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Release date:2024/3/28 13:36:07

Covalent attachment of poly(ethylene glycol) (PEG), known as PEGylation, is widely employed to enhance the pharmacokinetics and biodistribution of therapeutic proteins and nanoparticles. However, despite these advantages, PEGylation can trigger immune responses in certain individuals, resulting in the production of anti-PEG antibodies (APA). The presence of APA poses significant implications for patient care, as it can diminish the efficacy of PEGylated drugs by interfering with their distribution and pharmacokinetics. Moreover, APA can induce allergic responses, ranging from mild hypersensitivity to severe anaphylaxis, necessitating prompt medical intervention and discontinuation of PEGylated therapy.

Unfortunately, clinical interventions to specifically mitigate allergic reactions to PEGylated drugs without broad immunosuppression are currently lacking, highlighting the need for targeted strategies aimed at modulating the immune response against PEG while preserving the therapeutic benefits of PEGylation.

In a study conducted by Samuel K. Lai and his team at the University of North Carolina, Chapel Hill, the efficacy of free PEG in preventing anaphylaxis induced by PEG-specific allergies in swine was examined. Injection of PEG-liposomes (PL) led to anaphylactoid shock (pseudoanaphylaxis) within 1–3 minutes in both naïve and PL-sensitized swine. Conversely, repeated injections of free PEG alone did not trigger allergic responses. Moreover, administering free PEG effectively suppressed allergic reactions to PL, even in previously sensitized swine. These findings strongly advocate for further exploration of free PEG as a means to mitigate APA and allergic reactions to PEGylated therapies.

The author's prior research has shown that administering high molecular weight-free PEG can safely and effectively suppress the induction of APA in mice and restore the prolonged circulation capability of PEGylated therapeutic agents. The author posits that grafting PEG onto scaffolds (such as proteins or nanoparticles) may heighten the likelihood of B cell receptor cross-linking, substantially enhancing the hapten effect and thereby generating stronger immunogenicity compared to the use of free PEG alone. Conversely, the presence of less immunogenic-free PEG not only competitively inhibits APA binding to PEGylated drugs but also reduces immune stimulation. Studies have also demonstrated that weekly repeated administration of free PEG in mice does not elevate pre-existing APA levels, and no organ toxicity was observed. These findings prompt further exploration into whether free PEG can serve as an intervention for PEG-specific pseudoallergic reactions. To this end, the author opts to investigate using the swine model for complement activation-related pseudoallergy (CARPA), which exhibits sensitivity to allergic reactions 1000 times greater than rodent models and has previously been utilized to study PEG-specific cardiac allergic reactions (Figure 1).

Swine Model For CARPA

Figure 1. Swine Model For CARPA [1]

The study found that free PEG had unexpectedly effective results in alleviating allergic reactions to PL in both non-PL sensitized and PL-sensitized swine. Similarly, despite the evident sensitivity of the model to PEG, repeated administration of free PEG remained remarkably safe, showing no apparent kidney, liver, or heart toxicity, no induction of increased APA levels, no induction of any detectable hypersensitivity reactions, and effectively blocked PL-induced allergic reactions (Figure 2). These findings, combined with earlier work, demonstrate that free PEG can also reduce APA induction and restore the prolonged circulation capability of PEGylated drugs in APA-induced animal models, supporting further investigation of free PEG as an intervention to restore the safe and effective use of selectively PEGylated drugs.

Evaluate the effectiveness of PEG intervention against allergic reactions by monitoring hemodynamic changes.

Figure 2. Evaluate the effectiveness of PEG intervention against allergic reactions by monitoring hemodynamic changes. [1]

Conclusion

The study sheds light on the promising potential of free PEG as an intervention to mitigate allergic reactions induced by PEGylated therapies. Further research in this area holds significant promise for improving patient outcomes and advancing the field of drug delivery and therapeutics.

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References:
[1] Free PEG Suppresses Anaphylaxis to PEGylated Nanomedicine in Swine, Limei Shen, Zhongbo Li, Alice Ma, Carlos Cruz-Teran, Anne Talkington, Steven T. Shipley, and Samuel K. Lai, ACS Nano 2024 18 (12), 8733-8744, DOI: 10.1021/acsnano.3c11165

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