Multiscale Modeling of Antibody-Drug Conjugates: Connecting Tissue and Cellular Distribution to Whole Animal Pharmacokinetics and Potential Implications for Efficacy

Abstract

Antibody drug conjugates exhibit complex pharmacokinetics due to their combination of macromolecular and small molecule properties. These issues range from systemic concerns, such as deconjugation of the small molecule drug during the long antibody circulation time or rapid clearance from non-specific interactions, to local tumor tissue heterogeneity, cell bystander effects, and endosomal escape. Mathematical models can be used to study the impact of these processes on overall distribution in an efficient manner, and several types of models have been used to analyze varying aspects of antibody distribution including physiologically based pharmacokinetic (PBPK) models and tissue-level simulations. However, these processes are quantitative in nature and cannot be handled qualitatively in isolation. For example, free antibody from deconjugation of the small molecule will impact the distribution of conjugated antibodies within the tumor. To incorporate these effects into a unified framework, we have coupled the systemic and organ-level distribution of a PBPK model with the tissue-level detail of a distributed parameter tumor model. We used this mathematical model to analyze new experimental results on the distribution of the clinical antibody drug conjugate Kadcyla in HER2 positive mouse xenografts. This model is able to capture the impact of the drug antibody ratio (DAR) on tumor penetration, the net result of drug deconjugation, and the effect of using unconjugated antibody to drive ADC penetration deeper into the tumor tissue. This modeling approach will provide quantitative and mechanistic support to experimental studies trying to parse the impact of multiple mechanisms of action for these complex drugs.

Antibody–Drug Conjugates: Pharmacokinetic/Pharmacodynamic Modeling, Preclinical Characterization, Clinical Studies, and Lessons Learned

“…Using this model, the authors were able to examine the impact of the drug-antibody ratio on tumor penetration, the net result of drug deconjugation, and the impact of using an unconjugated antibody to assist the ADC in further penetrating the tumor tissue. Overall, this model, which is based on in vivo mouse tumor xenograft studies, offers quantitative mechanistic support to experimental studies working to elucidate the complex mechanisms of action of these drug conjugate therapies [67]. …”

Development of a Translational Physiologically Based Pharmacokinetic Model for Antibody-Drug Conjugates: a Case Study with T-DM1

“…In addition, being a minimal PBPK model, the model was not able to characterize or predict the concentration of ADC and its components at the site-of-action in tumor and other tissues. Very recently, in this special issue on system PK of ADCs, Cilliers et al (25) have presented a multi-scale PBPK model to track the systemic distribution of the ADC and antibody. The model couples systemic and organ-level PBPK model of the antibody with a tissue-level distributed parameter model for the tumor to characterize biodistribution of fluorescently labeled T-DM1.…”

Quantitative modeling of the dynamics and intracellular trafficking of far-red light-activatable prodrugs: implications in stimuli-responsive drug delivery system

“…Several researchers have investigated the production, diffusion, and distribution of SO in tumor tissue using the Krogh cylinder model [60,61]. The Krogh cylinder model could be further applied to link the plasma PK of the prodrug and the current in vitro PK/PD model [62]. …”