Adaptation of Aglycosylated Monoclonal Antibodies for Improved
Production in Komagataella phaffii
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.