ArticlemAbs
Prevention of Fab-arm exchange and antibody reduction via stabilization of the IgG4 hinge region.
Article in mAbs. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
20 citing papers in PubMed, 31 citations in OpenAlex.
- Engineered CTLA-4 targeting chimeras for targeted protein degradation and immune synapse reprogramming.bioRxiv : the preprint server for biology · 2026Article
- Generation and Characterization of the Human Anti-HTNV Antibody KJJ4.International journal of molecular sciences · 2026Article
- Structure and function of therapeutic antibodies approved by the US FDA in 2025.Antibody therapeutics · 2026Review
- Neuropathic Pain and Distinct CASPR2 Autoantibody IgG Subclasses Drive Neuronal Hyperexcitability.Neurology(R) neuroimmunology & neuroinflammation · 2025Article
- Structure and function of therapeutic antibodies approved by the US FDA in 2024.Antibody therapeutics · 2025Review
- Antibody-drug conjugate: a newly developed biological missile for tumor treatment.Frontiers in oncology · 2025Review
- Plant-derived Durvalumab variants show efficient PD-1/PD-L1 blockade and therapeutically favourable FcR binding.Plant biotechnology journal · 2024Article
- Structure and function of therapeutic antibodies approved by the US FDA in 2023.Antibody therapeutics · 2024Review
- Engineering therapeutic monoclonal antibodies.The Journal of allergy and clinical immunology · 2024Review
- Tau-targeting therapies for Alzheimer disease: current status and future directions.Nature reviews. Neurology · 2023Review
- IgG1 and IgG4 antibodies sample initial structure dependent local conformational states and exhibit non-identical Fab dynamics.Scientific reports · 2023Article
- A homogeneous bioluminescent immunoassay for parallel characterization of binding between a panel of antibodies and a family of Fcγ receptors.Scientific reports · 2022Article
- Targeting tau only extracellularly is likely to be less efficacious than targeting it both intra- and extracellularly.Seminars in cell & developmental biology · 2022Review
- Mechanistic insights into inter-chain disulfide bond reduction of IgG1 and IgG4 antibodies.Applied microbiology and biotechnology · 2022Article
- Communication pathways bridge local and global conformations in an IgG4 antibody.Scientific reports · 2021Article
- Picomolar inhibition of SARS-CoV-2 variants of concern by an engineered ACE2-IgG4-Fc fusion protein.Antiviral research · 2021Article
- Anti-CD40 antibody KPL-404 inhibits T cell-mediated activation of B cells from healthy donors and autoimmune patients.Arthritis research & therapy · 2021Article
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Corrections and comments
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Authors and funding
8 authors at 1 institution in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
IgG4s are dynamic molecules that undergo a process called Fab-arm exchange. Disulfide bonds between heavy chains are transiently reduced, resulting in half antibodies that reform intact antibodies with other IgG4 half antibodies. In vivo, therapeutic IgG4s can recombine with endogenous IgG4s, resulting in a heterogeneous mixture of bispecific antibodies. A related issue that can occur for any therapeutic protein during manufacturing is interchain disulfide bond reduction. For IgG4s, this primarily results in high levels of half-mAb that persist through purification processes. The S228P mutation has been used to prevent half-mAb formation. However, we demonstrated that IgG4s with the S228P mutation are subject to half-mAb formation and Fab-arm exchange in reducing environments. We identified two novel mutations that stabilize the heavy-heavy chain interaction via incorporation of additional disulfide bonds in the hinge region. Individually, these mutations increase stability toward reduction and lessen Fab-arm exchange. Combination of all three mutations, Y219C, G220C, and S228P, has an additive benefit resulting in an IgG4 with ˃7-fold increase in stability toward reduction while preventing Fab-arm exchange. Importantly, the mutations do not affect antigen binding or Fc effector function. These mutations hold great promise for solving mAb reduction during manufacturing and preventing Fab-arm exchange in vivo.
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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.