![]() The notion that the frequency of pre-existing anti-PEG antibodies is increasing over time is probably due to a shift to more sensitive assays. Differences in assay cut-off criteria also impact positive frequencies since many donors have relatively low levels of pre-existing anti-PEG antibodies in their plasma. Direct binding assays using beads or ELISA plates coated with PEG derivatives provide high sensitivities, whereas bridging assays underestimate the presence of anti-PEG IgG antibodies. Differences in assay formats can explain much of the differences in the reported values. (39,40) Subsequent studies verified the presence of pre-existing anti-PEG antibodies, but a wide range of positive frequencies have been reported ( Table 4). Early studies using hemagglutination of PEG-modified red blood cells found between 0.2% and 25% of normal donors had antibodies specific to PEG in their plasma. Many people who have never taken pegylated medicines have anti-PEG antibodies in their circulation. We survey the literature as well as draw from personal experience over the past 20 years on creating anti-PEG monoclonal antibodies, (17) developing anti-PEG antibody assays, (18−20) assaying and discovering genetic markers for anti-PEG antibodies, (21,22) investigating the effects of anti-PEG antibodies on pegylated medicines, (17,23−25) and creating recombinant anti-PEG receptors and targeting molecules (26−34) to provide a framework to understand what makes a pegylated drugs immunogenic, how anti-PEG antibodies affect the efficacy and safety of pegylated medicines, and some experience with how anti-PEG antibodies behave in practice. (10,14−16) In the present review, we aim to clear up some misconceptions about PEG immunogenicity, realistically assess the impact of anti-PEG antibodies on pegylated medicines, and describe the specificity and binding behavior of anti-PEG antibodies. Several excellent reviews cover PEG chemistry, (11,12) assay of pegylated compounds, (13) and immunogenicity of pegylated medicines. ![]() A more realistic illustration of common formats of pegylated therapeutics is shown in Figure 1. Although PEG is typically depicted as a small linear molecule with dimensions on the order of a small protein, the actual contour lengths of commonly used PEG molecules range from 12.5 nm for PEG 2000 to 253 nm for linear PEG 40,000 ( Table 3). Hundreds or even thousands of mPEG 2000–lipid molecules are incorporated in liposomes and nanoparticles to reduce uptake by resident macrophages in the liver. On the other hand, multiple mPEG 5000 molecules are attached to the surface of foreign enzymes to increase in vivo stability and block binding of anti-enzyme antibodies. A single linear or branched methoxy PEG (mPEG) molecule ranging in size from 12 to 60 kDa is attached to peptides, nucleotides, and small recombinant proteins to increase their hydrodynamic diameter, thereby reducing uptake by the kidney. ![]() The size and number of PEG molecules attached to a compound can be varied depending on the desired purpose. The widespread use of SARS-CoV-2 RNA vaccines that incorporate PEG in lipid nanoparticles make understanding possible effects of anti-PEG antibodies on pegylated medicines even more critical. Experimental studies of anti-PEG antibody binding to different forms, sizes, and immobilization states of PEG are also provided. ![]() Analysis of published studies reveals rules for predicting accelerated blood clearance of pegylated medicine and therapeutic liposomes. Here we provide a framework to better understand PEG immunogenicity and how antibodies against PEG affect pegylated drug and nanoparticles. Some naïve individuals have pre-existing antibodies that can bind to PEG, and some PEG-modified compounds induce additional antibodies against PEG, which can adversely impact drug efficacy and safety. Polyethylene glycol (PEG) is a flexible, hydrophilic simple polymer that is physically attached to peptides, proteins, nucleic acids, liposomes, and nanoparticles to reduce renal clearance, block antibody and protein binding sites, and enhance the half-life and efficacy of therapeutic molecules. ![]()
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