| Autor: |
Rocamora F; Department of Pediatrics, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States., Schoffelen S; National Biologics Facility, Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark., Arnsdorf J; National Biologics Facility, Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark., Toth EA; Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850, United States., Abdul Y; Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850, United States., Cleveland TE 4th; National Institute of Standards and Technology, Rockville, MD, 20850, USA., Bjørn SP; National Biologics Facility, Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark., Wu MYM; Department of Pediatrics, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States., McElvaney NG; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, United States.; Department of Medicine, Irish Center for Genetic Lung Disease, Royal College of Surgeons in Ireland, Dublin, Ireland., Voldborg BGR; National Biologics Facility, Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark., Fuerst TR; Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850, United States.; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, United States.; NeuImmune, Inc., Sykesville, MD, United States., Lewis NE; Department of Pediatrics, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States.; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, United States.; NeuImmune, Inc., Sykesville, MD, United States. |
| Abstrakt: |
Alpha-1-antitrypsin (A1AT) is a multifunctional, clinically important, high value therapeutic glycoprotein that can be used for the treatment of many diseases such as alpha-1-antitrypsin deficiency, diabetes, graft-versus-host-disease, cystic fibrosis and various viral infections. Currently, the only FDA-approved treatment for A1AT disorders is intravenous augmentation therapy with human plasma-derived A1AT. In addition to its limited supply, this approach poses a risk of infection transmission, since it uses therapeutic A1AT harvested from donors. To address these issues, we sought to generate recombinant human A1AT (rhA1AT) that is chemically and biologically indistinguishable from its plasma-derived counterpart using glycoengineered Chinese Hamster Ovary (geCHO-L) cells. By deleting nine key genes that are part of the CHO glycosylation machinery and expressing the human ST6GAL1 and A1AT genes, we obtained stable, high producing geCHO-L lines that produced rhA1AT having an identical glycoprofile to plasma-derived A1AT (pdA1AT). Additionally, the rhA1AT demonstrated in vitro activity and in vivo half-life comparable to commercial pdA1AT. Thus, we anticipate that this platform will help produce human-like recombinant plasma proteins, thereby providing a more sustainable and reliable source of therapeutics that are cost-effective and better-controlled with regard to purity, clinical safety and quality. |
