The Mystery of Antibodies Against Polyethylene Glycol (PEG) - What do we Know?

Lubich, Christian; Allacher, Peter; Rosa, Maurus de la; Bauer, Alexander; Prenninger, Thomas; Horling, Frank; Siekmann, Jürgen; Oldenburg, Johannes; Scheiflinger, Friedrich; Reipert, Birgit M.

doi:10.1007/s11095-016-1961-x

Cited by 132 publications

(96 citation statements)

References 43 publications

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“…PEG was long considered to be nonimmunogenic, but recent reports show that anti-PEG antibodies can be induced by injection of some types of pegylated liposomes or proteins in clinical trials [6][7][8][9][10][11][12][13][14] and animal studies [15][16][17][18][19][20][21][22][23][24]. Although anti-PEG antibodies do not appear to be induced when most pegylated human proteins are administered to patients, a large proportion of the general population never exposed to pegylated drugs has pre-existing anti-PEG antibodies in their circulation, possibly due to widespread exposure to PEG in commonly used products such as cosmetics, soaps, and medicines [10][11][12]16,[25][26][27][28][29][30][31]. For example, we recently found that over 40% of 1504 normal donors had measurable anti-PEG IgM and IgG antibodies in their plasma [25].…”

Section: Introductionmentioning

confidence: 99%

Both IgM and IgG Antibodies against Polyethylene Glycol Can Alter the Biological Activity of Methoxy Polyethylene Glycol-Epoetin Beta in Mice

et al. 2019

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Pre-existing antibodies that bind polyethylene glycol are present in about 40% of healthy individuals. It is currently unknown if pre-existing anti-polyethylene glycol (PEG) antibodies can alter the bioactivity of pegylated drugs with a single long PEG chain, which represents the majority of newly developed pegylated medicines. Methoxy polyethylene glycol-epoetin beta (PEG-EPO) contains a single 30 kDa PEG chain and is used to treat patients suffering from anemia. We find that the pre-existing human anti-PEG IgM and IgG antibodies from normal donors can bind to PEG-EPO. The prevalence and concentrations of anti-PEG IgM and IgG antibodies were also higher in patients that responded poorly to PEG-EPO. Monoclonal anti-PEG IgM and IgG antibodies at concentrations found in normal donors blocked the biological activity of PEG-EPO to stimulate the production of new erythrocytes in mice and accelerated the clearance of 125 I-PEG-EPO, resulting in PEG-EPO accumulation primarily in the liver and spleen. Accelerated clearance by the anti-PEG IgG antibody was mediated by the Fc portion of the antibody. Importantly, infusing higher doses of PEG-EPO could compensate for the inhibitory effects of anti-PEG antibodies, suggesting that pre-existing anti-PEG antibodies can be "dosed through." Our study indicates that the bioactivity and therapeutic activity of PEG-EPO may be reduced in patients with elevated levels of pre-existing anti-PEG antibodies. New pegylated medicines with a single long PEG chain may also be affected in patients with high levels of anti-PEG antibodies.

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Section: Introductionmentioning

confidence: 99%

Both IgM and IgG Antibodies against Polyethylene Glycol Can Alter the Biological Activity of Methoxy Polyethylene Glycol-Epoetin Beta in Mice

et al. 2019

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“…They showed that low levels of anti-PEG antibodies are detectable in the plasma of 47 to 72% of patients, irrespective of the collection date. Parallel studies in healthy donors without prior exposure to PEGylated therapeutics living in Austria, the US and Taiwan also show that anti-PEG immunoglobulins are present in 20 to 44% of blood samples [21,22]. Recently, a genome-wide association study conducted in patients from Taiwan identified the immunoglobulin heavy chain locus as a site of genetic variation that could predispose to the development of anti-PEG IgMs [23].…”

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confidence: 98%

Anti-polyethylene glycol antibodies alter the protein corona deposited on nanoparticles and the physiological pathways regulating their fate in vivo

Grenier

Viana

Lima

et al. 2018

Journal of Controlled Release

103

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Multiple studies highlight the strong prevalence of anti-poly(ethylene glycol) (anti-PEG) antibodies in the general human population. As we develop therapeutic modalities using this polymer, it is increasingly relevant to assess the importance of anti-PEG antibodies on biological performances. Here, we show that the anti-PEG Immunoglobulin M (IgM) raised in mice following the injection of polymeric nanoparticles could have significant neutralizing effects on subsequent doses of PEGylated nanosystems in vivo. The circulation times of PEGylated nanoparticles and liposomes were strongly reduced in animals with circulating anti-PEG IgMs, irrespective of the PEG density or the surface properties of the system. In comparison, despite that anti-PEG IgMs could bind free methoxy-terminated PEG and PEGylated bovine serum albumin, the circulation kinetics of these systems remained unaltered in the presence of antibodies. The binding of IgMs to the PEGylated surface of nanoparticles alters the nature of the proteins adsorbed in the surrounding corona, notably due to the activation of the complement cascade. These changes are responsible for the observed differences in circulation times. In comparison, the PEG-BSA is unable to activate complement, even in the presence of anti-PEG IgMs. These results inform on how anti-PEG antibodies can affect the fate of PEGylated nanomaterials and highlight how the architecture of nanoparticles impacts the deposition of the protein corona.

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“…[11,14,15] Despite the broad applicability of PLL-g-PEG films, several drawbacks have been associated with the application of PEG derivatives,i ncluding their tendency to undergo oxidative degradation to yield toxic compounds, [16,17] and the expression of antibodies specific for PEGs in vivo. [18][19][20] Appropriate alternatives that display improved chemical stability would be highly desirable,while polymers presenting more easily tailorable chemistries would give access to alarger variety of functional surfaces.…”

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confidence: 99%

Chemical Design of Non‐Ionic Polymer Brushes as Biointerfaces: Poly(2‐oxazine)s Outperform Both Poly(2‐oxazoline)s and PEG

et al. 2018

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The era of poly(ethylene glycol) (PEG) brushes as a universal panacea for preventing non-specific protein adsorption and providing lubrication to surfaces is coming to an end. In the functionalization of medical devices and implants, in addition to preventing non-specific protein adsorption and cell adhesion, polymer-brush formulations are often required to generate highly lubricious films. Poly(2-alkyl-2-oxazoline) (PAOXA) brushes meet these requirements, and depending on their side-group composition, they can form films that match, and in some cases surpass, the bioinert and lubricious properties of PEG analogues. Poly(2-methyl-2-oxazine) (PMOZI) provides an additional enhancement of brush hydration and main-chain flexibility, leading to complete bioinertness and a further reduction in friction. These data redefine the combination of structural parameters necessary to design polymer-brush-based biointerfaces, identifying a novel, superior polymer formulation.

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The Mystery of Antibodies Against Polyethylene Glycol (PEG) - What do we Know?

Abstract: We confirm that some healthy individuals and some patients with hemophilia express specific antibodies against PEG which are not associated with any pathology and do not bind to human tissues.

Cited by 132 publications

References 43 publications

Both IgM and IgG Antibodies against Polyethylene Glycol Can Alter the Biological Activity of Methoxy Polyethylene Glycol-Epoetin Beta in Mice

Both IgM and IgG Antibodies against Polyethylene Glycol Can Alter the Biological Activity of Methoxy Polyethylene Glycol-Epoetin Beta in Mice

Anti-polyethylene glycol antibodies alter the protein corona deposited on nanoparticles and the physiological pathways regulating their fate in vivo

Chemical Design of Non‐Ionic Polymer Brushes as Biointerfaces: Poly(2‐oxazine)s Outperform Both Poly(2‐oxazoline)s and PEG

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