ArticlemAbs2015
Balancing charge in the complementarity-determining regions of humanized mAbs without affecting pI reduces non-specific binding and improves the pharmacokinetics.
Article in mAbs, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 100 papers.
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Who cites it
100 citing papers in PubMed, 145 citations in OpenAlex.
- Article
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- Predicting Aberrant Fc-fusion Protein Pharmacokinetics from In Silico Structural Properties and Physiologically Based Pharmacokinetic (PBPK) Modeling.The AAPS journal · 2026Article
- Integrative structural insights into the IgG-FcRn interactions revealed by engineered FcRn-immobilized affinity chromatography.Communications biology · 2026Article
- Enhancing polyreactivity prediction of preclinical antibodies through fine-tuned protein language models.Journal of pharmaceutical analysis · 2025Article
- Antibody Polyreactivity: A Challenger of Immune Paradigms.Immunology · 2025Review
- Probing the extent of importin-α targeting of the TAF8 NLS by eliminating its cationic net-charge.Protein science : a publication of the Protein Society · 2025Article
- Enhanced plasma half-life and efficacy of engineered human albumin-fused GLP-1 despite enzymatic cleavage of its C-terminal end.Communications biology · 2025Article
- Antigen-presenting cell internalization is key for understanding and evaluating therapeutic antibodies' immunogenicity.Frontiers in immunology · 2025Review
- Isoelectric point, net charge and amino acid analysis of experimentally validated therapeutic antibodies.In silico pharmacology · 2025Article
- Steered molecular dynamics simulation as a post-process to optimize the iBRAB-designed Fab model.Journal of computer-aided molecular design · 2024Article
- Human antibody polyreactivity is governed primarily by the heavy-chain complementarity-determining regions.Cell reports · 2024Article
- Engineering of pH-dependent antigen binding properties for toxin-targeting IgG1 antibodies using light-chain shuffling.Structure (London, England : 1993) · 2024Article
- Protein language models enable prediction of polyreactivity of monospecific, bispecific, and heavy-chain-only antibodies.Antibody therapeutics · 2024Article
- Long-Acting Strategies for Antibody Drugs: Structural Modification, Controlling Release, and Changing the Administration Route.European journal of drug metabolism and pharmacokinetics · 2024Review
- Antibody Drug Clearance: An Underexplored Marker of Outcomes with Checkpoint Inhibitors.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Review
- Tau-targeting therapies for Alzheimer disease: current status and future directions.Nature reviews. Neurology · 2023Review
- Defining and Studying B Cell Receptor and TCR Interactions.Journal of immunology (Baltimore, Md. : 1950) · 2023Article
- Physiologically Based Pharmacokinetic Modeling to Characterize the Effect of Molecular Charge on Whole-Body Disposition of Monoclonal Antibodies.The AAPS journal · 2023Article
40 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Lowering the isoelectric point (pI) through engineering the variable region or framework of an IgG can improve its exposure and half-life via a reduction in clearance mediated through non-specific interactions. As such, net charge is a potentially important property to consider in developing therapeutic IgG molecules having favorable pharmaceutical characteristics. Frequently, it may not be possible to shift the pI of monoclonal antibodies (mAbs) dramatically without the introduction of other liabilities such as increased off-target interactions or reduced on-target binding properties. In this report, we explored the influence of more subtle modifications of molecular charge on the in vivo properties of an IgG1 and IgG4 monoclonal antibody. Molecular surface modeling was used to direct residue substitutions in the complementarity-determining regions (CDRs) to disrupt positive charge patch regions, resulting in a reduction in net positive charge without affecting the overall pI of the mAbs. The effect of balancing the net positive charge on non-specific binding was more significant for the IgG4 versus the IgG1 molecule that we examined. This differential effect was connected to the degree of influence on cellular degradation in vitro and in vivo clearance, distribution and metabolism in mice. In the more extreme case of the IgG4, balancing the charge yielded an ∼7-fold improvement in peripheral exposure, as well as significantly reduced tissue catabolism and subsequent excretion of proteolyzed products in urine. Balancing charge on the IgG1 molecule had a more subtle influence on non-specific binding and yielded only a modest alteration in clearance, distribution and elimination. These results suggest that balancing CDR charge without affecting the pI can lead to improved mAb pharmacokinetics, the magnitude of which is likely dependent on the relative influence of charge imbalance and other factors affecting the molecule's disposition.
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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.