ArticleProtein science : a publication of the Protein Society2019
A stable engineered human IgG3 antibody with decreased aggregation during antibody expression and low pH stress.
Article in Protein science : a publication of the Protein Society, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed.
- Development of a Diagnostic Autoantibody Assay to a Consensus Motif for the Risk Prediction of Epstein-Barr Virus-Related Multiple Sclerosis.Neurology(R) neuroimmunology & neuroinflammation · 2026Article
- Yeast Display of Single-Chain Fc Fragments with Modulated Binding of Effector Molecules.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Development of a Komagataella phaffii-based expression system for high-activity anti-SARS-CoV-2 neutralizing antibodies.AMB Express · 2025Article
- Review
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- Effects and mechanisms of monoclonal and polyclonal human antibodies in protection of humanized mice from HIV-1 challenge.bioRxiv : the preprint server for biology · 2025Article
- Neutralizing Antibodies vs. Viruses: Interacting Mechanisms and Escape Tactics.Microorganisms · 2025Review
- A case study of a bispecific antibody manufacturability assessment and optimization during discovery stage and its implications.Antibody therapeutics · 2024Article
- The hinge-engineered IgG1-IgG3 hybrid subclass IgGhNature communications · 2024Article
- Regulatory considerations in the design, development and quality of monoclonal antibodies and related products for the diagnosis and treatment of cancer.Frontiers in oncology · 2024Review
- IgG1 versus IgG3: influence of antibody-specificity and allotypic variance on virus neutralization efficacy.Frontiers in immunology · 2024Article
- Reply to Pandey: IgG3 allotypes, modulation of antigen binding by constant domain changes, and therapeutic applications of Fc engineering.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Constant domain polymorphisms influence monoclonal antibody stability and dynamics.Protein science : a publication of the Protein Society · 2023Article
- Engineering the supernatural: monoclonal antibodies for challenging infectious diseases.Current opinion in biotechnology · 2022Review
- Exploring complement-dependent cytotoxicity by rituximab isotypes in 2D and 3D-cultured B-cell lymphoma.BMC cancer · 2022Article
- Potent TRIM21 and complement-dependent intracellular antiviral immunity requires the IgG3 hinge.Science immunology · 2022Article
- Comprehensive Analysis of Nivolumab, A Therapeutic Anti-Pd-1 Monoclonal Antibody: Impact of Handling and Stress.Pharmaceutics · 2022Article
- Building a better antibody through the Fc: advances and challenges in harnessing antibody Fc effector functions for antiviral protection.Human vaccines & immunotherapeutics · 2021Review
- HIV Broadly Neutralizing Antibodies Expressed as IgG3 Preserve Neutralization Potency and Show Improved Fc Effector Function.Frontiers in immunology · 2021Article
- Antibody-Drug Conjugates for Cancer Therapy.Molecules (Basel, Switzerland) · 2020Review
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Authors and funding
5 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Human IgG comprises four subclasses with different biological functions. The IgG3 subclass has a unique character, exhibiting high effector function and Fab arm flexibility. However, it is not used as a therapeutic drug owing to an enhanced susceptibility to proteolysis. Antibody aggregation control is also important for therapeutic antibody development. To date, there have been few reports of IgG3 aggregation during protein expression and the low pH conditions needed for purification and virus inactivation. This study explored the potential of IgG3 antibody for therapeutics using anti-CD20 IgG3 as a model to investigate aggregate formation. Initially, anti-CD20 IgG3 antibody showed substantial aggregate formation during expression and low pH treatment. To circumvent this phenomenon, we systematically exchanged IgG3 constant domains with those of IgG1, a stable IgG. IgG3 antibody with the IgG1 CH3 domain exhibited reduced aggregate formation during expression. Differential scanning calorimetric analysis of individual amino acid substitutions revealed that two amino acid mutations in the CH3 domain, N392K and M397V, reduced aggregation and increased CH3 transition temperature. The engineered human IgG3 antibody was further improved by additional mutations of R435H to obtain IgG3KVH to achieve protein A binding and showed similar antigen binding as wild-type IgG3. IgG3KVH also exhibited high binding activity for FcγRIIIa and C1q. In summary, we have successfully established an engineered human IgG3 antibody with reduced aggregation during bioprocessing, which will contribute to the better design of therapeutic antibodies with high effector function and Fab arm flexibility.
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