GLP2-2G-XTEN: a pharmaceutical protein with improved serum half-life and efficacy in a rat Crohn's disease model

Glucagon-like peptide 2 (GLP2) is an intestinal growth factor that has been shown to stimulate intestinal growth and reduce disease severity in preclinical models of short bowel syndrome and inflammatory bowel disease. Teduglutide, a recombinant human GLP2 variant (GLP2-2G), has increased half-life...

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Bibliographic Details
Published in:PloS one 2012-11, Vol.7 (11), p.e50630
Main Authors: Alters, Susan E, McLaughlin, Bryant, Spink, Benjamin, Lachinyan, Tigran, Wang, Chia-wei, Podust, Vladimir, Schellenberger, Volker, Stemmer, Willem P C
Format: Article
Language:English
Subjects:
Amino acids
Animal models
Animals
Biology
Crohn Disease - blood
Crohn Disease - chemically induced
Crohn Disease - drug therapy
Crohns disease
Disease Models, Animal
Dosage
Effectiveness
Female
Fusion protein
Gastroenterology
Gastrointestinal diseases
Glucagon
Glucagon-like peptide 2
Glucagon-Like Peptide 2 - chemistry
Glucagon-Like Peptide 2 - pharmacokinetics
Glucagon-Like Peptide 2 - therapeutic use
Half-life
Health aspects
Histochemistry
Histopathology
Humans
Indomethacin
Inflammation
Inflammatory bowel disease
Inflammatory bowel diseases
Intestine, Small - drug effects
Intestine, Small - pathology
Macaca fascicularis
Male
Medical treatment
Medicine
Mice
Monkeys
Peptides
Pharmacokinetics
Pharmacology
Proteins
Rats
Recombinant Fusion Proteins - chemistry
Recombinant Fusion Proteins - pharmacokinetics
Recombinant Fusion Proteins - therapeutic use
Rodents
Scaling
Short bowel syndrome
Small intestine
Tumor necrosis factor-TNF
Tumor necrosis factor-α
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Summary:Glucagon-like peptide 2 (GLP2) is an intestinal growth factor that has been shown to stimulate intestinal growth and reduce disease severity in preclinical models of short bowel syndrome and inflammatory bowel disease. Teduglutide, a recombinant human GLP2 variant (GLP2-2G), has increased half-life and stability as compared to the native GLP2 peptide, but still requires twice daily dosing in preclinical models and daily dosing in the clinic. The goal of this study was to produce and characterize the preclinical pharmacokinetic and therapeutic properties of GLP2-2G-XTEN, a novel, long-acting form of GLP2-2G. A GLP2-2G-XTEN fusion protein with extended exposure profile was produced by genetic fusion of GLP2-2G peptide to XTEN, a long, unstructured, non-repetitive, hydrophilic sequence of amino acids. The serum half-life of GLP2-2G-XTEN in mice, rats and monkeys was 34, 38 and 120 hours, respectively. Intestinotrophic effects were demonstrated in normal rats, where GLP2-2G-XTEN administration resulted in a significant increase in both small intestine weight and length. Efficacy of the GLP2-2G-XTEN protein was compared to that of GLP2-2G peptide in a rat Crohn's disease model, indomethacin-induced inflammation. Prophylactic administration of GLP2-2G-XTEN significantly increased the length, reduced the number of trans-ulcerations and adhesions, and reduced the TNFα content of the small intestine. GLP2-2G-XTEN demonstrated greater in vivo potency as compared to GLP2-2G peptide, and improvement in histopathology supported the GLP2-2G-XTEN treatment effects. GLP2-2G-XTEN is intestinotrophic and demonstrates efficacy in a rat Crohn's disease model requiring a lower molar dose and less frequent dosing relative to GLP2-2G peptide. Allometric scaling based on pharmacokinetics from mouse, rat and monkey projects a human half-life of 240 hours. These improvements in preclinical pharmacokinetics and dosing indicate that GLP2-2G-XTEN may offer a superior therapeutic benefit for treatment of gastrointestinal diseases including Crohn's disease.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0050630