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In Vivo Testing of Drug-Linker Stability

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Antibody-Drug Conjugates

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1045))

Abstract

Antibody-drug conjugates (ADCs) are promising biotherapeutics designed to selectively deliver highly cytotoxic drugs to tumor cells while sparing normal tissues. They can be viewed as prodrugs, stable in the bloodstream in order to minimize drug release in circulation and efficiently converted into active drugs in the tumor tissues. Designing the right combination of monoclonal antibody (mAb), linker and drug, requires monitoring and understanding the behavior of all three components in the bloodstream and tumor. In particular, linkers have been shown to influence efficacy and safety profiles of ADCs, and monitoring in vivo “drug-linker stability” is therefore critical to help the linker choice and is performed by identifying the pharmacokinetics (PK) profiles. PK properties of ADCs are measured by following the profiles of three entities: (a) the conjugate (mAb entity carrying at least one drug), (b) the total antibody (mAb entity regardless of drug load), as well as (c) the free drugs and metabolites entities. This chapter focuses on the key analytical methods (ELISA immunoassays, TFC-MS/MS, and HRMS) used to support the PK profiles assessment of the three entities, allowing the characterization of ADC “drug-linker stability”.

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Acknowledgements

The authors would like to greatly thank Patrick Verdier, Marie-Hélène Pascual, and Olivier Pasquier for providing their lab protocols, for their constructive input, and careful review of this chapter. The authors are grateful to Ingrid Sassoon and Veronique Blanc for giving high-level background and critical reading of the manuscript. We also thank Delphine Valente, Christine Mauriac, Gerard Sanderink, and John Newton for giving relevant review and their support.

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Authors and Affiliations

  1. DSAR (Disposition, Safety & Animal Research), Sanofi, Vitry-sur-Seine, France

    Pierre-Yves Abecassis & Céline Amara

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  1. Pierre-Yves Abecassis
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  2. Céline Amara
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  1. Lonza Ltd, Visp, Switzerland

    Laurent Ducry

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Abecassis, PY., Amara, C. (2013). In Vivo Testing of Drug-Linker Stability. In: Ducry, L. (eds) Antibody-Drug Conjugates. Methods in Molecular Biology, vol 1045. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-541-5_6

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  • DOI: https://doi.org/10.1007/978-1-62703-541-5_6

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  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-62703-540-8

  • Online ISBN: 978-1-62703-541-5

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