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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.