Journal
COMMUNICATIONS CHEMISTRY
Volume 3, Issue 1, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s42004-020-00369-y
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Funding
- National Science Foundation Graduate Research Fellowship Program [DGE-1650116]
- NIDCR of the National Institutes of Health [F32DE026683]
- National Science Foundation [DMR-1810168]
- David and Lucile Packard Foundation [2013-39274]
- National Institutes of Health [R01 HL141934]
- Eshelman Institute for Innovation
- Eshelman School of Pharmacy
- Lineberger Comprehensive Cancer Center at the University of North Carolina-Chapel Hill
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]
- National Cancer Institute of the National Institutes of Health [P30CA016086]
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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. 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.
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