Intravenous Administration of Polyethylene Glycol-Coated (PEGylated) Proteins and PEGylated Adenovirus Elicits an Anti-PEG Immunoglobulin M Response

Shimizu, Taro; Ichihara, Masako; Yoshioka, Yasuo; Ishida, Tatsuhiro; Nakagawa, Shinsaku; Kojima, Hiroshi

doi:10.1248/bpb.b12-00276

Cited by 85 publications

(68 citation statements)

References 40 publications

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“…Anti-PEG IgM levels in the serum samples were detected using a simple enzyme-linked immunosorbent assay (ELISA), as described previously. 17) When determining the concentration of anti-PEG IgM in the serum, an anti-PEG IgM monoclonal antibody, HIK-M09, that we had recently generated 18) was used as a standard. The ELISA system showed a good linear relationship between the absorption and the anti-PEG IgM concentration (see supplemental Fig.…”

Section: Methodsmentioning

confidence: 99%

Relationship between the Concentration of Anti-polyethylene Glycol (PEG) Immunoglobulin M (IgM) and the Intensity of the Accelerated Blood Clearance (ABC) Phenomenon against PEGylated Liposomes in Mice

Hashimoto

Shimizu

Lila

et al. 2015

Biological & Pharmaceutical Bulletin

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PEGylation, which is the surface modification of nanocarriers with polyethylene glycol (PEG), has increased the circulation time and reduced the immunogenic responses to nanocarriers. However, many reports have demonstrated that the intravenous injection of sterically stabilized PEGylated liposome (SL) causes an accelerated blood clearance (ABC) of subsequent doses via anti-PEG immunoglobulin M (IgM)-mediated complement activation. In the present study, the relationships between serum anti-PEG IgM concentration, the intensity of complement activation and the hepatic clearance of SL were quantitatively investigated for their role in the ABC phenomenon. Interestingly, with increasing serum anti-PEG IgM concentrations, the intensity of complement activation increased linearly, while the intensity of the hepatic clearance of SL was increased and then saturated. In addition, only 15-17% of anti-PEG IgM in blood circulation induced by SL at different doses was associated with a second dose SL. The present results indicate that it is the hepatic uptake of SL that is the limiting step in the ABC phenomenon, rather than the association of anti-PEG IgM to the SL and a subsequent complement activation.

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Section: Methodsmentioning

confidence: 99%

Relationship between the Concentration of Anti-polyethylene Glycol (PEG) Immunoglobulin M (IgM) and the Intensity of the Accelerated Blood Clearance (ABC) Phenomenon against PEGylated Liposomes in Mice

Hashimoto

Shimizu

Lila

et al. 2015

Biological & Pharmaceutical Bulletin

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“…We have also very recently shown that a single intravenous administration of PEGylated bovine serum albumin (BSA) and oVA elicits an anti-PEG antibody response, similar to that from PEGylated liposomes, although the administration does not elicit specific neutralizing antibodies to BSA and OVA. 16) It seems that the PEG on anchoring protein functions as a hapten to generate anti-PEG antibody formation. A hapten is a small molecule that can elicit an immune response only when attached to a large carrier such as a protein.…”

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

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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“…PEGylation of particles clearly extends their circulation time in vivo (4,10); however, up to 25% of patients exhibit circulating anti-PEG antibodies prior to treatment or develop anti-PEG antibodies after the first administration of PEGylated particles (11,12). These factors limit the utility of PEGylation of nanoparticles in the clinic and suggest that a better understanding of the biomolecular interactions of nanoparticles and the MPS is critical for the development of alternative methods to PEGylation that will extend nanoparticle circulation times in vivo.…”

Section: Introductionmentioning

confidence: 99%

Nanoparticle clearance is governed by Th1/Th2 immunity and strain background

Jones¹,

Roberts²,

Robbins³

et al. 2013

J. Clin. Invest.

172

164

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Extended circulation of nanoparticles in blood is essential for most clinical applications. Nanoparticles are rapidly cleared by cells of the mononuclear phagocyte system (MPS). Approaches such as grafting polyethylene glycol onto particles (PEGylation) extend circulation times; however, these particles are still cleared, and the processes involved in this clearance remain poorly understood. Here, we present an intravital microscopybased assay for the quantification of nanoparticle clearance, allowing us to determine the effect of mouse strain and immune system function on particle clearance. We demonstrate that mouse strains that are prone to Th1 immune responses clear nanoparticles at a slower rate than Th2-prone mice. Using depletion strategies, we show that both granulocytes and macrophages participate in the enhanced clearance observed in Th2-prone mice. Macrophages isolated from Th1 strains took up fewer particles in vitro than macrophages from Th2 strains. Treating macrophages from Th1 strains with cytokines to differentiate them into M2 macrophages increased the amount of particle uptake. Conversely, treating macrophages from Th2 strains with cytokines to differentiate them into M1 macrophages decreased their particle uptake. Moreover, these results were confirmed in human monocyte-derived macrophages, suggesting that global immune regulation has a significant impact on nanoparticle clearance in humans. IntroductionThe potential clinical applications of nanoparticles and nanoformulations have been investigated for more than 30 years. Nanoparticle approaches have the potential to revolutionize drug delivery by allowing for the encapsulation of drugs with poor solubility or stability in a stable carrier particle. In addition, targeting nanoparticles to specific pathological sites may allow an increased effective dose of drug at the needed site, while decreasing systemic drug exposure, and therefore side effects. However, to date, only 2 nanoformulations for cancer treatment have been approved for clinical use (liposomal doxorubicin [Doxil] and protein-bound paclitaxel [Abraxane]) (1-3). One major obstacle for the use of nanoparticles in vivo is rapid clearance by the cells of the reticuloendothelial system (RES)/mononuclear phagocyte system (MPS) (4-7). In addition to rapid clearance, variable activity of the MPS among patients leads to widely variable pharmacokinetics of nanoformulations in the clinic, reducing the efficacy of both approved and future experimental nanoformulations (8).

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Intravenous Administration of Polyethylene Glycol-Coated (PEGylated) Proteins and PEGylated Adenovirus Elicits an Anti-PEG Immunoglobulin M Response

Cited by 85 publications

References 40 publications

Relationship between the Concentration of Anti-polyethylene Glycol (PEG) Immunoglobulin M (IgM) and the Intensity of the Accelerated Blood Clearance (ABC) Phenomenon against PEGylated Liposomes in Mice

Relationship between the Concentration of Anti-polyethylene Glycol (PEG) Immunoglobulin M (IgM) and the Intensity of the Accelerated Blood Clearance (ABC) Phenomenon against PEGylated Liposomes in Mice

Anti-polyethyleneglycol Antibody Response to PEGylated Substances

Nanoparticle clearance is governed by Th1/Th2 immunity and strain background

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