The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
Reduced elimination of IgG antibodies by engineering the variable region
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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Igawa et al. showed that lowering the total pI by 1–2 units resulted in longer half‐lives and slower elimination rates.41”
From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [41]
Citations
Cites
A JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Lindemann, L., Jaeschke, G., Michalon, A., Vieira, E., Honer, M., Spooren, W., Porter, R., Hartung, T., Kolczewski, S., Büttelmann, B., et al. (1909) · JAMA · doi:10.1001/jama.1909.02550020033007 · Cited by 7,889
Antibody Pharmacokinetics and Pharmacodynamics
Lobo, E. D., Hansen, R. J., & Balthasar, J. P. (2004) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.20178 · Cited by 909
Challenges in the development of high protein concentration formulations
Shire, S. J., Shahrokh, Z., & 刘, J. 军. L. (2004) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.20079 · Cited by 886
Sturniolo, T., Bono, E. B., Ding, J., Raddrizzani, L., Tuereci, O., Şahin, U., Braxenthaler, M., Gallazzi, F., Protti, M. P., Sinigaglia, F., et al. (1999) · Nature Biotechnology · doi:10.1038/9858 · Cited by 743
Challenges in the Development of High Protein Concentration Formulations
Shire, S. J., Shahrokh, Z., & Liu, J. (2009) · Springer eBooks · doi:10.1007/978-0-387-76643-0_9 · Cited by 657
Properties of Human IgG1s Engineered for Enhanced Binding to the Neonatal Fc Receptor (FcRn)
Dall’Acqua, W. F., Kiener, P. A., & Wu, H. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m604292200 · Cited by 648
Stability engineering of antibody single-chain Fv fragments
Wörn, A., & Plückthun, A. (2001) · Journal of Molecular Biology · doi:10.1006/jmbi.2000.4265 · Cited by 616
Therapeutic antibodies for human diseases at the dawn of the twenty-first century
Brekke, O. H., & Sandlie, I. (2002) · Nature Reviews Drug Discovery · doi:10.1038/nrd984 · Cited by 572
Ober, R. J., Radu, C. G., Ghetie, V. F., & Ward, E. S. (2001) · International Immunology · doi:10.1093/intimm/13.12.1551 · Cited by 502
Elimination mechanisms of therapeutic monoclonal antibodies
Tabrizi, M. A., Tseng, C.-M. L., & Roskos, L. K. (2006) · Drug Discovery Today · doi:10.1016/s1359-6446(05)03638-x · Cited by 479
Research works printed but not linked: 4
- Almagro, 2008, Frontiers in bioscience : a journal and virtual library, 13, 1619
- Devenny, 1985, Microcirculation, endothelium, and lymphatics, 2, 15
- Kobayashi, 1999, Cancer Research, 59, 422
- Onda, 2001, Cancer Research, 61, 5070
Cited by
Sorted by citations
Next generation antibody drugs: pursuit of the 'high-hanging fruit'
Carter, P. J., & Lazar, G. A. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.227 · Cited by 780
Antibody Structure and Function: The Basis for Engineering Therapeutics
Chiu, M. L., Goulet, D. R., Teplyakov, A., & Gilliland, G. L. (2019) · Antibodies · doi:10.3390/antib8040055 · Cited by 711
“Consistent with this explanation, engineering IgG variable regions to remove patches of positive charge (without greatly altering protein pI) has also been used to reduce non-specific binding and improve PK [455].”
Kitazawa, T., Igawa, T., Sampei, Z., Muto, A., Kojima, T., Soeda, T., Yoshihashi, K., Okuyama-Nishida, Y., Saito, H., Tsunoda, H., et al. (2012) · Nature Medicine · doi:10.1038/nm.2942 · Cited by 520
Self-citationShah, D. K., & Betts, A. M. (2011) · Journal of Pharmacokinetics and Pharmacodynamics · doi:10.1007/s10928-011-9232-2 · Cited by 431
“[63] suggest that lowering the pI by engineering the variable region could reduce the elimination of mAbs and results from Boswell et al.”
BackgroundKhawli, 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
“Evidence has been presented that deliberately modifying the pI of an antibody by approximately one pI unit or more can give noticeable differences in the pharmacokinetics (PK) of an intact mAb.(29,30) Most studies of antibody charge modifications have involved intravenous (IV) administration; in contrast, there is lit…”
Background
Metadata
- 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)
- 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
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
