HALF-LIFE EXTENSION

Fig 1 Halflife

XTEN proteins lack secondary and tertiary structure and their solution behavior resembles chemically prepared polymers with very large hydrodynamic radii. By size exclusion chromatography, XTEN protein polymers appear much larger than typical globular proteins of similar molecular weight. The bulking effect of XTEN greatly reduces renal clearance of attached molecules, thus greatly increasing their in vivo half-lives. The length of XTEN polymers can be customized to optimize the pharmacokinetics as well as the bio-distribution of attached payloads.

Fig 2 Halflife

XTEN can be recombinantly fused to therapeutic proteins to increase their in vivo half-life. An obvious benefit of genetic fusion constructs is the convenience of expression, purification and characterization of a single molecule which includes both the therapeutic and bulking moieties. Recombinant fusion allows attaching multiple XTEN chains per protein in precisely-defined locations resulting in best-in-class pharmacokinetics as exemplified by XTENylated growth hormone (Somavaratan, Versartis) and FVIII-XTEN (with Biogen).

Fig 3 Halflife

XTEN protein polymers can be produced as free intermediates for chemical conjugation to peptides, peptidomimetics, and other synthetic molecules. Reactive groups (thiol, amine) are inserted in precisely-defined positions via introduction of cysteine or lysine residues into XTEN-encoding genes. Amunix has developed XTENs containing 1 to 9 thiol groups with various spacing which can be provided to partners. Orthogonal conjugation to amino and thiol groups in XTEN facilitates the production of bi-functional molecules.

Fig 4 Halflife

Pharmacokinetics in children receiving different doses of XTENylated growth hormone (Somavaratan, Versartis). With our partner Versartis we optimized the molecule to reduce receptor-mediated elimination in addition to kidney clearance resulting in best-in-class half-life.