Kinetics and efficacy of antibody drug conjugates in 3D tumour models

Abstract

ABSTRACTAntibody-drug conjugates (ADCs) are emerging targeted agents against cancer. Current studies of ADCs are performed on monolayer cultures which do not mimic the biophysical property of a tumour. Hence,in vitromodels that can better predict the efficacy of ADCsin vivoare needed. In this study, we aim to optimise 3-dimentional cancer spheroid systems, which preserve the features of the tumour structure, to test the efficacy of two ADCs (T-DM1 and T-vcMMAE). Firstly, a set of reproducible spheroid models using epithelial ovarian cancer cell lines were established. Subsequently, phenotypic changes in spheroids were characterised upon ADC treatment. The penetration dynamics of ADCs into 3D tumour structure were also studied. Our data revealed that spheroids are less sensitive to ADCs compared to monolayer cultures. Interestingly, the small molecule component of ADCs-the cytotoxic payload-showed a similar decrease in efficacy in spheroids compared to monolayer cultures. Furthermore, we also gained new insight into ADC penetration dynamics and showed that ADCs can fully penetrate a tumour-like spheroid within 24h. The results suggest that although ADCs, as large molecule biological drugs, are likely to have slower penetration dynamics than small molecule compounds such as their cytotoxic payload, they could have comparable capability to kill cancer cells in 3D structures. This may be explained by the fact that multiple cytotoxic payloads are conjugated with each single antibody, which compensates the penetration deficiency of the large molecules. In conclusion, our work confirms that the tumour 3D structure could limit the therapeutic efficacy of ADCs. Nevertheless, optimising ADC design such as adjusting drug-to-antibody ratios could help to overcome this hurdle.