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Detection of host cell microprotein impurities in antibody drug products

Author

Listed:
  • Ioanna Tzani
  • Marina Castro-Rivadeneyra
  • Paul Kelly
  • Lisa Strasser
  • Lin Zhang

    (Pfizer Inc. Andover)

  • Martin Clynes

    (Dublin City University)

  • Barry L. Karger

    (360 Huntington Ave)

  • Niall Barron
  • Jonathan Bones
  • Colin Clarke

Abstract

Chinese hamster ovary (CHO) cells are used to produce almost 90% of therapeutic monoclonal antibodies (mAbs) and antibody fusion proteins (Fc-fusion). The annotation of non-canonical translation events in these cellular factories remains incomplete, limiting our ability to study CHO cell biology and detect host cell protein (HCP) impurities in the final antibody drug product. We utilised ribosome footprint profiling (Ribo-seq) to identify novel open reading frames (ORFs) including N-terminal extensions and thousands of short ORFs (sORFs) predicted to encode microproteins. Mass spectrometry-based HCP analysis of eight commercial antibody drug products (7 mAbs and 1 Fc-fusion protein) using the extended protein sequence database revealed the presence of microprotein impurities. We present evidence that microprotein abundance varies with growth phase and can be affected by the cell culture environment. In addition, our work provides a vital resource to facilitate future studies of non-canonical translation and the regulation of protein synthesis in CHO cell lines.

Suggested Citation

  • Ioanna Tzani & Marina Castro-Rivadeneyra & Paul Kelly & Lisa Strasser & Lin Zhang & Martin Clynes & Barry L. Karger & Niall Barron & Jonathan Bones & Colin Clarke, 2024. "Detection of host cell microprotein impurities in antibody drug products," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51870-0
    DOI: 10.1038/s41467-024-51870-0
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