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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Background
Charge variants in IgG1
Khawli, L. A., Goswami, S., Hutchinson, R., Glover, Z. K., Yang, J., Wang, X., Yao, Z., Sreedhara, A., Cano, T., Tesar, D. B., et al. (2010) · mAbs · doi:10.4161/mabs.2.6.13333 · Cited by 437
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Background

See all 265

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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