A recombinant polypeptide extends the in vivo half-life of peptides and proteins in a tunable manner.
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.
Schellenberger
Volker
V
Amunix, Inc., Mountain View, California, USA.
Wang
Chia-Wei
CW
Geething
Nathan C
NC
Spink
Benjamin J
BJ
Campbell
Andrew
A
To
Wayne
W
Scholle
Michael D
MD
Yin
Yong
Y
Yao
Yi
Y
Bogin
Oren
O
Cleland
Jeffrey L
JL
Silverman
Joshua
J
Stemmer
Willem P C
WP
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*
D010455:Peptides; D011506:Proteins; D011993:Recombinant Fusion Proteins