Polyethylene Glycol Reactive Antibodies in Man: Titer Distribution in Allergic Patients Treated with Monomethoxy Polyethylene Glycol Modified Allergens or Placebo, and in Healthy Blood Donors

Richter, A. W.; Åkerblom, Eva

doi:10.1159/000233512

Cited by 198 publications

(170 citation statements)

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“…Interestingly, there have been several reports on the detection of anti-PEG antibodies in healthy blood donors, who have not received PEGylated biopharmaceuticals, suggesting that environmental PEG exposure may lead to the development of anti-PEG antibodies in a subset of the population (Richter and Akerblom 1984;Garratty 2004Garratty , 2008Armstrong et al 2007;Garay et al 2012). Moreover, PEG is used during manufacturing of certain vaccines and plasma-derived biopharmaceuticals, for example, certain influenza virus vaccines (Polson 1976), hepatitis B virus vaccines (Takao et al 1986), and plasma-derived FVIII products (Chtourou 2012).…”

Section: Immunogenicity Of Pegmentioning

confidence: 99%

PEGylated Biopharmaceuticals

et al. 2015

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PEGylation (the covalent binding of one or more polyethylene glycol molecules to another molecule) is a technology frequently used to improve the half-life and other pharmaceutical or pharmacological properties of proteins, peptides, and aptamers. To date, 11 PEGylated biopharmaceuticals have been approved and there is indication that many more are in nonclinical or clinical development. Adverse effects seen with those in toxicology studies are mostly related to the active part of the drug molecule and not to polyethylene glycol (PEG). In 5 of the 11 approved and 10 of the 17 PEGylated biopharmaceuticals in a 2013 industry survey presented here, cellular vacuolation is histologically observed in toxicology studies in certain organs and tissues. No other effects attributed to PEG alone have been reported. Importantly, vacuolation, which occurs mainly in phagocytes, has not been linked with changes in organ function in these toxicology studies. This article was authored through collaborative efforts of industry toxicologists/nonclinical scientists to address the nonclinical safety of large PEG molecules (>10 kilo Dalton) in PEGylated biopharmaceuticals. The impact of the PEG molecule on overall nonclinical safety assessments of PEGylated biopharmaceuticals is discussed, and toxicological information from a 2013 industry survey on PEGylated biopharmaceuticals under development is summarized. Results will contribute to the database of toxicological information publicly available for PEG and PEGylated biopharmaceuticals.

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Section: Immunogenicity Of Pegmentioning

confidence: 99%

PEGylated Biopharmaceuticals

et al. 2015

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“…It appears that the haptogenic character of PEG depends on its structure and molecular weight, immunogenicity of the anchoring protein, and the presence of adjuvant. 9,15,17) Several reports have demonstrated that PEGylated protein products elicit anti-PEG antibodies (mainly anti-PEG IgM) in animals and humans.…”

Section: Anti-peg Immunoglobulin M (Igm) Response To Pegylated Proteinsmentioning

confidence: 99%

“…In addition, surprisingly, in healthy blood donors with no known prior exposure to PEG, the prevalence of anti-PEG antibodies has been detected up to 25%, 8) which contrasts with a 0.2% occurrence reported over 20 years ago. 9) This increase may be due to greater exposure to PEG in cosmetics, pharmaceuticals and processed foods. There is concern that anti-PEG antibodies limit the efficacy of PEGylated substances because they lead to enhanced blood clearance of PEGylated substances and decreased biological activity of the substances by neutralization.…”

Section: Introductionmentioning

confidence: 99%

Anti-polyethyleneglycol Antibody Response to PEGylated Substances

Ishida

Kojima

2013

Biological & Pharmaceutical Bulletin

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In contrast to the general assumption that polyethyleneglycol (PEG)-conjugated substances lack immunogenicity and antigenic, it has been reported that they can elicit antibodies against PEG (mainly anti-PEG immunoglobulin M (IgM)). In patients, the presence of anti-PEG antibodies may limit therapeutic efficacy of PEGylated substances as a consequence of inducing rapid clearance of and neutralizing biological activity of the substances. Here, we introduce specific examples of PEGylated substances including several PEGylated proteins and PEGylated particles (PEGylated nanocarriers) which induce anti-PEG antibody responses. Finally, we emphasize that the immunogenicity of PEGylated substances should be tested in the development stage and that the titer of anti-PEG antibodies in patients should be pre-screened and monitored prior to and throughout a course of treatment with a PEGylated substance.

