title: PASylation: a biological alternative to PEGylation for extending the plasma half-life of pharmaceutically active proteins.
abstract: A major limitation of biopharmaceutical proteins is their fast clearance from circulation via kidney filtration, which strongly hampers efficacy both in animal studies and in human therapy. We have developed conformationally disordered polypeptide chains with expanded hydrodynamic volume comprising the small residues Pro, Ala and Ser (PAS). PAS sequences are hydrophilic, uncharged biological polymers with biophysical properties very similar to poly-ethylene glycol (PEG), whose chemical conjugation to drugs is an established method for plasma half-life extension. In contrast, PAS polypeptides offer fusion to a therapeutic protein on the genetic level, permitting Escherichia coli production of fully active proteins and obviating in vitro coupling or modification steps. Furthermore, they are biodegradable, thus avoiding organ accumulation, while showing stability in serum and lacking toxicity or immunogenicity in mice. We demonstrate that PASylation bestows typical biologics, such as interferon, growth hormone or Fab fragments, with considerably prolonged circulation and boosts bioactivity in vivo.
authors.affiliation: Munich Center for Integrated Protein Science CIPS-M & Lehrstuhl für Biologische Chemie, Technische Universität München, Emil-Erlenmeyer-Forum 5, 85350 Freising-Weihenstephan, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schlapschy
authors.forename: Uli
authors.initials: U
authors.lastname: Binder
authors.forename: Claudia
authors.initials: C
authors.lastname: Börger
authors.forename: Ina
authors.initials: I
authors.lastname: Theobald
authors.forename: Klaus
authors.initials: K
authors.lastname: Wachinger
authors.forename: Sigrid
authors.initials: S
authors.lastname: Kisling
authors.forename: Dirk
authors.initials: D
authors.lastname: Haller
authors.forename: Arne
authors.initials: A
authors.lastname: Skerra
mesh_terms: D000409:Alanine / Q000737:chemistry / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D004926:Escherichia coli / Q000235:genetics; D013006:Growth Hormone / Q000737:chemistry* / Q000235:genetics / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000235:genetics; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000235:genetics; D011092:Polyethylene Glycols / Q000737:chemistry*; D011392:Proline / Q000737:chemistry / Q000235:genetics; D017433:Protein Structure, Secondary; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000235:genetics / Q000493:pharmacokinetics*; D012694:Serine / Q000737:chemistry / Q000235:genetics
chemical_list: D007140:Immunoglobulin Fab Fragments; D010455:Peptides; D011993:Recombinant Fusion Proteins; D011092:Polyethylene Glycols; D012694:Serine; D013006:Growth Hormone; D011392:Proline; D000409:Alanine
keywords: biologic; dosing; kidney filtration; pharmacokinetics; therapeutic protein