Abstract
Polyethylene glycol (PEG) is a polymer routinely used to modify biologics and nanoparticles to prolong blood circulation and reduce immunogenicity of the underlying therapeutic. However, several PEGylated therapeutics induce the development of anti-PEG antibodies (APA), leading to reduced efficacy and increased adverse events. Given the highly flexible structure of PEG, how APA specifically bind PEG remains poorly understood. Here, we report a crystal structure illustrating the structural properties and conformation of the APA 6-3 Fab bound to the backbone of PEG. The structure reveals an open ring-like sub-structure in the Fab paratope, whereby PEG backbone is captured and then stabilized via Van der Waals interactions along the interior and exterior of the ring paratope surface. Our finding illustrates a strategy by which antibodies can bind highly flexible repeated structures that lack fixed conformations, such as polymers. This also substantially advances our understanding of the humoral immune response generated against PEG.
Highlights
Polyethylene glycol (PEG) is a polymer routinely used to modify biologics and nanoparticles to prolong blood circulation and reduce immunogenicity of the underlying therapeutic
20 PEGylated systems have been approved by the United States Food and Drug Administration (US FDA), and more than a dozen others are currently in clinical trials[7]
anti-PEG antibodies (APA) is directly responsible for the loss of efficacy in nearly half of the patients receiving either PEGasparaginase and PEG-uricase[10,11], as well as the early termination of a number of clinical trials due to APA-triggered adverse events[12,13,14]
Summary
Polyethylene glycol (PEG) is a polymer routinely used to modify biologics and nanoparticles to prolong blood circulation and reduce immunogenicity of the underlying therapeutic. PEG chains create a stable hydration layer through hydrogen bonding with nearby water molecules[1,2] These physicochemical properties increase drug solubility and stability[3], reduce renal filtration[4], and enable PEGylated surfaces to effectively resist nonspecific protein adsorption[4,5], including by opsonins that drive rapid clearance from the systemic circulation. APA is directly responsible for the loss of efficacy in nearly half of the patients receiving either PEGasparaginase and PEG-uricase[10,11], as well as the early termination of a number of clinical trials due to APA-triggered adverse events[12,13,14] This came as a surprise to many in the field; due to PEG’s highly flexible nature and ability to resist protein adsorption, PEG was long assumed by most to be nonimmunogenic[15,16]. Recent clinical studies have started assessing induction of APA, and the FDA requires specific monitoring of APA responses in clinical studies[22]
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