On the origin of the low immunogenicity and biosafety of a neutral α-helical polypeptide as an alternative to polyethylene glycol

Jialing Sun; Junyi Chen; Yiming Sun; Yingqin Hou; Zhibo Liu; Hua Lu

Bioactive Materials (Feb 2024)

On the origin of the low immunogenicity and biosafety of a neutral α-helical polypeptide as an alternative to polyethylene glycol

Jialing Sun,
Junyi Chen,
Yiming Sun,
Yingqin Hou,
Zhibo Liu,
Hua Lu

Affiliations

Jialing Sun: Beijing National Laboratory for Molecular Sciences, Center for Soft Matter Science and Engineering, Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China
Junyi Chen: Beijing National Laboratory for Molecular Sciences, Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China
Yiming Sun: Beijing National Laboratory for Molecular Sciences, Center for Soft Matter Science and Engineering, Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China
Yingqin Hou: Beijing National Laboratory for Molecular Sciences, Center for Soft Matter Science and Engineering, Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China
Zhibo Liu: Beijing National Laboratory for Molecular Sciences, Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China; Peking University–Tsinghua University Center for Life Sciences, Peking University, Beijing, 100871, China; Corresponding author. Beijing National Laboratory for Molecular Sciences, Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijin, 100871, China.
Hua Lu: Beijing National Laboratory for Molecular Sciences, Center for Soft Matter Science and Engineering, Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China; Corresponding author.

Journal volume & issue: Vol. 32
pp. 333 – 343

Abstract

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Poly(ethylene glycol) (PEG) is a prominent synthetic polymer widely used in biomedicine. Despite its notable success, recent clinical evidence highlights concerns regarding the immunogenicity and adverse effects associated with PEG in PEGylated proteins and lipid nanoparticles. Previous studies have found a neutral helical polypeptide poly(γ-(2-(2-(2-methoxyethoxy)ethoxy)ethyl l-glutamate), namely L-P(EG3Glu), as a potential alternative to PEG, displaying lower immunogenicity. To comprehensively assess the immunogenicity, distribution, degradation, and biosafety of L-P(EG3Glu), herein, we employ assays including enzyme-linked immunosorbent assay, positron emission tomography-computed tomography, and fluorescent resonance energy transfer. Our investigations involve in vivo immune responses, biodistribution, and macrophage activation of interferon (IFN) conjugates tethered with helical L-P(EG3Glu) (L20k-IFN), random-coiled DL-P(EG3Glu) (DL20k-IFN), and PEG (PEG20k-IFN). Key findings encompass: minimal anti-IFN and anti-polymer antibodies elicited by L20k-IFN; length-dependent affinity of PEG to anti-PEG antibodies; accelerated clearance of DL20k-IFN and PEG20k-IFN linked to anti-IFN and anti-polymer IgG; complement activation for DL20k-IFN and PEG20k-IFN but not L20k-IFN; differential clearance with L20k-IFN kidney-based, and DL20k-IFN/PEG20k-IFN accumulation mainly in liver/spleen; enhanced macrophage activation by DL20k-IFN and PEG20k-IFN; L-P(EG3Glu) resistance to proteolysis; and safer repeated administrations of L-P(EG3Glu) in rats. Overall, this study offers comprehensive insights into the lower immunogenicity of L-P(EG3Glu) compared to DL-P(EG3Glu) and PEG, supporting its potential clinical use in protein conjugation and nanomedicines.

Published in Bioactive Materials

ISSN: 2452-199X (Online)
Publisher: KeAi Communications Co., Ltd.
Country of publisher: China
LCC subjects: Technology: Electrical engineering. Electronics. Nuclear engineering: Materials of engineering and construction. Mechanics of materials; Science: Biology (General)
Website: https://www.keaipublishing.com/en/journals/bioactive-materials/

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