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Reduced elimination of IgG antibodies by engineering the variable region.

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Title: Reduced elimination of IgG antibodies by engineering the variable region.
Authors: Igawa, T.1 igawatmy@chugai-pharm.co.jp, Tsunoda, H.1, Tachibana, T.1, Maeda, A.1, Mimoto, F.1, Moriyama, C.1, Nanami, M.1, Sekimori, Y.1, Nabuchi, Y.1, Aso, Y.1, Hattori, K.1
Source: PEDS: Protein Engineering, Design & Selection. May2010, Vol. 23 Issue 5, p385-392. 8p. 1 Diagram, 4 Charts, 5 Graphs.
Subjects: Immunoglobulin G, Laboratory mice, Bioengineering, Pharmacokinetics, Immunoglobulins
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 Β2-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. [ABSTRACT FROM AUTHOR]
Copyright of PEDS: Protein Engineering, Design & Selection is the property of Oxford University Press / USA and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
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DbLabel: Engineering Source
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PubType: Academic Journal
PubTypeId: academicJournal
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  Data: Reduced elimination of IgG antibodies by engineering the variable region.
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  Data: <searchLink fieldCode="AR" term="%22Igawa%2C+T%2E%22">Igawa, T.</searchLink><relatesTo>1</relatesTo><i> igawatmy@chugai-pharm.co.jp</i><br /><searchLink fieldCode="AR" term="%22Tsunoda%2C+H%2E%22">Tsunoda, H.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Tachibana%2C+T%2E%22">Tachibana, T.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Maeda%2C+A%2E%22">Maeda, A.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Mimoto%2C+F%2E%22">Mimoto, F.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Moriyama%2C+C%2E%22">Moriyama, C.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Nanami%2C+M%2E%22">Nanami, M.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Sekimori%2C+Y%2E%22">Sekimori, Y.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Nabuchi%2C+Y%2E%22">Nabuchi, Y.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Aso%2C+Y%2E%22">Aso, Y.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Hattori%2C+K%2E%22">Hattori, K.</searchLink><relatesTo>1</relatesTo>
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  Data: <searchLink fieldCode="JN" term="%22PEDS%3A+Protein+Engineering%2C+Design+%26+Selection%22">PEDS: Protein Engineering, Design & Selection</searchLink>. May2010, Vol. 23 Issue 5, p385-392. 8p. 1 Diagram, 4 Charts, 5 Graphs.
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  Data: <searchLink fieldCode="DE" term="%22Immunoglobulin+G%22">Immunoglobulin G</searchLink><br /><searchLink fieldCode="DE" term="%22Laboratory+mice%22">Laboratory mice</searchLink><br /><searchLink fieldCode="DE" term="%22Bioengineering%22">Bioengineering</searchLink><br /><searchLink fieldCode="DE" term="%22Pharmacokinetics%22">Pharmacokinetics</searchLink><br /><searchLink fieldCode="DE" term="%22Immunoglobulins%22">Immunoglobulins</searchLink>
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  Data: 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 Β2-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. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of PEDS: Protein Engineering, Design & Selection is the property of Oxford University Press / USA and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1093/protein/gzq009
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        Text: English
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        PageCount: 8
        StartPage: 385
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      – SubjectFull: Immunoglobulin G
        Type: general
      – SubjectFull: Laboratory mice
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      – SubjectFull: Bioengineering
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      – TitleFull: Reduced elimination of IgG antibodies by engineering the variable region.
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              M: 05
              Text: May2010
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