ArticleProtein engineering, design & selection : PEDS2019
Electrostatic interactions modulate the differential aggregation propensities of IgG1 and IgG4P antibodies and inform charged residue substitutions for improved developability.
Article in Protein engineering, design & selection : PEDS, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- Electrostatic Interactions Guide the Detrimental Effect of Oleic Acid on Monoclonal Antibody Stability.Pharmaceutical research · 2026Article
- Predicting Agitation Stability of Monoclonal Antibodies during Developability Assessment.Molecular pharmaceutics · 2026Article
- Current Advances and Challenges in CAR-T Therapy for Hematological and Solid Tumors.ImmunoTargets and therapy · 2025Review
- Optimization of therapeutic antibodies for reduced self-association and non-specific binding via interpretable machine learning.Nature biomedical engineering · 2024Article
- Tau-targeting therapies for Alzheimer disease: current status and future directions.Nature reviews. Neurology · 2023Review
- Tuning charge density of chimeric antigen receptor optimizes tonic signaling and CAR-T cell fitness.Cell research · 2023Article
- An overview of descriptors to capture protein properties - Tools and perspectives in the context of QSAR modeling.Computational and structural biotechnology journal · 2023Review
- Ionic Liquid-Based Strategy for Predicting Protein Aggregation Propensity and Thermodynamic Stability.JACS Au · 2022Article
- Targeting tau only extracellularly is likely to be less efficacious than targeting it both intra- and extracellularly.Seminars in cell & developmental biology · 2022Review
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Authors and funding
11 authors.
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Abstract
Native state aggregation is an important concern in the development of therapeutic antibodies. Enhanced knowledge of mAb native state aggregation mechanisms would permit sequence-based selection and design of therapeutic mAbs with improved developability. We investigated how electrostatic interactions affect the native state aggregation of seven human IgG1 and IgG4P mAb isotype pairs, each pair having identical variable domains that are different for each set of IgG1 and IgG4P constructs. Relative aggregation propensities were determined at pH 7.4, representing physiological conditions, and pH 5.0, representing commonly used storage conditions. Our work indicates that the net charge state of variable domains relative to the net charge state of the constant domains is predominantly responsible for the different native state aggregation behavior of IgG1 and IgG4P mAbs. This observation suggests that the global net charge of a multi domain protein is not a reliable predictor of aggregation propensity. Furthermore, we demonstrate a design strategy in the frameworks of variable domains to reduce the native state aggregation propensity of mAbs identified as being aggregation-prone. Importantly, substitution of specifically identified residues with alternative, human germline residues, to optimize Fv charge, resulted in decreased aggregation potential at pH 5.0 and 7.4, thus increasing developability.
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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.