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Therapeutic protein aggregation: mechanisms, design, and control
Open accessAbstract
Although it is well known that proteins are only marginally stable in their folded states, it is often less well appreciated that most proteins are inherently aggregation-prone in their unfolded or partially unfolded states, and the resulting aggregates can be extremely stable and long-lived. For therapeutic proteins, aggregates are a significant risk factor for deleterious immune responses in patients, and can form via a variety of mechanisms. Controlling aggregation using a mechanistic approach may allow improved design of therapeutic protein stability, as a complement to existing design strategies that target desired protein structures and function. Recent results highlight the importance of balancing protein environment with the inherent aggregation propensities of polypeptide chains.
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“Aggregates of capsids, as the third potential CQA, represent another product-related impurity with detrimental impact on safety and long-term stability of the vector product, as even trace amounts (e.g., <1%) provide nucleation sites for further aggregation.28,44,45”
From Analytical methods for process and product characterization of recombinant adeno-associated virus-based gene therapies (2021) · cites this paper as [45]
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Metadata
- Authors
- Roberts, C. J.
- Affiliations
- University of Delaware (US)
- Corresponding author
- Roberts, Christopher J.
- Venue
- Trends in Biotechnology
- Publisher
- Elsevier BV
- Published
- 2014-07
- Volume
- 32
- Issue
- 7
- Pages
- 372-380
- ISSN
- 0167-7799 (ISSN-L)
- PMC
- PMC4146573
- OpenAlex
- W1972260684
- Cited by
- 455
- References
- 102
- Citations by year
- 2026: 46 · 2025: 35 · 2024: 39 · 2023: 41 · 2022: 38 · 2021: 48 · 2020: 53 · 2019: 58 · 2018: 46 · 2017: 26 · 2016: 16 · 2015: 7 · 2014: 2
- FWCI
- 1.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Trends in biotechnology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Science Foundation
- Foundation for the National Institutes of Health
- National Institute of Biomedical Imaging and Bioengineering (R01EB006006)
- National Center for Research Resources (P20RR015588)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- protein stability, aggregation-prone proteins, partially unfolded state, aggregation control, protein design, protein environment
- MeSH terms
- Biopharmaceutics, Biotechnology, Humans, Models, Molecular, Protein Conformation, Proteins, Protein Folding, Protein Stability, Protein Aggregates
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