Cited by 265Monoclonal and Polyclonal Antibodies ResearchProtein purification and stabilityBiosimilars and Bioanalytical Methods

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Reduced elimination of IgG antibodies by engineering the variable region

Igawa, T., Tsunoda, H., Tachibana, T., Maeda, A., Mimoto, F., Moriyama, C., Nanami, M., Sekimori, Y., Nabuchi, Y., Aso, Y., Hattori, K.·2010·Protein Engineering Design and Selection

DOI 10.1093/protein/gzq009

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Abstract

Fc engineering to increase the binding affinity of IgG antibodies to FcRn has been reported to reduce the elimination of IgG antibodies. Herein, we present a novel non-FcRn-dependent approach to reduce the elimination of IgG antibodies. Pharmacokinetic studies conducted in normal mice of various humanized IgG4 antibodies, which had identical constant regions but different variable region sequences, revealed that an antibody with a lower isoelectric point (pI) has a longer half-life. These antibodies exhibited comparable binding affinity to FcRn, and with the antibodies with lower pIs, a longer half-life was also observed in beta2-microglobulin knockout mice, suggesting that differences in the pharmacokinetics were due to a non-FcRn-dependent mechanism. On the basis of our findings, we attempted to engineer the pharmacokinetic properties of a humanized anti-IL6 receptor IgG1 antibody. Selected substitutions in the variable region, without substitution in the Fc region, lowered the pI but did not reduce the biological activity and showed a significant reduction in the clearance of the antibody in cynomolgus monkey. These results suggest that lowering the pI by engineering the variable region could reduce the elimination of IgG antibodies and could provide an alternative to Fc engineering of IgG antibodies.

