The Immunogenicity of Polyethylene Glycol: Facts and Fiction

Schellekens, Huub; Hennink, Wim E.; Brinks, Vera

doi:10.1007/s11095-013-1067-7

Cited by 311 publications

(213 citation statements)

References 26 publications

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“…Polyethylene glycol (PEG) polymers have become widely used to improve the pharmacokinetics of therapeutic peptides by improving half-life and reducing the susceptibility to proteolytic degradation resulting in many commercial therapeutic peptide products (60)(61)(62). However, there are concerns about the toxicological effects (i.e., renal toxicity), the metabolic fate of the PEG moiety and immunogenicity (63,64). The latter having the opposite intended effect in that induced anti-PEG antibodies have been linked to enhanced blood clearance and reduced efficacy of the therapeutic.…”

Section: Proteolytic Degradation and Hydrolysismentioning

confidence: 99%

Early Engineering Approaches to Improve Peptide Developability and Manufacturability

Furman

Chiu

Hunter

2014

AAPS J

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Abstract. Downstream success in Pharmaceutical Development requires thoughtful molecule design early in the lifetime of any potential therapeutic. Most therapeutic monoclonal antibodies are quite similar with respect to their developability properties. However, the properties of therapeutic peptides tend to be as diverse as the molecules themselves. Analysis of the primary sequence reveals sites of potential adverse posttranslational modifications including asparagine deamidation, aspartic acid isomerization, methionine, tryptophan, and cysteine oxidation and, potentially, chemical and proteolytic degradation liabilities that can impact the developability and manufacturability of a potential therapeutic peptide. Assessing these liabilities, both biophysically and functionally, early in a molecule's lifetime can drive a more effective path forward in the drug discovery process. In addition to these potential liabilities, more complex peptides that contain multiple disulfide bonds can pose particular challenges with respect to production and manufacturability. Approaches to reducing the disulfide bond complexity of these peptides are often explored with mixed success. Proteolytic degradation is a major contributor to decreased half-life and efficacy. Addressing this aspect of peptide stability early in the discovery process increases downstream success. We will address aspects of peptide sequence analysis, molecule complexity, developability analysis, and manufacturing routes that drive the decision making processes during peptide therapeutic development.

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Section: Proteolytic Degradation and Hydrolysismentioning

confidence: 99%

Early Engineering Approaches to Improve Peptide Developability and Manufacturability

Furman

Chiu

Hunter

2014

AAPS J

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“…PEG polymers have been extensively used to improve the pharmacokinetics of biologics. (21) Despite recent concerns about potential immunogenicity of PEG, (22) this remains controversial, (23) and they are still the polymer of choice for in vivo applications.…”

Section: Introductionmentioning

confidence: 99%

Influence of Polymer Size on Uptake and Cytotoxicity of Doxorubicin-Loaded DNA–PEG Conjugates

et al. 2016

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“…This recommendation has proven to be a tall order, as developing and validating assays to detect antibodies against a PEG moiety is a major challenge. In a review paper by Schellekens et al (3), the authors concluded that most, if not all, assays used for detecting anti-PEG antibodies are flawed due to the lack of specificity as well as poor characterization of positive controls (3,4). Until recently, traditional bridge immunoassay format assays have been able to detect anti-PEG IgM antibodies but have struggled to detect IgG isotype antibodies with sufficient sensitivity in human matrix (5,6), suggesting that the type of PEG and/or protein therapeutic may play a role.…”

Section: Introductionmentioning

confidence: 99%

Development of a Generic Anti-PEG Antibody Assay Using BioScale’s Acoustic Membrane MicroParticle Technology

Dong

Mora

Brockus

et al. 2015

AAPS J

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Abstract. Immunogenicity testing for PEGylated biotherapeutics should include methods to detect both anti-protein and anti-PEG antibodies (anti-PEG). Although some methods have been published for the detection of anti-PEG antibodies, the information is incomplete and, in some cases, reagents used (such as Tween-20) are known to interfere with detection. This rapid communication describes the use of BioScale's Acoustic Membrane MicroParticle (AMMP®) technology using the ViBE® Workstation to measure anti-PEG antibodies in human serum samples. Briefly, a sample spiked with monoclonal human IgG anti-PEG antibody is diluted in buffer and incubated with paramagnetic beads coated with linear chain mPEG to capture anti-PEG antibodies. The complex is then captured on an acoustic membrane coated with Protein A. The change in mass on the membrane caused by the binding of the complex to the membrane results in a signal proportional to the mass of anti-PEG antibodies. The data indicate that an assay with a sensitivity of less than 1000 ng/mL for IgG is achievable. This level of sensitivity is better than current published reports on IgG anti-PEG antibody detection.

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The Immunogenicity of Polyethylene Glycol: Facts and Fiction

Cited by 311 publications

References 26 publications

Early Engineering Approaches to Improve Peptide Developability and Manufacturability

Early Engineering Approaches to Improve Peptide Developability and Manufacturability

Influence of Polymer Size on Uptake and Cytotoxicity of Doxorubicin-Loaded DNA–PEG Conjugates

Development of a Generic Anti-PEG Antibody Assay Using BioScale’s Acoustic Membrane MicroParticle Technology

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