and reduce disease severity in preclinical models of short bowel syndrome and inflammatory bowel disease. Teduglutide, a\r\nrecombinant human GLP2 variant (GLP2-2G), has increased half-life and stability as compared to the native GLP2 peptide,\r\nbut still requires twice daily dosing in preclinical models and daily dosing in the clinic. The goal of this study was to produce\r\nand characterize the preclinical pharmacokinetic and therapeutic properties of GLP2-2G-XTEN, a novel, long-acting form of\r\nGLP2-2G.\r\nMethodology and Results: A GLP2-2G-XTEN fusion protein with extended exposure profile was produced by genetic fusion\r\nof GLP2-2G peptide to XTEN, a long, unstructured, non-repetitive, hydrophilic sequence of amino acids. The serum half-life\r\nof GLP2-2G-XTEN in mice, rats and monkeys was 34, 38 and 120 hours, respectively. Intestinotrophic effects were\r\ndemonstrated in normal rats, where GLP2-2G-XTEN administration resulted in a significant increase in both small intestine\r\nweight and length. Efficacy of the GLP2-2G-XTEN protein was compared to that of GLP2-2G peptide in a rat Crohn�s disease\r\nmodel, indomethacin-induced inflammation. Prophylactic administration of GLP2-2G-XTEN significantly increased the\r\nlength, reduced the number of trans-ulcerations and adhesions, and reduced the TNFa content of the small intestine. GLP2-\r\n2G-XTEN demonstrated greater in vivo potency as compared to GLP2-2G peptide, and improvement in histopathology\r\nsupported the GLP2-2G-XTEN treatment effects.\r\nConclusions and Significance: GLP2-2G-XTEN is intestinotrophic and demonstrates efficacy in a rat Crohn�s disease model\r\nrequiring a lower molar dose and less frequent dosing relative to GLP2-2G peptide. Allometric scaling based on\r\npharmacokinetics from mouse, rat and monkey projects a human half-life of 240 hours. These improvements in preclinical\r\npharmacokinetics and dosing indicate that GLP2-2G-XTEN may offer a superior therapeutic benefit for treatment of\r\ngastrointestinal diseases including Crohn�s disease.
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