ArticlePharmaceutical research2016
Monoclonal Antibodies Follow Distinct Aggregation Pathways During Production-Relevant Acidic Incubation and Neutralization.
Article in Pharmaceutical research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 60 citations in OpenAlex.
- Article
- Comparative Evaluation of Carbohydrate, Amino Acid, and Ionic Liquid Excipients for Flavivirus Vaccine Stabilization.ACS omega · 2026Article
- Characterization of Conformational Instability of Monoclonal Antibodies During Chromatographic Purification.International journal of molecular sciences · 2026Review
- Understanding the Role of Polyols and Sugars in Reducing Aggregation in IgGPharmaceuticals (Basel, Switzerland) · 2025Article
- Immobilizing calcium-dependent affinity ligand onto iron oxide nanoparticles for mild magnetic mAb separation.Biotechnology reports (Amsterdam, Netherlands) · 2025Article
- Investigation on environmental factors contributing to bispecific antibody stability and the reversal of self-associated aggregates.Bioresources and bioprocessing · 2024Article
- Role of Domain-Domain Interactions on the Self-Association and Physical Stability of Monoclonal Antibodies: Effect of pH and Salt.The journal of physical chemistry. B · 2023Article
- Optimization of Radiolabeling of a [Cancers · 2023Article
- Getting Smaller by Denaturation: Acid-Induced Compaction of Antibodies.The journal of physical chemistry letters · 2023Article
- A fully human connective tissue growth factor blocking monoclonal antibody ameliorates experimental rheumatoid arthritis through inhibiting angiogenesis.BMC biotechnology · 2023Article
- Decreasing hydrophobicity or shielding hydrophobic areas of CH2 attenuates low pH-induced IgG4 aggregation.Frontiers in bioengineering and biotechnology · 2023Article
- Protein Aggregation in the Pathogenesis of Ischemic Stroke.Cellular and molecular neurobiology · 2021Review
- An experimental approach probing the conformational transitions and energy landscape of antibodies: a glimmer of hope for reviving lost therapeutic candidates using ionic liquid.Chemical science · 2021Article
- Protein aggregation and immunogenicity of biotherapeutics.International journal of pharmaceutics · 2020Review
- Modelling of pH-dependence to develop a strategy for stabilising mAbs at acidic steps in production.Computational and structural biotechnology journal · 2020Review
- Article
- LmAbs · 2019Article
- Evolving SAXS versatility: solution X-ray scattering for macromolecular architecture, functional landscapes, and integrative structural biology.Current opinion in structural biology · 2019Review
- Solution-Based Determination of Dissociation Constants for the Binding of Aβ42 to Antibodies.ChemistryOpen · 2019Article
- Solution pH jump during antibody and Fc-fusion protein thaw leads to increased aggregation.Journal of pharmaceutical analysis · 2018Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeAggregation aspects of therapeutic monoclonal antibodies (mAbs) are of common concern to the pharmaceutical industry. Low pH treatment is applied during affinity purification and to inactivate endogenous retroviruses, directing interest to the mechanisms of acid-induced antibody aggregation.
methodsWe characterized the oligomerization kinetics at pH 3.3, as well as the reversibility upon neutralization, of three model mAbs with identical variable regions, representative of IgG1, IgG2 and IgG4 respectively. We applied size-exclusion high performance liquid chromatography and orthogonal analytical methods, including small-angle X-ray scattering and dynamic light scattering and supplemented the experimental data with crystal structure-based spatial aggregation propensity (SAP) calculations.
resultsWe revealed distinct solution behaviors between the three mAb models: At acidic pH IgG1 retained monomeric, whereas IgG2 and IgG4 exhibited two-phase oligomerization processes. After neutralization, IgG2 oligomers partially reverted to the monomeric state, while on the contrary, IgG4 oligomers tended to aggregate. Subclass-specific aggregation-prone motifs on the Fc fragments were identified, which may lead to two distinct pathways of reversible and irreversible aggregation, respectively.
conclusionsWe conclude that subtle variations in mAb sequence greatly affect responses towards low-pH incubation and subsequent neutralization, and demonstrate how orthogonal biophysical methods distinguish between reversible and irreversible mAb aggregation pathways at early stages of acidic treatment.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.