title: BAY 81-8973, a full-length recombinant factor VIII: Human heat shock protein 70 improves the manufacturing process without affecting clinical safety.
abstract: BAY 81-8973 is a full-length, unmodified recombinant human factor VIII (FVIII) approved for the treatment of hemophilia A. BAY 81-8973 has the same amino acid sequence as the currently marketed sucrose-formulated recombinant FVIII (rFVIII-FS) product and is produced using additional advanced manufacturing technologies. One of the key manufacturing advances for BAY 81-8973 is introduction of the gene for human heat shock protein 70 (HSP70) into the rFVIII-FS cell line. HSP70 facilitates proper folding of proteins, enhances cell survival by inhibiting apoptosis, and potentially impacts rFVIII glycosylation. HSP70 expression in the BAY 81-8973 cell line along with other manufacturing advances resulted in a higher-producing cell line and improvements in the pharmacokinetics of the final product as determined in clinical studies. HSP70 protein is not detected in the harvest or in the final BAY 81-8973 product. However, because this is a new process, clinical trial safety assessments included monitoring for anti-HSP70 antibodies. Most patients, across all age groups, had low levels of anti-HSP70 antibodies before exposure to the investigational product. During BAY 81-8973 treatment, 5% of patients had sporadic increases in anti-HSP70 antibody levels above a predefined threshold (cutoff value, 239 ng/mL). No clinical symptoms related to anti-HSP70 antibody development occurred. In conclusion, addition of HSP70 to the BAY 81-8973 cell line is an innovative technology for manufacturing rFVIII aimed at improving protein folding and expression. Improved pharmacokinetics and no effect on safety of BAY 81-8973 were observed in clinical trials in patients with hemophilia A.
authors.affiliation: Bayer Pharma AG, Aprather Weg, D-42096 Wuppertal, Germany. Electronic address: monika.maasenriquez@bayer.com.
authors.forename: Monika
authors.initials: M
authors.lastname: Maas Enriquez
authors.affiliation: Bayer, 800 Dwight Way, Berkeley, CA 94710, USA. Electronic address: john.thrift@bayer.com.
authors.forename: John
authors.initials: J
authors.lastname: Thrift
authors.affiliation: Bayer, 800 Dwight Way, Berkeley, CA 94710, USA. Electronic address: stephen.garger@bayer.com.
authors.forename: Stephen
authors.initials: S
authors.lastname: Garger
authors.affiliation: Bayer Pharma AG, Building S109, 205, 13342 Berlin, Germany. Electronic address: yvonne.katterle@bayer.com.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Katterle
mesh_terms: D002986:Clinical Trials as Topic; D005169:Factor VIII / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use
chemical_list: D018840:HSP70 Heat-Shock Proteins; D011994:Recombinant Proteins; C078147:F8 protein, human; D005169:Factor VIII
keywords: BAY 81-8973; Cell line; HSP70; Hemophilia A; Manufacturing