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“have generally near-neutral or basic pHis (pHis 6.5–9.5; Igawa et al., 2010) and could be adsorbed onto the cation-exchanger and then desorbed all along the ionic strength gradient.”
BackgroundInfluential
Effect of copper variation in yeast hydrolysate on C‐terminal lysine levels of a monoclonal antibody
Mitchelson, F. G., Mondia, J. P., & Hughes, E. H. (2016) · Biotechnology Progress · doi:10.1002/btpr.2411 · Cited by 13
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Improved antibody pharmacokinetics by disruption of contiguous positive surface potential and charge reduction using alternate human framework
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“While the correlation between charge and clearance has been demonstrated for a given mAb, studies performed on a larger and more diverse set of mAbs suggested otherwise, illustrating a complex relationship.(5,20,38) Several studies have even highlighted the limitations of charge reduction on mAb disposition, and the p…”
Background
Elimination of plasma soluble antigen in cynomolgus monkeys by combining pH-dependent antigen binding and novel Fc engineering
Hori, Y., Ohmine, K., Katada, H., Noguchi, Y., Sato, K., Nambu, T., Adeline, L. R., Gan, S. W., Haraya, K., Ozeki, K., et al. (2022) · mAbs · doi:10.1080/19420862.2022.2068213 · Cited by 12
Self-citation
Modulation of protein A binding allows single-step purification of mouse bispecific antibodies that retain FcRn binding
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Background
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Cell Penetrating Peptides Conjugated to Anti-Carcinoembryonic Antigen “Catch-and-Release” Monoclonal Antibodies Alter Plasma and Tissue Pharmacokinetics in Colorectal Cancer Xenograft Mice
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“It its worth to mention that for monoclonal antibodies, it has been reported that specific glycan isoforms could affect the affinity to the receptors involved in their effector functions and stability due to charge and steric hindrances [20, 22–25].”
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“This result was to be expected, as all alterations were limited to the Fc-region, even though some studies have suggested that changes in the Fc-region can influence the functionality of the Fab domain and vice versa (Cooper et al., 1994; Igawa et al., 2010; Tudor et al., 2012; Schoch et al., 2015; Jensen et al., 2017…”
Background
Improved pharmacokinetics of HIV-neutralizing VRC01-class antibodies achieved by reduction of net positive charge on variable domain
Kwon, Y. D., Pegu, A., Yang, E. S., Zhang, B., Bender, M. F., Asokan, M., Liu, Q., McKee, K., Lin, B. C., Liu, T. W. B., et al. (2023) · mAbs · doi:10.1080/19420862.2023.2223350 · Cited by 9
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“Some previous efforts to modify charge for pharmacokinetic impact studied large molecules, such as antibody Fc (Boswell et al., 2010; Igawa et al., 2010) in which a few amino acid mutations are less likely to affect protein properties.”
Background
Generation of a Nebulizable CDR-Modified MERS-CoV Neutralizing Human Antibody
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“We preferred negatively charged amino acids to positively charged amino acids as lowering the isoelectric point of an antibody may reduce the non-specific in vivo clearance [43].”
Conformational changes in a Vernier zone region: Implications for antibody dual specificity
Arslan, M., Karadağ, D., & Kalyoncu, S. (2020) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.25964 · Cited by 9
Preferential precipitation of acidic variants from monoclonal antibody pools
Rumanek, T., Kołodziej, M., Piątkowski, W., & Antos, D. (2022) · Biotechnology and Bioengineering · doi:10.1002/bit.28257 · Cited by 9
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Key Physicochemical Characteristics Influencing ADME Properties of Therapeutic Proteins
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Effects of SA237, a humanized anti‐interleukin‐6 receptor monoclonal antibody, on pre‐ and postnatal development in cynomolgus monkey
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Molecular Interaction Characterization Strategies for the Development of New Biotherapeutic Antibody Modalities
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“An indirect capture format is often used in SPR analysis to evaluate protein–protein interactions [3,49].”
Method
Anion solvation enhanced by positive supercharging mutations preserves thermal stability of an antibody in a wide pH range
Kasahara, K., Kuroda, D., Tanabe, A., Kawade, R., Nagatoishi, S., & Tsumoto, K. (2021) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2021.05.053 · Cited by 8
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“This was performed in order to extend the antibody half-life of 5A6.(12) These positions were previously identified during the systematic mutagenesis of the variable region using the 18 other amino acids.”
BackgroundSelf-citation
Evaluation of affibody charge modification identified by synthetic consensus design in molecular PET imaging of epidermal growth factor receptor
Case, B. A., Kruziki, M. A., Stern, L. A., & Hackel, B. J. (2017) · Molecular Systems Design & Engineering · doi:10.1039/c7me00095b · Cited by 8
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A Cell-Based FcRn-dependent Recycling assay for Predictive Pharmacokinetic assessment of Therapeutic Antibodies
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Utility of Cellular Measurements of Non-Specific Endocytosis to Assess the Target-Independent Clearance of Monoclonal Antibodies
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Physiologically Based Modeling of the Pharmacokinetics of “Catch-and-Release” Anti-Carcinoembryonic Antigen Monoclonal Antibodies in Colorectal Cancer Xenograft Mouse Models
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Balancing the Affinity and Pharmacokinetics of Antibodies by Modulating the Size of Charge Patches on Complementarity-Determining Regions
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“[14] that the effect of the antibody charge pI on the PK of IgG antibody is due to non-FcRn binding mechanism and there is a positive correlation between charge and IgG clearance in normal and β2-microglobulin knockout mouse [14].”
Background
Epitope-dependent mechanisms of CD27 neutralization revealed by X-ray crystallography
Obmolova, G., Teplyakov, A., Malia, T., Wunderler, N., Kwok, D. C., Barone, L. R., Sweet, R. W., Ort, T., Scully, M. S., & Gilliland, G. L. (2017) · Molecular Immunology · doi:10.1016/j.molimm.2017.01.005 · Cited by 8
Engineered Charge Redistribution of Gp2 Proteins through Guided Diversity for Improved PET Imaging of Epidermal Growth Factor Receptor
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Utility of physiologically based pharmacokinetic modeling to predict inter-antibody variability in monoclonal antibody pharmacokinetics in mice
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Preclinical pharmacokinetics of a recombinant humanized rabbit anti-VEGF monoclonal antibody in rabbits and monkeys
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Authors: Igawa, T., Tsunoda, H., Tachibana, T., Maeda, A., Mimoto, F., Moriyama, C., Nanami, M., Sekimori, Y., Nabuchi, Y., Aso, Y., & Hattori, K.
Affiliations: Chugai Pharmaceutical Co., Ltd. (Japan) (JP)
ORCID: Igawa, T.
Tsunoda, H.
Tachibana, T.
Maeda, A.
Mimoto, F.
Hattori, K.
Venue: Protein Engineering Design and Selection
Publisher: Oxford University Press (OUP)
Published: 2010-02-15
Volume: 23
Issue: 5
Pages: 385-392
ISSN: 0269-2139 (ISSN-L)
1741-0126
1741-0134
DOI: 10.1093/protein/gzq009
OpenAlex: W2104198642
Cited by: 265
References: 44
Citations by year: 2026: 12 · 2025: 8 · 2024: 15 · 2023: 21 · 2022: 20 · 2021: 22 · 2020: 14 · 2019: 19 · 2018: 25 · 2017: 22 · 2016: 12 · 2015: 22 · 2014: 12 · 2013: 12 · 2012: 17
FWCI: 10.67
Type: journal article
Language: en
Open access: closed
Locations: Protein Engineering Design and Selection (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
Life Sciences › Immunology and Microbiology › Immunology › Biosimilars and Bioanalytical Methods
Keywords: antibody half-life, isoelectric point, humanized monoclonal antibody, IgG4 antibodies, pharmacokinetics, Macaca fascicularis, antibody clearance
MeSH terms: Animals, Antibodies, Monoclonal, Cricetulus, Genetic Engineering, Half-Life, Cricetinae, Humans, Immunoglobulin G, Immunoglobulin Variable Region, Isoelectric Point, Receptors, Fc, Protein Engineering, Histocompatibility Antigens Class I, CHO Cells, Mice

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Reduced elimination of IgG antibodies by engineering the variable region

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