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A Manufacturing Strategy Utilizing a Continuous-Mode Reactor toward Homogeneous PEGylated Bioconjugate Production
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Abstract
Protein PEGylation is a traditional bioconjugation technology that enhances the therapeutic efficacy and in vivo half-life of proteins by the formation of covalent bonds with highly activated ester group linked polyethylene glycol (PEG). However, the high reactivity of these reagents induces a random reaction with lysine residues on the protein surface, resulting in a heterogeneous mixture of PEGylated proteins. Moreover, the traditional batch-mode reaction has risks relating to scalability and aggregation. To overcome these risks of traditional batch-mode PEGylation, a manufacturing strategy utilizing structural analysis and a continuous-flow-mode reaction was examined. A solvent exposure analysis revealed the most reactive lysine of a protein, and the continuous-flow mode modified this lysine to achieve the mono-PEGylation of two different proteins within 2 seconds. This ultrarapid modification reaction can be applied to the gram-scale manufacturing of PEGylated bioconjugates without generating aggregates. A similar trend of the exposure level of protein lysine and mono-selectivity performed by continuous-flow PEGylation was observed, which indicated that this manufacturing strategy has the potential to be applied to the production of a wide variety of bioconjugates.
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Metadata
- Authors
- Nakahara, Y., Endo, Y., Matsuda, Y., Nagaki, A., Takahashi, K., Kawaguchi, T., & Kato, K.
- Affiliations
- Hokkaido University (JP)
- Ajinomoto Co., Inc.
- Corresponding author
- Nakahara, Yuichi
- Matsuda, Yutaka
- Venue
- Synthesis
- Publisher
- Georg Thieme Verlag KG
- Published
- 2023-04-19
- Volume
- 56
- Issue
- 04
- Pages
- 597-602
- ISSN
- 0039-7881 (ISSN-L)
- 1437-210X
- OpenAlex
- W4366365475
- Cited by
- 5
- References
- 36
- Citations by year
- 2024: 3 · 2023: 2
- FWCI
- 0.44
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Synthesis (publishedVersion)
- ChemRxiv (acceptedVersion, cc-by-nc-nd)
- Funders
- Japan Society for the Promotion of Science (23K21114, 20KK0121)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
- Physical Sciences › Chemical Engineering › Fluid Flow and Transfer Processes › Innovative Microfluidic and Catalytic Techniques Innovation
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Keywords
- protein PEGylation, continuous flow reactor, lysine reactivity, protein aggregation, therapeutic proteins
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