Professor KAKUTA, Assistant Professor TERAMOTO, and their research group (Laboratory of Biophysical Chemistry) have elucidated the mechanism of antibody production against polyethylene glycol through collaborative research

Expectations for the Design of Polymers that Do Not Induce Antibody Production

Point

• For many years, polyethylene glycol (PEG) was believed to be "non-immunogenic," but antibodies are indeed produced against PEG, leading to reduced drug efficacy.
• The study elucidated the process by which PEG is recognized by B cell receptors, which are precursors to antibodies, leading to antibody production, as well as the process by which antibodies enhance their affinity for PEG.
• These findings are expected to enable the development of polymers that truly do not induce antibody production.

Abstract

Polyethylene glycol (PEG) has long been recognized as a polymer that does not induce antibody production. This is attributed to its high flexibility and the absence of distinctive functional groups, making it less likely to interact with proteins in the bloodstream. Consequently, PEG has been used to modify pharmaceuticals to enhance their stability in the blood. By leveraging its property of minimal interaction with blood proteins, PEG has been employed to improve the stability of drugs administered to humans. However, recent findings have revealed that antibodies against PEG are generated in the human body, compromising the efficacy of PEGylated drugs. There is a pressing need to develop polymers that genuinely do not induce antibody production, but there are currently no guidelines for designing such polymers.

A research group led by Mr. MORI Takahiro, a first-year doctoral student at the Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, along with Assistant Professor TERAMOTO Takamasa and Professor KAKUTA Yoshimitsu from the Faculty of Agriculture, conducted a collaborative study with Associate Professor MORI Takeshi from the Faculty of Engineering at the same university, Professor MAENAKA Katsumi and Professor KUROKI Kimiko from the Graduate School of Pharmaceutical Sciences, Hokkaido University, and Professor KITAO Akio from the School of Life Science and Technology, Tokyo University of Science. The aim of the study was to establish guidelines for designing polymers that do not induce antibody production by elucidating the mechanism by which the immune system produces antibodies against PEG. As expected, the interaction between B cell receptors, which are precursors to antibodies, and PEG was very weak. However, due to the repetitive sequence of PEG's simple structure, B cell receptors can capture PEG for a sufficient amount of time by allowing the sliding of PEG chains, leading to B cell activation and subsequent antibody production. Additionally, while B cell receptors generally enhance their affinity for targets through repeated mutations, it was found that PEG, being an extremely thin polymer chain, produces antibodies that strongly capture PEG through a simple mutation strategy that creates a tunnel structure.

This study elucidated the mechanism by which PEG is recognized by B cell receptors, leading to antibody production, thereby providing guidelines for the development of polymers that do not induce antibody production. It is expected that these guidelines will be utilized in the future to develop polymers that genuinely do not induce antibody production.

This research was published in the official journal of the Controlled Release Society, Journal of Controlled Release, on February 10, 2025 (Japan time).

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Paper Information

Journal: Journal of Controlled Release
Title: The strategy used by naïve anti-PEG antibodies to capture flexible and featureless PEG chains
Authors: Yiwei Liu#, Takahiro Mori#, Yusei Ito#, Kimiko Kuroki#, Seiichiro Hayashi, Daisuke Kohda, Taro Shimizu, Tatsuhiro Ishida, Steve R. Roffler, Mika K. Kaneko, Yukinari Kato, Takao Arimori, Takamasa Teramoto, Kazuhiro Takemura, Kenta Ishibashi, Yoshiki Katayama, Katsumi Maenaka,* Yoshimitsu Kakuta,* Akio Kitao,* Takeshi Mori* # contributed equally, * Corresponding authors
DOI：10.1016/j.jconrel.2025.02.001

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KAKUTA Yoshimitsu, Professor