A ‘Dual’ Cell-Level Systems PK-PD Model to Characterize the Bystander Effect of ADC

Abstract

Here we have developed a cell-level systems PK-PD model to characterize the bystander effect of ADCs. Cytotoxicity data generated following incubation of Trastuzumab-vc-MMAE in cocultures of high HER2 expressing N87 and low HER2 expressing GFP-MCF7 cells were used to build the model. Single cell PK model for ADC was used to characterize the PK of Trastuzumab-vc-MMAE and released MMAE in N87 and GFP-MCF7 cells. The two cell-level PK models were mechanistically integrated to mimic the coculture condition. MMAE induced intracellular occupancy of tubulin was used to drive the efficacy of ADC, and improvement in the tubulin occupancy of GFP-MCF7 cells in the presence of N87 cells was used to drive the bystander effect of Trastuzumab-vc-MMAE. The ‘dual’ cell-level PK-PD model was able to capture the observed data reasonably well. It was found that similar and high occupancy of tubulin by MMAE was required to achieve the cytotoxic effect in each cell line. In addition, estimated model parameters suggested that ~60% improvement in the tubulin occupancy was required to attain half of the maximum bystander killing effect by the ADC. The presented model provides foundation for in vivo systems PK-PD model to characterize and predict the bystander effect of ADCs.