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      Multivalent Antiviral XTEN–Peptide Conjugates with Long in Vivo Half-Life and Enhanced Solubility

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          Abstract

          XTENs are unstructured, nonrepetitive protein polymers designed to prolong the in vivo half-life of pharmaceuticals by introducing a bulking effect similar to that of poly(ethylene glycol). While XTEN can be expressed as a recombinant fusion protein with bioactive proteins and peptides, therapeutic molecules of interest can also be chemically conjugated to XTEN. Such an approach permits precise control over the positioning, spacing, and valency of bioactive moieties along the length of XTEN. We have demonstrated the attachment of T-20, an anti-retroviral peptide indicated for the treatment of HIV-1 patients with multidrug resistance, to XTEN. By reacting maleimide-functionalized T-20 with cysteine-containing XTENs and varying the number and positioning of cysteines in the XTENs, a library of different peptide–polymer combinations were produced. The T-20-XTEN conjugates were tested using an in vitro antiviral assay and were found to be effective in inhibiting HIV-1 entry and preventing cell death, with the copy number and spacing of the T-20 peptides influencing antiviral activity. The peptide–XTEN conjugates were also discovered to have enhanced solubilities in comparison with the native T-20 peptide. The pharmacokinetic profile of the most active T-20-XTEN conjugate was measured in rats, and it was found to exhibit an elimination half-life of 55.7 ± 17.7 h, almost 20 times longer than the reported half-life for T-20 dosed in rats. As the conjugation of T-20 to XTEN greatly improved the in vivo half-life and solubility of the peptide, the XTEN platform has been demonstrated to be a versatile tool for improving the properties of drugs and enabling the development of a class of next-generation therapeutics.

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          HIV entry and its inhibition.

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            Strategies for extended serum half-life of protein therapeutics.

            With a growing number of protein therapeutics being developed, many of them exhibiting a short plasma half-life, half-life extension strategies find increasing attention by the biotech and pharmaceutical industry. Extension of the half-life can help to reduce the number of applications and to lower doses, thus are beneficial for therapeutic but also economic reasons. Here, a comprehensive overview of currently developed half-life extension strategies is provided including those aiming at increasing the hydrodynamic volume of a protein drug but also those implementing recycling processes mediated by the neonatal Fc receptor. Copyright © 2011 Elsevier Ltd. All rights reserved.
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              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.
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                Author and article information

                Journal
                Bioconjug Chem
                Bioconjug. Chem
                bc
                bcches
                Bioconjugate Chemistry
                American Chemical Society
                1043-1802
                1520-4812
                16 June 2015
                16 June 2014
                16 July 2014
                : 25
                : 7
                : 1351-1359
                Affiliations
                []Amunix Operating Inc. , 500 Ellis Street, Mountain View, California 94043 United States
                []PolyPeptide Laboratories Inc. , 365 Maple Avenue, Torrance, California 90503 United States
                Author notes
                Article
                10.1021/bc500215m
                4157762
                24932887
                235df9f7-d820-42ad-8dae-a472a6744987
                Copyright © 2014 American Chemical Society

                Terms of Use

                History
                : 15 May 2014
                : 13 June 2014
                Funding
                National Institutes of Health, United States
                Categories
                Article
                Custom metadata
                bc500215m
                bc-2014-00215m

                Biochemistry
                Biochemistry

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