Antigenicity Extension: A Novel Concept Explained by the Immunogenicity of PEG

Poly(ethylene glycol)-related immune responses have been a great concern regarding mRNA vaccination for the SARS-CoV2 virus, because PEG-lipids are an essential component for the lipid nanoparticles of mRNA vaccines. Meanwhile, no research has elucidated the mechanisms underlying hapten-like PEG-related immunogenicity. For the current study, we uncovered a process by which haptenic PEGs transition into immunogenic PEG-conjugates by means of ELISA and microfluidic diffusional sizing (MDS). We named the process "antigenicity extension." Although PEGs exhibit specific interactions with anti-PEG antibodies, the specific interactions of PEGs with anti-PEG Abs are relatively weak. By contrast, we revealed that exposure of non-PEG moieties to the PEG-specific paratope greatly and directly contributes to PEG's stable bindings through the specific interaction between PEG and anti-PEG antibodies by MDS measurements. This indicates that non-PEG moieties are directly involved in the molecular recognitions between PEG and the PEG-specific paratope to improve the affinity. Occurring antigenicity extension makes PEG-conjugates immunogenic by strengthening the affinity for PEG-specific paratopes. Thus, additional interactions at non-PEG moieties with the PEG-specific paratope are key to the transition of haptenic PEGs into immunogenic PEGs. To this extent, antigenicity extension is a commonly occurring phenomenon in the hapten-to-immunogen transitions occurring in both antigen-antibody interactions and ligand-receptor interactions.