Structure of an anti-PEG antibody reveals an open ring that captures highly flexible PEG polymers

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 a...

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Bibliographic Details
Published in:Communications chemistry 2020-09, Vol.3 (1), p.124-124, Article 124
Main Authors: Huckaby, Justin T., Jacobs, Tim M., Li, Zhongbo, Perna, Robert J., Wang, Anting, Nicely, Nathan I., Lai, Samuel K.
Format: Article
Language:English
Subjects:
101/1
631/45/881
631/535/1266
631/92/612
639/301/54/1754
639/925/352/152
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Antibodies
Backbone
Binding
Biocompatibility
Biomedical materials
Blood circulation
Chemistry
Chemistry and Materials Science
Chemistry/Food Science
Crystal structure
Flexible structures
Immune system
Nanoparticles
Polyethylene glycol
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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. 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. Polyethylene glycol (PEG) is a widely used, biocompatible material, but can promote the development of anti-PEG antibodies. Here, crystal structures of an anti-PEG antibody binding fragment bound to PEG are reported and key binding residues are identified by site-directed mutagenesis.
ISSN:2399-3669
2399-3669
DOI:10.1038/s42004-020-00369-y