ABSTRACT
INTRODUCTION: Antibody-drug conjugates (ADCs) show significant clinical efficacy in the treatment of solid tumors, but a major limitation to their success is poor intratumoral distribution. Adding a carrier dose improves both distribution and overall drug efficacy of ADCs, but the optimal carrier dose has not been outlined for different payload classes. OBJECTIVE: In this work, we study two carrier dose regimens: 1) matching payload potency to cellular delivery but potentially not reaching cells farther away from blood vessels, or 2) dosing to tumor saturation but risking a reduction in cell killing from a lower amount of payload delivered per cell. METHODS: We use a validated computational model to test four different payloads conjugated to trastuzumab to determine the optimal carrier dose as a function of target expression, ADC dose, and payload potency. RESULTS: We find that dosing to tumor saturation is more efficacious than matching payload potency to cellular delivery for all payloads because the increase in the number of cells targeted by the ADC outweighs the loss in cell killing on targeted cells. An important exception exists if the carrier dose reduces the payload uptake per cell to the point where all cell killing is lost. Likewise, receptor downregulation can mitigate the benefits of a carrier dose. CONCLUSIONS: Because tumor saturation and in vitro potency can be measured early in ADC design, these results provide insight into maximizing ADC efficacy and demonstrate the benefits of using simulation to guide ADC design.
