Structural determination of an antibody that specifically recognizes polyethylene glycol with a terminal methoxy group

Minh Tram T. Nguyen, Yu Chien Shih, Meng Hsuan Lin, Steve R. Roffler, Chiao Yu Hsiao, Tian Lu Cheng, Wen Wei Lin, En Chi Lin, Yuh Jyh Jong, Chin Yuan Chang*, Yu Cheng Su

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Covalent attachment of methoxy poly(ethylene) glycol (mPEG) to therapeutic molecules is widely employed to improve their systemic circulation time and therapeutic efficacy. mPEG, however, can induce anti-PEG antibodies that negatively impact drug therapeutic effects. However, the underlying mechanism for specific binding of antibodies to mPEG remains unclear. Here, we determined the first co-crystal structure of the humanized 15-2b anti-mPEG antibody in complex with mPEG, which possesses a deep pocket in the antigen-binding site to accommodate the mPEG polymer. Structural and mutational analyses revealed that mPEG binds to h15-2b via Van der Waals and hydrogen bond interactions, whereas the methoxy group of mPEG is stabilized in a hydrophobic environment between the VH:VL interface. Replacement of the heavy chain hydrophobic V37 residue with a neutral polar serine or threonine residue offers additional hydrogen bond interactions with methoxyl and hydroxyl groups, resulting in cross-reactivity to mPEG and OH-PEG. Our findings provide insights into understanding mPEG-binding specificity and antigenicity of anti-mPEG antibodies.

Original languageEnglish
Article number88
JournalCommunications Chemistry
Volume5
Issue number1
DOIs
StatePublished - Dec 2022

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