Therapeutic protein aggregation: mechanisms, design, and control

Roberts, Christopher J.

doi:10.1016/j.tibtech.2014.05.005

Cited by 455Protein purification and stabilityProtein Structure and DynamicsHeat shock proteins research

Therapeutic protein aggregation: mechanisms, design, and control

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Roberts, Christopher J.·2014·Trends in Biotechnology

DOI 10.1016/j.tibtech.2014.05.005PMC PMC4146573

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Abstract

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 represent another product-related impurity with detrimental impact on safety and long-term stability of the vector product, as even trace amounts below 1% provide nucleation sites for further aggregation.
“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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Relating particle formation to salt‐ and pH‐dependent phase separation of non‐native aggregates of alpha‐chymotrypsinogen a
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Relating Protein–Protein Interactions and Aggregation Rates From Low to High Concentrations
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Optimizing the Bioavailability of Subcutaneously Administered Biotherapeutics Through Mechanochemical Drivers
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Small molecules targeting protein–protein interactions for cancer therapy
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Stress Factors in mAb Drug Substance Production Processes: Critical Assessment of Impact on Product Quality and Control Strategy
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Non-polyphenolic natural inhibitors of amyloid aggregation
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Aggregation and Its Influence on the Immunomodulatory Activity of Synthetic Innate Defense Regulator Peptides
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Protein-Polydimethylsiloxane Particles in Liquid Vial Monoclonal Antibody Formulations Containing Poloxamer 188
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Protein aggregation and mitigation strategy in low pH viral inactivation for monoclonal antibody purification
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pH-Dependent Aggregation in Intrinsically Disordered Proteins Is Determined by Charge and Lipophilicity
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Engaging with Raman Spectroscopy to Investigate Antibody Aggregation
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Understanding mAb aggregation during low pH viral inactivation and subsequent neutralization
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Assessment of Structural and Functional Comparability of Biosimilar Products: Trastuzumab as a Case Study
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A Review on the Stability Challenges of Advanced Biologic Therapeutics
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Injectables and Depots to Prolong Drug Action of Proteins and Peptides
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Bioengineering of nano metal-organic frameworks for cancer immunotherapy
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Unusual Aggregates Formed by the Self-Assembly of Proline, Hydroxyproline, and Lysine
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Pulsed Electric Field-Induced Modification of Proteins: A Comprehensive Review
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Characterization of mAb dimers reveals predominant dimer forms common in therapeutic mAbs
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Evaluation of in vitro Assays to Assess the Modulation of Dendritic Cells Functions by Therapeutic Antibodies and Aggregates
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Influence and effect of osmolytes in biopharmaceutical formulations
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Accelerating therapeutic protein design with computational approaches toward the clinical stage
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Isothermal chemical denaturation as a complementary tool to overcome limitations of thermal differential scanning fluorimetry in predicting physical stability of protein formulations
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Coaggregation of κ‐Casein and β‐Lactoglobulin Produces Morphologically Distinct Amyloid Fibrils
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Preferential interactions of trehalose, L-arginine.HCl and sodium chloride with therapeutically relevant IgG1 monoclonal antibodies
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Characterisation of protein aggregation with the Smoluchowski coagulation approach for use in biopharmaceuticals
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CPAD 2.0: a repository of curated experimental data on aggregating proteins and peptides
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Authors: Roberts, C. J.
Affiliations: University of Delaware (US)
Corresponding author: Roberts, Christopher J.
ORCID: 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)
DOI: 10.1016/j.tibtech.2014.05.005
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
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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Therapeutic protein aggregation: mechanisms, design, and control

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