Subvisible Particles Derived by Dropping Stress Enhance Anti-PEG Antibody Production and Clearance of PEGylated Proteins in Mice

Bioconjugation with polyethylene glycol (PEG) is important for protein drug development as it has improved biological stability. In contrast, proteins including PEGylated ones are susceptible to physicochemical stresses. Particularly, protein drugs in solution may form aggregates or subvisible parti...

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Bibliographic Details
Published in:Journal of pharmaceutical sciences 2022-05, Vol.111 (5), p.1363-1369
Main Authors: Nakajima, Takaki, Nagano, Kazuya, Fukuda, Yuka, Ishima, Yu, Shibata, Hiroko, Isaka, Ryo, Zhang, Tian-qi, Haga, Yuya, Higashisaka, Kazuma, Tsujino, Hirofumi, Ishida, Tatsuhiro, Ishii-Watabe, Akiko, Tsutsumi, Yasuo
Format: Article
Language:English
Subjects:
Animals
Antibody
Antibody Formation
Clearance
Mice
Ovalbumin
PEGylation
Pharmaceutical Preparations
Physical stability
Polyethylene Glycols - chemistry
Protein aggregation
Proteins
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Summary:Bioconjugation with polyethylene glycol (PEG) is important for protein drug development as it has improved biological stability. In contrast, proteins including PEGylated ones are susceptible to physicochemical stresses. Particularly, protein drugs in solution may form aggregates or subvisible particles if they are exposed to dropping stress during transportation. However, many PEGylation studies have focused on its usefulness, such as the extension of half-life in blood, and changes in the physical properties or biological responses of PEGylated proteins under dropping stress remain unexplored. Here, we prepared four PEGylated ovalbumin (PEG-OVA) molecules conjugated with different lengths (5 or 20 kDa) and numbers (large [L] or small [S]) of PEG, analyzed the formation of subvisible particles under dropping stress, and examined their impact on antibody production and clearance. Under dropping stress, the aggregated particle concentration of 20 kDa PEG-OVA (S) and (L) solutions was approximately 3-fold that of the OVA solution. Moreover, administration of 20 kDa PEG-OVA with dropping stress induced anti-PEG antibody production and clearance of PEG-OVA. As a mechanism, dropping stress could enhance the uptake of 20 kDa PEG-OVA (L) by macrophages. These findings could provide insights into proper transportation conditions to ensure the quality of PEGylated protein drugs.
ISSN:0022-3549
1520-6017
DOI:10.1016/j.xphs.2022.01.023