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Evolution of Antibody-Drug Conjugate Tumor Disposition Model to Predict Preclinical Tumor Pharmacokinetics of Trastuzumab-Emtansine (T-DM1)

  • Research Article
  • Theme: Systems Pharmacokinetics Models for Antibody-Drug Conjugates
  • Published:
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ABSTRACT

A mathematical model capable of accurately characterizing intracellular disposition of ADCs is essential for a priori predicting unconjugated drug concentrations inside the tumor. Towards this goal, the objectives of this manuscript were to: (1) evolve previously published cellular disposition model of ADC with more intracellular details to characterize the disposition of T-DM1 in different HER2 expressing cell lines, (2) integrate the improved cellular model with the ADC tumor disposition model to a priori predict DM1 concentrations in a preclinical tumor model, and (3) identify prominent pathways and sensitive parameters associated with intracellular activation of ADCs. The cellular disposition model was augmented by incorporating intracellular ADC degradation and passive diffusion of unconjugated drug across tumor cells. Different biomeasures and chemomeasures for T-DM1, quantified in the companion manuscript, were incorporated into the modified model of ADC to characterize in vitro pharmacokinetics of T-DM1 in three HER2+ cell lines. When the cellular model was integrated with the tumor disposition model, the model was able to a priori predict tumor DM1 concentrations in xenograft mice. Pathway analysis suggested different contribution of antigen-mediated and passive diffusion pathways for intracellular unconjugated drug exposure between in vitro and in vivo systems. Global and local sensitivity analyses revealed that non-specific deconjugation and passive diffusion of the drug across tumor cell membrane are key parameters for drug exposure inside a cell. Finally, a systems pharmacokinetic model for intracellular processing of ADCs has been proposed to highlight our current understanding about the determinants of ADC activation inside a cell.

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Acknowledgments

This work was supported by NIH grant GM114179 to DKS, and the Center for Protein Therapeutics at the State University of New York at Buffalo. K.F.M. was supported by a Hertz Foundation Fellowship and a National Science Foundation Graduate Research Fellowship. C.K. was supported by the Pfizer Worldwide Research & Development Post-Doctoral Program.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, 455 Kapoor Hall, Buffalo, New York, 14214-8033, USA

    Aman P. Singh, Antari Khot & Dhaval K. Shah

  2. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Katie F. Maass & K. Dane Wittrup

  3. David H. Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Katie F. Maass & K. Dane Wittrup

  4. Translational Research Group, Department of Pharmacokinetics Dynamics and Metabolism, Pfizer, Groton, Connecticut, USA

    Alison M. Betts & Lindsay E. King

  5. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    K. Dane Wittrup

  6. Oncology Medicinal Chemistry, Worldwide Medicinal Chemistry, Pfizer, Groton, Connecticut, USA

    Chethana Kulkarni

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  1. Aman P. Singh
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  2. Katie F. Maass
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  6. Lindsay E. King
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Corresponding author

Correspondence to Dhaval K. Shah.

Additional information

Guest editor: Dhaval K. Shah

Electronic supplementary material

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Supplementary Fig 1

Local sensitivity of the improved cellular disposition model with respect to unconjugated unbound (free) drug inside the cell as an output. (GIF 111 kb)

High resolution image

(TIF 35.7 kb)

Supplementary Fig 2

Local sensitivity of the improved cellular disposition model with respect to unconjugated unbound (free) drug in media as an output. (GIF 93.9 kb)

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(TIF 33.8 kb)

Supplementary Fig 3

Local sensitivity of the improved cellular disposition model with respect to total maytansinoid in media as an output. (GIF 88.9 kb)

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(TIF 24.2 kb)

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Singh, A.P., Maass, K.F., Betts, A.M. et al. Evolution of Antibody-Drug Conjugate Tumor Disposition Model to Predict Preclinical Tumor Pharmacokinetics of Trastuzumab-Emtansine (T-DM1). AAPS J 18, 861–875 (2016). https://doi.org/10.1208/s12248-016-9904-3

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  • DOI: https://doi.org/10.1208/s12248-016-9904-3

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