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Next\u2010generation biomanufacturing using alternative hosts like <jats:italic>Komagataella phaffii<\/jats:italic> 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 <jats:italic>K. phaffii<\/jats:italic>, however, may manifest unique molecular quality attributes, like host\u2010dependent, product\u2010related 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\u2010related variations when secreted by <jats:italic>K. phaffii<\/jats:italic>. A combination of 2\u20133 changes of amino acids reduced variations across six different aglycosylated versions of commercial mAbs. Expression of a modified sequence of NIST mAb in both <jats:italic>K. phaffii<\/jats:italic> and CHO cells showed comparable biophysical properties and molecular variations. These results suggest a path toward the production of high\u2010quality 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\u2010characterized biopharmaceuticals could accelerate global accessibility and innovations.<\/jats:p>","DOI":"10.1002\/bit.28878","type":"journal-article","created":{"date-parts":[[2024,11,15]],"date-time":"2024-11-15T01:05:06Z","timestamp":1731632706000},"page":"361-372","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Adaptation of Aglycosylated Monoclonal Antibodies for Improved Production in <i>Komagataella phaffii<\/i>"],"prefix":"10.1002","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6843-9034","authenticated-orcid":false,"given":"Yuchen","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering Massachusetts Institute of Technology Cambridge Massachusetts USA"},{"name":"The Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7912-0309","authenticated-orcid":false,"given":"Neil C.","family":"Dalvie","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering Massachusetts Institute of Technology Cambridge Massachusetts USA"},{"name":"The Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph R.","family":"Brady","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering Massachusetts Institute of Technology Cambridge Massachusetts USA"},{"name":"The Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher A.","family":"Naranjo","sequence":"additional","affiliation":[{"name":"The Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Lorgeree","sequence":"additional","affiliation":[{"name":"The Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6271-7918","authenticated-orcid":false,"given":"Sergio A.","family":"Rodriguez\u2010Aponte","sequence":"additional","affiliation":[{"name":"The Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology Cambridge Massachusetts USA"},{"name":"Department of Biological Engineering Massachusetts Institute of Technology Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan S.","family":"Johnston","sequence":"additional","affiliation":[{"name":"The Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary K.","family":"Tracey","sequence":"additional","affiliation":[{"name":"The Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen M.","family":"Elenberger","sequence":"additional","affiliation":[{"name":"The Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Lee","sequence":"additional","affiliation":[{"name":"Biogen Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Ti\u00e9","sequence":"additional","affiliation":[{"name":"Biogen Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerry R.","family":"Love","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering Massachusetts Institute of Technology Cambridge Massachusetts USA"},{"name":"The Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0921-3144","authenticated-orcid":false,"given":"J. 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