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Adaptation of Aglycosylated Monoclonal Antibodies for Improved Production in Komagataella phaffii
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  • Yuchen Yang,
  • Neil C. Dalvie,
  • Joseph R. Brady,
  • Christopher Naranjo,
  • Timothy Lorgeree,
  • Sergio Rodriguez,
  • Ryan Johnston,
  • Mary Kate Tracey,
  • Carmen M. Elenberger,
  • Eric Lee,
  • Mark Tié,
  • Kerry R. Love,
  • John Love
Yuchen Yang
Massachusetts Institute of Technology Department of Chemical Engineering
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Neil C. Dalvie
Massachusetts Institute of Technology Department of Chemical Engineering
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Joseph R. Brady
Massachusetts Institute of Technology Department of Chemical Engineering
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Christopher Naranjo
Massachusetts Institute of Technology Koch Institute for Integrative Cancer Research
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Timothy Lorgeree
Massachusetts Institute of Technology Koch Institute for Integrative Cancer Research
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Sergio Rodriguez
Massachusetts Institute of Technology Koch Institute for Integrative Cancer Research
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Ryan Johnston
Massachusetts Institute of Technology Koch Institute for Integrative Cancer Research
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Mary Kate Tracey
Massachusetts Institute of Technology Koch Institute for Integrative Cancer Research
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Carmen M. Elenberger
Massachusetts Institute of Technology Koch Institute for Integrative Cancer Research
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Eric Lee
Biogen
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Mark Tié
Biogen
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Kerry R. Love
Massachusetts Institute of Technology Koch Institute for Integrative Cancer Research
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John Love
Massachusetts Institute of Technology Department of Chemical Engineering

Corresponding Author:[email protected]

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Abstract

Monoclonal antibodies (mAbs) are a major class of biopharmaceuticals manufactured by well-established processes using Chinese Hamster Ovary (CHO) cells. Next-generation biomanufacturing using alternative hosts like Komagataella phaffii could improve the accessibility of these medicines, address broad societal goals for sustainability, and offer financial advantages for accelerated development of new products. Antibodies produced by K. phaffii, however, may manifest unique molecular quality attributes, like host-dependent, product-related variants, that could raise potential concerns for clinical use. We demonstrate here conservative modifications to the amino acid sequence of aglycosylated antibodies based on the human IgG1 isotype that minimize product-related variations when secreted by K. phaffii. A combination of 2-3 changes of amino acids reduced variations across six different aglycosylated versions of commercial mAbs. Expression of a modified sequence of NIST mAb in both K. phaffii and CHO cells showed comparable biophysical properties and molecular variations. These results suggest a path towards production of high-quality mAbs that could be expressed interchangeably by either yeast or mammalian cells. Improving molecular designs of proteins to enable a range of manufacturing strategies for well-characterized biopharmaceuticals could accelerate global accessibility and innovations.
Submitted to Biotechnology and Bioengineering
Submission Checks Completed
Assigned to Editor
Reviewer(s) Assigned
04 Jul 2024Review(s) Completed, Editorial Evaluation Pending
07 Jul 2024Reviewer(s) Assigned
08 Sep 2024Editorial Decision: Revise Major
11 Oct 20241st Revision Received
23 Oct 2024Submission Checks Completed
23 Oct 2024Assigned to Editor
23 Oct 2024Review(s) Completed, Editorial Evaluation Pending
23 Oct 2024Reviewer(s) Assigned
26 Oct 2024Editorial Decision: Accept