Background
Polyethylene glycol (PEG) is one of the few biocompatible synthetic polymers approved for food, cosmetics, and sanitary products. It has been used in clinical drug development, including osmotic laxatives, fusion agents for repairing injured nerves and cell membranes, oxidative stress inhibitors, and axonal regeneration promoters. PEG is covalently or non-covalently coupled with macromolecular drugs or drug delivery nanosystems (DDS), increasing their hydrodynamic size and water solubility, thereby reducing their self-aggregation and interaction with blood proteins and mononuclear phagocytic system (MPS) cells. The result is to increase the stability in vitro and in vivo, prolong the storage time, reduce the clearance rate of kidney, proteolysis, and phagocytes, thus prolong the circulation time, reduce adverse reactions, and improve the applicability and treatment index in an all-round way.
PEGs, whose molecular weight is within the range of 0.440kDa, are highly flexible linear or branched chain polymers with different terminal groups. One of the end groups is used to covalently connect to macromolecules, DDS, or free carboxyl, amino, or sulfhydryl groups on the connectors that combine PEG with DDS through various chemical reaction functional groups, and the other end group is the most common one is methyl. The PEG chain is constructed from repeated S-shaped fragments, which are composed of 10 ethylene oxide units. The embedded cavity of the polymer can hold water molecules, so it has strong hydrophilicity and can form a water barrier around the anchored nanostructure. The shielding effect depends on the length of PEG and the distance between the end group and PEG grafting.
Figure 1. Chemical details of PEG structure via different presentations
(Source: Kozma GT, et al. 2020)
As PEGylated drugs have become more widely available and used in the clinic, reports of severe PEG-related anaphylaxis and infusion reactions have increased. In addition, anti-PEG antibodies are becoming a growing problem. The potential immunogenicity and antigenicity of PEGs to induce specific antibodies was reported as early as the last century, and subsequent studies have found that anti-PEG antibodies are predominantly IgM, and that typical PEGylated therapeutic agents induce anti-PEG IgM and IgG in patients. Anti-PEG antibodies are naturally present in certain healthy populations, and pre-existing anti-PEG antibodies may affect the therapeutic efficacy and safety of PEGylated drugs, necessitating the need to monitor anti-PEG antibody levels before, during, and after PEGylated drug therapy.
Alternative Names
Polyethylene glycol mAb
Anti-polyethylene glycol mAb
References
- 1. Hong L, et al. Antibodies against polyethylene glycol in human blood: A literature review. J Pharmacol Toxicol Methods. 2020 Mar-Apr;102:106678.
- 2. Kozma GT, et al. Anti-PEG antibodies: Properties, formation, testing and role in adverse immune reactions to PEGylated nano-biopharmaceuticals. Adv Drug Deliv Rev. 2020;154-155:163-175.
References
Anti-PEG IgM production induced by PEGylated liposomes as a function of administration route
J Control Release
Authors: Takata H, Shimizu T, Yamade R, Elsadek NE, Emam SE, Ando H, Ishima Y, Ishida T.
Abstract
Modifying the surface of nanoparticles with polyethylene glycol (PEG) is a commonly used approach for improving the in vitro stability of nanoparticles such as liposomes and increasing their circulation half-lives. We have demonstrated that, in certain conditions, an intravenous (i.v.) injection of PEGylated liposomes (PEG-Lip) induced anti-PEG IgM antibodies, which led to rapid clearance of second doses in mice. SARS-CoV-2 vaccines, composed of mRNA-containing PEGylated lipid nanoparticles, have been widely administered as intramuscular (i.m.) injections, so it is important to determine if PEGylated formulations can induce anti-PEG antibodies. If the favorable properties that PEGylation imparts to therapeutic nanoparticles are to be widely applicable this should apply to various routes of administration. However, there are few reports on the effect of different administration routes on the in vivo production of anti-PEG IgM. In this study, we investigated anti-PEG IgM production in mice following i.m., intraperitoneal (i.p.) and subcutaneous (s.c.) administration of PEG-Lip. PEG-Lip appeared to induce anti-PEG IgM by all the tested routes of administration, although the lipid dose causing maximum responses varied. Splenectomy attenuated the anti-PEG IgM production for all routes of administration, suggesting that splenic immune cells may have contributed to anti-PEG IgM production. Interestingly, in vitro experiments indicated that not only splenic cells but also cells in the peritoneal cavity induced anti-PEG IgM following incubation with PEG-Lip. These observations confirm previous experiments that have shown that measurable amounts of PEG-Lip administered i.p., i.m. or s.c. are absorbed to some extent into the blood circulation, where they can be distributed to the spleen and/or peritoneal cavity, and are recognized by B cells, triggering anti-PEG IgM production. The results obtained in this study have important implications for developing efficient PEGylated nanoparticular delivery system.
Evaluation of association of anti-PEG antibodies with anaphylaxis after mRNA COVID-19 vaccination
Vaccine
Authors: Zhou ZH, Cortese MM, Fang JL, Wood R, Hummell DS, Risma KA, Norton AE, KuKuruga M, Kirshner S, Rabin RL, Agarabi C, Staat MA, Halasa N, Ware RE, Stahl A, McMahon M, Browning P, Maniatis P, Bolcen S, Edwards KM, Su JR, Dharmarajan S, Forshee R, Broder KR, Anderson S, Kozlowski S.
Abstract
Background: The mechanism for anaphylaxis following mRNA COVID-19 vaccination has been widely debated; understanding this serious adverse event is important for future vaccines of similar design. A mechanism proposed is type I hypersensitivity (i.e., IgE-mediated mast cell degranulation) to polyethylene glycol (PEG). Using an assay that, uniquely, had been previously assessed in patients with anaphylaxis to PEG, our objective was to compare anti-PEG IgE in serum from mRNA COVID-19 vaccine anaphylaxis case-patients and persons vaccinated without allergic reactions. Secondarily, we compared anti-PEG IgG and IgM to assess alternative mechanisms.
Methods: Selected anaphylaxis case-patients reported to U.S. Vaccine Adverse Event Reporting System December 14, 2020-March 25, 2021 were invited to provide a serum sample. mRNA COVID-19 vaccine study participants with residual serum and no allergic reaction post-vaccination ("controls") were frequency matched to cases 3:1 on vaccine and dose number, sex and 10-year age category. Anti-PEG IgE was measured using a dual cytometric bead assay (DCBA). Anti-PEG IgG and IgM were measured using two different assays: DCBA and a PEGylated-polystyrene bead assay. Laboratorians were blinded to case/control status.
Results: All 20 case-patients were women; 17 had anaphylaxis after dose 1, 3 after dose 2. Thirteen (65 %) were hospitalized and 7 (35 %) were intubated. Time from vaccination to serum collection was longer for case-patients vs controls (post-dose 1: median 105 vs 21 days). Among Moderna recipients, anti-PEG IgE was detected in 1 of 10 (10 %) case-patients vs 8 of 30 (27 %) controls (p = 0.40); among Pfizer-BioNTech recipients, it was detected in 0 of 10 case-patients (0 %) vs 1 of 30 (3 %) controls (p >n 0.99). Anti-PEG IgE quantitative signals followed this same pattern. Neither anti-PEG IgG nor IgM was associated with case status with both assay formats.
Conclusion: Our results support that anti-PEG IgE is not a predominant mechanism for anaphylaxis post-mRNA COVID-19 vaccination.
COA
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