Immunogenicity of Polyethylene Glycol Conjugates

Polyethylene glycol (PEG) conjugates have been widely employed to enhance solubility, prolong circulation time and reduce the intrinsic immunogenicity of therapeutic proteins, peptides, nucleic acids and nanocarriers. Despite an initial assumption of PEG inertness, clinical experience and preclinical studies have revealed that exposure to PEGylated materials can elicit both pre-existing and treatment-induced anti-PEG antibodies. These immune responses manifest as accelerated blood clearance (ABC) upon repeat dosing, reduced therapeutic efficacy, hypersensitivity reactions and complement activation-related pseudoallergy (CARPA). The production of anti-PEG immunoglobulins—particularly IgM—is driven by a T-cell-independent mechanism and can involve high-affinity recognition of repeated ethylene glycol units. Structural insights have uncovered the molecular basis of antibody binding to flexible PEG chains, while investigations across diverse applications—from tissue engineering scaffolds to lipid nanoparticles—have underscored the clinical consequence of PEG immunogenicity. Emerging strategies to mitigate these responses include optimisation of PEG architecture, development of alternative stealth polymers and immunomodulatory regimens to preserve therapeutic performance.

Research from Nature Portfolio

Recent studies have examined the impact of anti-PEG immunity on tissue repair, revealing that mice pre-sensitised to PEG exhibit enhanced bone formation when treated with PEG-based hydrogels, yet display abnormal bone porosity and heightened immune cell infiltration at defect sites. These findings highlight sex-dependent variations in the immune response and underscore the influence of anti-PEG antibodies on regenerative outcomes. Complementing functional studies, structural investigations have elucidated how anti-PEG antibodies engage polymer backbones. A crystal structure of a PEG-specific Fab fragment demonstrates an open-ring paratope that captures the flexible PEG chain via van der Waals contacts, providing a molecular rationale for robust antibody binding despite the polymer’s conformational heterogeneity.

Immunogenicity of Polyethylene Glycol Conjugates publication trend

The graph below shows the total number of articles in immunogenicity of polyethylene glycol conjugates across all publications each year (not limited to Nature Index journals).

Technical terms

PEGylation: Covalent attachment of polyethylene glycol chains to biomolecules or nanocarriers to improve pharmacokinetics.

Anti-PEG antibodies: Immunoglobulins generated against PEG polymers that can neutralise or clear PEGylated therapeutics.

Accelerated blood clearance (ABC): Rapid removal of PEGylated agents from circulation upon repeated administration due to anti-PEG antibodies.

Complement activation-related pseudoallergy (CARPA): Hypersensitivity reaction mediated by complement activation leading to infusion-related symptoms.

Lipid nanoparticle (LNP): A vesicular delivery system composed of lipids, often incorporating PEG-lipid conjugates for stability and circulation.

Paratope: The antigen-binding site of an antibody that recognises and binds specific epitopes on an antigen.

References

1. PEGylated therapeutics in the clinic. Bioengineering & Translational Medicine (2023).
2. Induced and pre-existing anti-polyethylene glycol antibody in a trial of every 3-week dosing of pegloticase for refractory gout, including in organ transplant recipients. Arthritis Research & Therapy (2014).
3. Impact of PEG sensitization on the efficacy of PEG hydrogel-mediated tissue engineering. Nature Communications (2024).
4. Structure of an anti-PEG antibody reveals an open ring that captures highly flexible PEG polymers. Communications Chemistry (2020).
5. The Importance of Poly(ethylene glycol) Alternatives for Overcoming PEG Immunogenicity in Drug Delivery and Bioconjugation. Polymers (2020).
6. Anti-PEG antibodies compromise the integrity of PEGylated lipid-based nanoparticles via complement. Journal of Controlled Release (2021).
7. PEGylated Lipid Nanoparticle Formulations: Immunological Safety and Efficiency Perspective. Bioconjugate Chemistry (2023).