2.0 μg/mL. Three days after drug treatment, whole cells were harvested, centrifuged, and stained with propidium iodide (2 μl of 500 μg/mL stock solution in phosphate-buffered saline (PBS)).
RESULTS DS-8201 induced cell death with a mean IC50 value of 0.03 μM (p<0.0001); statistically significant differences were observed in 3+ HER2/neu ovarian CS cell lines, where the mean IC50 of DS-8201a was 0.03 μM; and in representative HER2/neu non-expressing cell lines, where the mean IC50 of DS-8201a was 20.02 μM. [2]

METHODS: Mouse models of HER2-positive tumors were treated with Trastuzumab Deruxtecan (DS-8201a) (10 mg/kg, i.v), and anti-PD-1 antibodies were also used in combination to evaluate synergistic effects, monitor tumor growth, and perform flow cytometric analysis. To analyze the composition and function of immune cells in tumors.
RESULTS Trastuzumab Deruxtecan (DS-8201a) significantly inhibited tumor growth and in some cases resulted in complete remission (CR); mice that achieved CR after treatment were able to reject revaccinated CT26.WT-hHER2 cells as well as non-transgenic CT26.WT-mock cells, showing the formation of immune memory; Trastuzumab Deruxtecan (DS-8201a) increased the number of CD8+ T cells infiltrating within the tumor, upregulated the expression of CD86, an activation marker of dendritic cells (DCs), and enhanced Expression of PD-L1 and MHC class I molecules on tumor cells; the combination of Trastuzumab Deruxtecan (DS-8201a) and an anti-PD-1 antibody is more effective in inhibiting tumor growth than monotherapy, suggesting that Trastuzumab Deruxtecan (DS-8201a) may Promote anti-tumor immunity by activating the immune system and upregulating PD-L1 expression. [1]