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Reducing hydrophobicity of homogeneous antibody-drug conjugates improves pharmacokinetics and therapeutic index

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Abstract

The in vitro potency of antibody-drug conjugates (ADCs) increases with the drug-to-antibody ratio (DAR); however, ADC plasma clearance also increases with DAR, reducing exposure and in vivo efficacy. Here we show that accelerated clearance arises from ADC hydrophobicity, which can be modulated through drug-linker design. We exemplify this using hydrophilic auristatin drug linkers and PEGylated ADCs that yield uniform, high-DAR ADCs with superior in vivo performance.

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Figure 1: Structures of drug linkers and characterization of ADCs.
Figure 2: Structures of glucuronide-MMAE drug linkers and characterization of ADCs.

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Acknowledgements

We thank our Seattle Genetics colleagues S. Alley for assistance in pharmacokinetic modeling; J. Miyamoto for in vitro cytotoxicity assays; A. Cronkite for competition binding studies; and C. Zapata, C. Balasubramanian and W. Schultz for rat toxicology studies.

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Authors and Affiliations

  1. Department of Chemistry, Seattle Genetics, Bothell, Washington, USA

    Robert P Lyon, Tim D Bovee, Svetlana O Doronina, Patrick J Burke, Joshua H Hunter, Jocelyn R Setter & Peter D Senter

  2. Department of Pharmacology and Toxicology, Seattle Genetics, Bothell,, Washington, USA

    Haley D Neff-LaFord

  3. Department of Translational Research, Seattle Genetics, Bothell, Washington, USA

    Mechthild Jonas

  4. Department of Preclinical Research, Seattle Genetics, Bothell, Washington, USA

    Martha E Anderson

Authors
  1. Robert P Lyon
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  2. Tim D Bovee
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  3. Svetlana O Doronina
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  4. Patrick J Burke
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  5. Joshua H Hunter
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  6. Haley D Neff-LaFord
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  7. Mechthild Jonas
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  8. Martha E Anderson
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  9. Jocelyn R Setter
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  10. Peter D Senter
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Contributions

R.P.L. designed drug linkers, prepared and characterized ADCs by HIC, designed in vivo studies, performed the pharmacokinetic data fitting and wrote the manuscript; T.D.B. synthesized drug linkers; S.O.D. designed and synthesized drug linkers, P.J.B. designed and synthesized PEGylated drug linkers; J.H.H. performed radiolabeling and quantification for pharmacokinetic studies; H.D.N.-L. designed and interpreted the rat toxicology studies; M.J. performed IHC analysis of ADC uptake by rat liver; M.E.A. performed in vivo work (activity, pharmacokinetics and biodistribution); J.R.S. performed mass spectrometry assays to characterize ADC drug loading and stability, and to quantify MMAE delivery in vivo; P.D.S. directed the synthetic chemistry and co-wrote the manuscript.

Corresponding author

Correspondence to Robert P Lyon.

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“All authors are employees of Seattle Genetics, Inc.”

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Supplementary Figures 1–9 and Supplementary Note (PDF 1171 kb)

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Lyon, R., Bovee, T., Doronina, S. et al. Reducing hydrophobicity of homogeneous antibody-drug conjugates improves pharmacokinetics and therapeutic index. Nat Biotechnol 33, 733–735 (2015). https://doi.org/10.1038/nbt.3212

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  • DOI: https://doi.org/10.1038/nbt.3212

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