Generation, characterization and in vivo biological activity of two distinct monoclonal anti-PEG IgMs

Hashimoto, Yuichi; Shimizu, Taro; Mima, Yu; Lila, Amr S. Abu; Ishida, Tatsuhiro; Kojima, Hiroshi

doi:10.1016/j.taap.2014.03.002

Cited by 38 publications

(34 citation statements)

References 31 publications

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“…into immune competent mice together with PEG-OVA or SL to study their impact on the in vivo clearance. The presence and the reactivity of serum anti-PEG IgM antibodies were not related to an enhanced or accelerated clearance of the product or its enzymatic activity (Hashimoto et al, 2014). This observation is in accordance with our results.…”

Section: Discussionsupporting

confidence: 92%

“…To the best of our knowledge, this is the first time that anti-PEG antibodies were successfully raised in immune competent animals without being conjugated to a carrier (e.g. KHL, ovalbumin, BSA, porcine superoxide dismutase or liposome) or using Freund's adjuvant (Richter and Akerblom, 1983;Ishida et al, 2006;Ganson et al, 2006;Armstrong et al, 2007;Liu et al, 2011;Sherman et al, 2012;Shimizu et al, 2012;Ishida and Kiwada, 2013;Schellekens et al, 2013;Verhoef et al, 2014;Hashimoto et al, 2014). Our results demonstrate that 40 kDa PEG-Diol itself behaves like a hapten.…”

Section: Discussionmentioning

confidence: 54%

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Impact of anti-PEG IgM antibodies on the pharmacokinetics of pegylated asparaginase preparations in mice

Poppenborg

Wittmann²,

Walther

et al. 2016

European Journal of Pharmaceutical Sciences

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 54%

Impact of anti-PEG IgM antibodies on the pharmacokinetics of pegylated asparaginase preparations in mice

Poppenborg

Wittmann²,

Walther

et al. 2016

European Journal of Pharmaceutical Sciences

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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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“…Another explanation is related to the PEG conformation on the surface of nanocarriers. Hashimoto et al 51 reported that anti-PEG IgM that was generated in response to a single intravenous immunization of PEGylated liposomes had the ability to bind to the dense PEG that was mainly in a brush conformation. Compared with PSLN-GMS, the PEG chains in the PE formulation are more brush-like in structure; therefore, the anti-PEG IgM preferentially binds to the brush conformation of PEGylated nanocarriers.…”

Section: Discussionmentioning

confidence: 99%

Accelerated blood clearance phenomenon upon cross-administration of PEGylated nanocarriers in beagle dogs

Cheng¹,

Su²,

Pei³

et al. 2015

IJN

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The cross-administration of nanocarriers modified by poly(ethylene glycol) (PEG), named PEGylated nanocarriers, a type of combination therapy, is becoming an increasingly important method of long-term drug delivery, to decrease side effects, avoid multidrug resistance, and increase therapeutic efficacy. However, repeated injections of PEGylated nanocarriers induces the accelerated blood clearance (ABC) phenomenon, prevents long circulation, and can cause adverse effects owing to alterations in the biodistribution of the drug. Although the nature of the ABC phenomenon that is induced by repeated injections of PEGylated nanocarriers has already been studied in detail, there are few reports on the immune response elicited by the cross-administration of PEGylated nanocarriers. In this study, we investigated the ABC phenomenon induced by the intravenous cross-administration of various PEGylated nanocarriers, including PEGylated liposomes (PL), PEG micelles (PM), PEGylated solid lipid nanoparticles (PSLN), and PEGylated emulsions (PE), in beagle dogs. The results indicated that the magnitude of the immune response elicited by the cross-administration was in the following order (from the strongest to the weakest): PL, PE, PSLN, PM. It is specifically PEG in the brush structure that elicits a significant immune response, in both the induction phase and the effectuation phase. Furthermore, the present study suggests that there is a considerable difference between the effect of repeated injections and cross-administration, depending on the colloidal structure. This work is a preliminary investigation into the cross-administration of PEGylated nanocarriers, and our observations can have serious implications for the design of combination therapies that use PEGylated vectors.

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Generation, characterization and in vivo biological activity of two distinct monoclonal anti-PEG IgMs

Cited by 38 publications

References 31 publications

Impact of anti-PEG IgM antibodies on the pharmacokinetics of pegylated asparaginase preparations in mice

Impact of anti-PEG IgM antibodies on the pharmacokinetics of pegylated asparaginase preparations 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

Accelerated blood clearance phenomenon upon cross-administration of PEGylated nanocarriers in beagle dogs

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