title: A recombinant polypeptide extends the in vivo half-life of peptides and proteins in a tunable manner.
abstract: Increasing the in vivo residence times of protein therapeutics could decrease their dosing frequencies. We show that genetic fusion of an unstructured recombinant polypeptide of 864 amino acids, called XTEN, to a peptide or protein provides an apparently generic approach to extend plasma half-life. Allometric scaling suggests that a fusion of XTEN to the exenatide peptide should increase exenatide half-life in humans from 2.4 h to a projected time of 139 h. We confirmed the biological activity of the exenatide-XTEN fusion in mice. As extended stability might exacerbate undesirable side effects in some cases, we show that truncating the XTEN sequence can regulate plasma half-life. XTEN lacks hydrophobic amino acid residues that often contribute to immunogenicity and complicate manufacture. Based on data on XTEN fusions to exenatide, glucagon, GFP and human growth hormone, we expect that XTEN will enable dosing of otherwise rapidly cleared protein drugs at up to monthly intervals in humans.
authors.affiliation: Amunix, Inc., Mountain View, California, USA.
authors.forename: Volker
authors.initials: V
authors.lastname: Schellenberger
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Wang
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Geething
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Spink
authors.forename: Andrew
authors.initials: A
authors.lastname: Campbell
authors.forename: Wayne
authors.initials: W
authors.lastname: To
authors.forename: Michael D
authors.initials: MD
authors.lastname: Scholle
authors.forename: Yong
authors.initials: Y
authors.lastname: Yin
authors.forename: Yi
authors.initials: Y
authors.lastname: Yao
authors.forename: Oren
authors.initials: O
authors.lastname: Bogin
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Cleland
authors.forename: Joshua
authors.initials: J
authors.lastname: Silverman
authors.forename: Willem P C
authors.initials: WP
authors.lastname: Stemmer
mesh_terms: D000818:Animals; D051379:Mice; D010455:Peptides / Q000737:chemistry*; D015202:Protein Engineering / Q000379:methods*; D011506:Proteins / Q000737:chemistry* / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000378:metabolism*
chemical_list: D010455:Peptides; D011506:Proteins; D011993:Recombinant Fusion Proteins