Alpha-1 antitrypsin (A1AT) is well-established as a biotherapeutic used for the treatment of alpha-1antitrypsin deficiency, and shows promise for treating a variety of other diseases. However, A1AT augmentationtherapy carries unnecessary risk since it relies upon the weekly transfusion of plasma-derived product, whichpresents supply chain and contaminant risks. This could be remedied with recombinant A1AT, if it adequatelymatches or improves upon the plasma-derived product, including its post-translational modifications andfunctional attributes. However, major hurdles to the development of recombinant A1AT exist, since post-translational modifications, such as glycosylation, impact drug activities and half-life, and it has remainedchallenging to match glycosylation of recombinant A1AT to the plasma derived isoforms. Here we developed alarge panel of diverse GMP-ready glycoengineered CHO (geCHO) cell lines that allowed us to discover a hostcell line, geCHO-L, that matches glycosylation of the plasma derived product. Here we will demonstrate ourplatform not only allows us to identify a CHO clone matches the glycosylation of the approved product, but thatwe can also match the function and half-life of the approved A1AT to enable the manufacturing of a recombinantA1AT to increase the safety and protect the supply of therapeutic A1AT. We further engineer the recombinantA1AT to obtain a product with improved activity and half-life as a candidate therapeutic for alpha-1 antitrypsindeficiency and other diseases.
Public Health Relevance Statement: PROJECT NARRATIVE
Alpha-1 antitrypsin (A1AT) deficiencies require replacement therapies derived from blood plasma, but
recombinant expression systems have limited the ability to produce safer recombinant A1AT matching the
approved drug. Using engineered CHO cells and further protein engineering, we develop effective production of
recombinant A1AT matching and exceeding plasma-derived product in quality, efficacy, safety and half-life,
yielding a safe and reliable drug source.
Project Terms: <α1-Antitrypsin><α1-Proteinase Inhibitor>| <α-1 anti-trypsin deficiency><α-1-antitrypsin deficiency><α1-Antitrypsin Deficiency>
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