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Volume 10, Number 5, 2020, Pages 1848-1868                                                                DOI:10.11948/20190232
Receptor-mediated endocytosis modeling of antibody-drug conjugates to the released payload within the intracellular space considering target antigen expression levels
Jong Hyuk Byun,Anna Park,Il Hyo Jung
Keywords:Antibody-drug conjugates (ADCs), ADC mathematical model, bystander-killing effect, target antigen expression level, drug delivery, receptor-mediated endocytosis.
Abstract:
      An antibody-drug conjugate (ADC) is one of the effective treatment modalities designed as a targeted therapy for treating tumors. Certain ADCs such as brentuximab vedotin are known to kill negative tumor cells indirectly via membrane permeability and bystander-killing effect and to kill positive tumor cells directly. In this study, we propose a mathematical model to describe the ADC-receptor endocytosis mechanism and to predict payloads over a time profile more accurately, while considering target antigen-positive (Ag+)/negative (Ag--) cells. We discuss how the target-antigen expression levels derived using a ratio of Ag+ to Ag-- cells determine the payload release in the intracellular space. The model is aimed at capturing the amount of the payloads based on the target expression levels with the total number of cells fixed. The results indicate that (i) the profile of the total payloads over a time within the intracellular space is less influenced by the target expression levels after a time period, but the slope at the growth phase in which the payload increases is determined by the target expression levels, (ii) the change in the area under the curve of the total intracellularly released payload with a change in the ratio of Ag+ to Ag-- cells is more significant due to the initial ADC injection, (iii) the fluctuations in the released payloads within the Ag+ cells increase as the target expression levels decrease, unlike in the case of Ag-- cells or extracellular space. In addition, the time $t_{max}$ that corresponds to the maximum payload concentration $C_{max}$ is shifted towards the right as the target-antigen levels decrease, and it is strengthened by an increase in the initial free ADCs. The proposed model may reduce the discrepancy between the experiment and the model in the prediction of payloads over time profile.
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