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An Agent-Based Systems Pharmacology Model of the Antibody-Drug Conjugate Kadcyla to Predict Efficacy of Different Dosing Regimens

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Abstract

The pharmaceutical industry has invested significantly in antibody-drug conjugates (ADCs) with five FDA-approved therapies and several more showing promise in late-stage clinical trials. The FDA-approved therapeutic Kadcyla (ado-trastuzumab emtansine or T-DM1) can extend the survival of patients with tumors overexpressing HER2. However, tumor histology shows that most T-DM1 localizes perivascularly, but coadministration with its unconjugated form (trastuzumab) improves penetration of the ADC into the tumor and subsequent treatment efficacy. ADC dosing schedule, e.g., dose fractionation, has also been shown to improve tolerability. However, it is still not clear how coadministration with carrier doses impacts efficacy in terms of receptor expression, dosing regimens, and payload potency. Here, we develop a hybrid agent-based model (ABM) to capture ADC and/or antibody delivery and to predict tumor killing and growth kinetics. The results indicate that a carrier dose improves efficacy when the increased number of cells targeted by the ADC outweighs the reduced fractional killing of the targeted cells. The threshold number of payloads per cell required for killing plays a pivotal role in defining this cutoff. Likewise, fractionated dosing lowers ADC efficacy due to lower tissue penetration from a reduced maximum plasma concentration. It is only beneficial when an increase in tolerability from fractionation allows a higher ADC/payload dose that more than compensates for the loss in efficacy from fractionation. Overall, the multiscale model enables detailed depictions of heterogeneous ADC delivery, cancer cell death, and tumor growth to show how carrier dosing impacts efficacy to design the most efficacious regimen.

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Acknowledgments

The authors acknowledge funding from NIH R01 CA196018 (JJL) and R35 GM128819 (GMT). The authors also thank Paul Wolberg for technical assistance.

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Authors and Affiliations

  1. Department of Chemical Engineering, University of Michigan, NCRC B28, 2800 Plymouth Road, Ann Arbor, Michigan, 48109-2800, USA

    Bruna Menezes, Cornelius Cilliers, Timothy Wessler, Greg M. Thurber & Jennifer J. Linderman

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

    Greg M. Thurber & Jennifer J. Linderman

Authors
  1. Bruna Menezes
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  2. Cornelius Cilliers
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  3. Timothy Wessler
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  4. Greg M. Thurber
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  5. Jennifer J. Linderman
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Correspondence to Jennifer J. Linderman.

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Menezes, B., Cilliers, C., Wessler, T. et al. An Agent-Based Systems Pharmacology Model of the Antibody-Drug Conjugate Kadcyla to Predict Efficacy of Different Dosing Regimens. AAPS J 22, 29 (2020). https://doi.org/10.1208/s12248-019-0391-1

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  • DOI: https://doi.org/10.1208/s12248-019-0391-1

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