Huckaby Justin T, Jacobs Tim M, Li Zhongbo, Perna Robert J, Wang Anting, Nicely Nathan I, Lai Samuel K
UNC/NCSU Joint Department of Biomedical Engineering, School of Medicine, University of North Carolina-Chapel Hill, Chapel Hill, NC, 27599, USA.
Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina-Chapel Hill, Chapel Hill, NC, 27599, USA.
Commun Chem. 2020 Sep 8;3(1):124. doi: 10.1038/s42004-020-00369-y.
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.
聚乙二醇（PEG）是一种常用于修饰生物制剂和纳米颗粒的聚合物，目的是延长血液循环时间并降低潜在治疗药物的免疫原性。然而，几种聚乙二醇化治疗药物会诱导抗聚乙二醇抗体（APA）的产生，导致疗效降低和不良事件增加。鉴于聚乙二醇高度灵活的结构，APA如何特异性结合聚乙二醇仍知之甚少。在此，我们报告了一种晶体结构，展示了与聚乙二醇主链结合的APA 6-3 Fab的结构特性和构象。该结构揭示了Fab互补决定区中一个开放的环状子结构，通过该结构，聚乙二醇主链被捕获，然后沿着环状互补决定区表面的内部和外部通过范德华相互作用得以稳定。我们的发现阐明了一种抗体能够结合缺乏固定构象的高度灵活的重复结构（如聚合物）的策略。这也极大地推进了我们对针对聚乙二醇产生的体液免疫反应的理解。
