GLP2-2G-XTEN: A Pharmaceutical Protein with Improved Serum Half-Life and Efficacy in a Rat Crohn’s Disease Model

Alters, Susan E.; McLaughlin, Bryant; Spink, Benjamin J.; Lachinyan, Tigran; Wang, Chia‐Wei; Podust, Vladimir N.; Schellenberger, Volker; Stemmer, Willem P.C.

doi:10.1371/journal.pone.0050630

Cited by 58 publications

(35 citation statements)

References 29 publications

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“…However, since only one peptide chain is attached to a protein, XTEN conjugation did not prevent anti-protein Ab generation. Several XTEN-modified peptides and small proteins have been tested in pre-clinical or clinical studies, including glucagon, [86] glucagon-like peptide 2,[87] human growth hormone (hGH),[88] and annexin A5. [89]…”

Section: Protein Modification Beyond Pegylationmentioning

confidence: 99%

Anti-PEG antibodies in the clinic: Current issues and beyond PEGylation

Zhang

Sun

Liu

et al. 2016

Journal of Controlled Release

523

360

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The technique of attaching the polymer polyethylene glycol (PEG), or PEGylation, has brought more than ten protein drugs into market. The surface conjugation of PEG on proteins prolongs their blood circulation time and reduces immunogenicity by increasing their hydrodynamic size and masking surface epitopes. Despite this success, an emerging body of literature highlights the presence of antibodies produced by the immune system that specifically recognize and bind to PEG (anti-PEG Abs), including both pre-existing and treatment-induced Abs. More importantly, the existence of anti-PEG Abs has been correlated with loss of therapeutic efficacy and increase in adverse effects in several clinical reports examining different PEGylated therapeutics. To better understand the nature of anti-PEG immunity, we summarize a number of clinical reports and some critical animal studies regarding pre-existing and treatment-induced anti-PEG Abs. Various anti-PEG detection methods used in different studies were provided. Several protein modification technologies beyond PEGylation were also highlighted.

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Section: Protein Modification Beyond Pegylationmentioning

confidence: 99%

Anti-PEG antibodies in the clinic: Current issues and beyond PEGylation

Zhang

Sun

Liu

et al. 2016

Journal of Controlled Release

523

360

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show abstract

“…XTEN generated no substantial immune response, toxicity or kidney vacuoles in several animal models [77●●]. This technology is being commercialized by Amunix Operating Inc. and has been applied to a variety of therapeutic biomolecules [78-80] and an imaging agent [81]. Exendin-XTEN (VRS-859) is currently in a Phase I clinical trial for biweekly s.c. administration for treatment of type 2 diabetes and an XTEN fusion of human growth hormone (hGH-XTEN, VRS-317) is undergoing a Phase II clinical trial as monthly administration for treament of hGH deficiency [80].…”

Section: Naturally Degradable Peg Alternativesmentioning

confidence: 99%

Protein–polymer conjugation — moving beyond PEGylation

Chilkoti

2015

Current Opinion in Chemical Biology

156

120

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In this review, we summarize —from a materials science perspective— the current state of the field of polymer conjugates of peptide and protein drugs, with a focus on polymers that have been developed as alternatives to the current gold standard, poly(ethylene glycol) (PEG). PEGylation, or the covalent conjugation of PEG to biological therapeutics to improve their therapeutic efficacy by increasing their circulation half-lives and stability, has been the gold standard in the pharmaceutical industry for several decades. After years of research and development, the limitations of PEG, specifically its non-degradability and immunogenicity have become increasingly apparent. While PEG is still currently the best polymer available with the longest clinical track record, extensive research is underway to develop alternative materials in an effort to address these limitations of PEG. Many of these alternative materials have shown promise, though most of them are still in an early stage of development and their in vivo distribution, mechanism of degradation, route of elimination and immunogenicity have not been investigated to a similar extent as for PEG. Thus, further in-depth in vivo testing is essential to validate whether any of the alternative materials discussed in this review qualify as a replacement for PEG.

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“…Because of GLP-2's short (approximately 7-min) half-life in humans [44], administration of DPP-IV inhibitors has been used to enhance the therapeutic effects of GLP-2 [45][46][47], and synthetic GLP-2 analogs that are resistant to DPP-IV degradation have been used to prolong and increase its biological activity. Modifications include replacing the Ala (2) residue with Gly [40,42], which increases the half-life of GLP-2 to approximately 3 h in humans [48], or conjugating the peptide to various polymers, which extends the half-life in humans to as great as 10 d, based on theoretical projections from animal models [49][50][51]. Further advances in our understanding of factors that increase GLP-2 synthesis and means to enhance its biological activity will support its potential use as an enhancer of animal productivity, health, and well-being.…”

Section: Glp-2 Synthesis and Degradationmentioning

confidence: 99%

Glucagon-like peptide 2 and its beneficial effects on gut function and health in production animals

Connor

Evock‐Clover

Wall³

et al. 2016

Domestic Animal Endocrinology

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Numerous endocrine cell subtypes exist within the intestinal mucosa and produce peptides contributing to the regulation of critical physiological processes including appetite, energy metabolism, gut function, and gut health. The mechanisms of action and the extent of the physiological effects of these enteric peptides are only beginning to be uncovered. One peptide in particular, glucagon-like peptide 2 (GLP-2) produced by enteroendocrine L cells, has been fairly well characterized in rodent and swine models in terms of its ability to improve nutrient absorption and healing of the gut after injury. In fact, a long-acting form of GLP-2 recently has been approved for the management and treatment of human conditions like inflammatory bowel disease and short bowel syndrome. However, novel functions of GLP-2 within the gut continue to be demonstrated, including its beneficial effects on intestinal barrier function and reducing intestinal inflammation. As knowledge continues to grow about GLP-2's effects on the gut and its mechanisms of release, the potential to use GLP-2 to improve gut function and health of food animals becomes increasingly more apparent. Thus, the purpose of this review is to summarize: (1) the current understanding of GLP-2's functions and mechanisms of action within the gut; (2) novel applications of GLP-2 (or stimulators of its release) to improve general health and production performance of food animals; and (3) recent findings, using dairy calves as a model, that suggest the therapeutic potential of GLP-2 to reduce the pathogenesis of intestinal protozoan infections.

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GLP2-2G-XTEN: A Pharmaceutical Protein with Improved Serum Half-Life and Efficacy in a Rat Crohn’s Disease Model

Cited by 58 publications

References 29 publications

Anti-PEG antibodies in the clinic: Current issues and beyond PEGylation

Anti-PEG antibodies in the clinic: Current issues and beyond PEGylation

Protein–polymer conjugation — moving beyond PEGylation

Glucagon-like peptide 2 and its beneficial effects on gut function and health in production animals

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