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Antibody Coadministration as a Strategy to Overcome Binding-Site Barrier for ADCs: a Quantitative Investigation

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

It has been proposed that the binding-site barrier (BSB) for antibody-drug conjugates (ADCs) can be overcome with the help of antibody coadministration. However, broad utility of this strategy remains in question. Consequently, here, we have conducted in vivo experiments and pharmacokinetics-pharmacodynamics (PK-PD) modeling and simulation (M&S) to further evaluate the antibody coadministration hypothesis in a quantitative manner. Two different Trastuzumab-based ADCs, T-DM1 (no bystander effect) and T-vc-MMAE (with a bystander effect), were evaluated in high-HER2 (N87) and low-HER2 (MDA-MB-453) expressing tumors, with or without the coadministration of 1, 3, or 8-fold higher Trastuzumab. The tumor growth inhibition (TGI) data was quantitatively characterized using a semi-mechanistic PK-PD model to determine the nature of drug interaction for each coadministration regimen, by estimating the interaction parameter ψ. It was found that the coadministration strategy improved ADC efficacy under certain conditions and had no impact on ADC efficacy in others. The benefit was more pronounced for N87 tumors with very high antigen expression levels where the effect on treatment was synergistic (a synergistic drug interaction, ψ = 2.86 [2.6–3.12]). The benefit was diminished in tumor with lower antigen expression (MDA-MB-453) and payload with bystander effect. Under these conditions, the coadministration regimens resulted in an additive or even less than additive benefit (ψ ≤ 1). As such, our results suggest that while antibody coadministration may be helpful for ADCs in certain circumstances, one should not broadly apply this strategy to all the scenarios without first identifying the costs and benefits of this approach.

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Acknowledgments

Authors would also like to thank Zhe Li and Farah Al Qaraqhuli for their technical help during TGI studies, and Cornelius Cilliers for helpful comments on the manuscript.

Funding

This work was financially supported by the Centre for Protein Therapeutics at University at Buffalo. D.K.S is supported by NIH grant GM114179 and AI138195.

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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 Pharmacy Building, Buffalo, New York, 14214-8033, USA

    Aman P. Singh, Leiming Guo, Ashwni Verma & Dhaval K. Shah

  2. Department of Biological Sciences, The State University of New York at Buffalo, Buffalo, New York, 14214-8033, USA

    Gloria Gao-Li Wong

  3. Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, USA

    Greg M. Thurber

  4. Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA

    Greg M. Thurber

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  1. Aman P. Singh
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Correspondence to Dhaval K. Shah.

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Singh, A.P., Guo, L., Verma, A. et al. Antibody Coadministration as a Strategy to Overcome Binding-Site Barrier for ADCs: a Quantitative Investigation. AAPS J 22, 28 (2020). https://doi.org/10.1208/s12248-019-0387-x

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