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

  • Research Article
  • Theme: Systems Pharmacokinetics Models for Antibody-Drug Conjugates
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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 nonspecific 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.

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Acknowledgments

The authors wish to thank John Rhoden, PhD, for helpful comments in the preparation of the manuscript. Funding for this work was provided by Eli Lilly and Company. Additional support was provided by the National Cancer Institute of the National Institutes of Health under award number P30CA046592.

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Authors and Affiliations

  1. Department of Chemical Engineering, University of Michigan, 2800 Plymouth Rd., Ann Arbor, Michigan, 48109, USA

    Cornelius Cilliers, Hans Guo, Jianshan Liao, Nikolas Christodolu & Greg M. Thurber

  2. Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, 48109, USA

    Greg M. Thurber

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  1. Cornelius Cilliers
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Cilliers, C., Guo, H., Liao, J. et al. Multiscale Modeling of Antibody-Drug Conjugates: Connecting Tissue and Cellular Distribution to Whole Animal Pharmacokinetics and Potential Implications for Efficacy. AAPS J 18, 1117–1130 (2016). https://doi.org/10.1208/s12248-016-9940-z

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