The curious case of anti-PEG antibodies

The components of nanoparticles can trigger the production of antibodies in patients and in model mammals such as mice. We focus on antibodies made against poly-ethylene-glycol (PEG), the most common polymer component of nanoparticles. Humans are frequently exposed to free PEG in processed foods, cosmetics, and over-the-counter drugs. These PEG-containing products trigger varying amounts of anti-PEG antibody production in consumers. In addition to consumer product usage, human exposure to PEG was greatly increased when millions were vaccinated with SARS-CoV-2 vaccine nanoparticles, which contained a PEGylated lipid. Thus, the chances of humans having anti-PEG antibodies is high and the ramifications of the presence of such antibodies must be addressed. The resulting antibodies could bind and negatively affect PEG-containing nanoparticles that are subsequently administered to patients. For example, a patient administered the PEGylated liposome DOXIL could have "pre-existing" anti-PEG antibodies from cosmetic products. The anti-PEG antibodies could bind the PEG component of DOXIL and take it to professional phagocytes. This would greatly reduce its ability to localize to cancer cells. In this review, we discuss the possible mechanisms by which PEG could generate immunoglobulin M (IgM) and how PEG could trigger a stronger and more mechanistically complex immunoglobulin G (IgG) response. We assess PEG-antibody binding. We discuss the various mechanisms by which PEG-containing nanoparticles may bind immune cells. We address gaps in our knowledge of the mechanisms of anti-PEG antibody formation. We discuss strategies for determining whether PEG triggers antibody production and how strong the antibody will interact with the PEG.