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“…Indeed, mPEG-RBCs (syngeneic, allogeneic and xenogeneic) show decreased immunogenicity. A number of studies show that, while PEG has low immunogenic potential, it does (under some circumstances) induce anti-PEG antibodies [32][33][34][35]. Typically, in animal models this has required the co-administration of Freund's Complete Adjuvant or coupling of PEG to highly immunogenic proteins [32,33].…”

Section: Discussionmentioning

confidence: 99%

“…A number of studies show that, while PEG has low immunogenic potential, it does (under some circumstances) induce anti-PEG antibodies [32][33][34][35]. Typically, in animal models this has required the co-administration of Freund's Complete Adjuvant or coupling of PEG to highly immunogenic proteins [32,33]. More recently, studies have reported that a significant percentage of normal blood donors show evidence of anti-PEG antibodies [34,35].…”

Section: Discussionmentioning

confidence: 99%

Polymer-mediated immunocamouflage of red blood cells: Effects of polymer size on antigenic and immunogenic recognition of allogeneic donor blood cells

Wang

Kyluik

Murad

et al. 2011

Sci. China Life Sci.

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Developing a practical means of reducing alloimmunization in chronically transfused patients would be of significant clinical benefit. Immunocamouflaging red blood cells (RBCs) by membrane grafting of methoxypoly(ethylene glycol) (mPEG) may reduce the risk of allo-immunization. The results of this study showed that antibody recognition of non-ABO antigens was significantly reduced in an mPEG-dose-and polymer size-dependent manner, with higher molecular weight mPEGs providing better immunoprotection. Furthermore, in vivo immunogenicity was significantly reduced in mice serially transfused with mPEG-modified xenogeneic (sheep; sRBCs), allogeneic (C57Bl/6), or syngeneic (Balb/c) RBCs. Following a primary transfusion of sRBCs, mice receiving mPEG-sRBCs showed a >90% reduction in anti-sRBC IgG antibody levels. After two transfusions, mice receiving mPEG-sRBCs showed reductions of >80% in anti-sRBC IgG levels. Importantly, mPEG-modified autologous cells did not induce neoantigens or an immune (IgG or IgM) response. These data suggest that the global immunocamouflage of RBCs by polymer grafting may provide a safe and cost-effective means of reducing the risk of alloimmunization. Safe and effective blood transfusions are arguably one of the most important medical advances made in the past century. These procedures are now common place and have saved millions of lives; however, until recently, this process has been of only limited interest to the research community.There is a substantial body of evidence showing that clinical problems can occur in chronically transfused patients because of alloimmunization [1][2][3]. These problems are compounded by the fact that it is difficult, time-consuming and expensive to phenotype blood cells for mismatched antigens at non-ABO/RhD epitopes. Yet these mismatches can, and do, have a significant impact on patient care--especially for chronically transfused sickle cell and thalassemic patients. Indeed, by some estimates, up to 35% of sickle patients show clinically significant levels of alloimmunization (i.e., shortened RBC survival and mild fever) to non-ABO/RhD antigens [4,5]. Of these alloimmunized patients, some become so reactive to donor RBCs that even the most closely matched samples cause a transfusion reaction, thus endangering the life of the patient.

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Polyethylene Glycol Reactive Antibodies in Man: Titer Distribution in Allergic Patients Treated with Monomethoxy Polyethylene Glycol Modified Allergens or Placebo, and in Healthy Blood Donors

Cited by 198 publications

References 5 publications

PEGylated Biopharmaceuticals

PEGylated Biopharmaceuticals

Anti-polyethyleneglycol Antibody Response to PEGylated Substances

Polymer-mediated immunocamouflage of red blood cells: Effects of polymer size on antigenic and immunogenic recognition of allogeneic donor blood cells

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