Divergent activities of an engineered antibody in murine and human systems have implications for therapeutic antibodies
Divergent activities of an engineered antibody in murine and human systems have implications for therapeutic antibodies
The MHC class I-related receptor, neonatal Fc receptor (FcRn), plays a central role in regulating the transport and in vivo persistence of immunoglobulin G (IgG). IgG-FcRn interactions can be targeted for engineering to modulate the in vivo longevity and transport of an antibody, and this has implications for the successful application of therapeutic IgGs. Although mice are widely used to preclinically test antibodies, human and mouse FcRn have significant differences in binding specificity. Here we show that an engineered human IgG1 has disparate properties in murine and human systems. The mutant shows improved transport relative to wild-type human IgG1 in assays of human FcRn function but has short in vivo persistence and competitively inhibits FcRn activity in mice. These studies indicate potential limitations of using mice as preclinical models for the analysis of engineered antibodies. Alternative assays are proposed that serve as indicators of the properties of IgGs in humans.
Antibody engineering, Half-life, Human IgG1, Maternofetal transfer, Neonatal Fc receptor
18709-18714
Vaccaro, Carlos
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Bawdon, Roger
c7a99f9d-00f9-4d82-8593-e41641819956
Wanjie, Sylvia
a0b1a79e-f760-4aa3-b3e8-39186a9c4ff0
Ober, Raimund J.
31f4d47f-fb49-44f5-8ff6-87fc4aff3d36
Ward, E. Sally
b31c0877-8abe-485f-b800-244a9d3cd6cc
5 December 2006
Vaccaro, Carlos
f576072e-379e-4f42-9bd7-595b2f5b7d58
Bawdon, Roger
c7a99f9d-00f9-4d82-8593-e41641819956
Wanjie, Sylvia
a0b1a79e-f760-4aa3-b3e8-39186a9c4ff0
Ober, Raimund J.
31f4d47f-fb49-44f5-8ff6-87fc4aff3d36
Ward, E. Sally
b31c0877-8abe-485f-b800-244a9d3cd6cc
Vaccaro, Carlos, Bawdon, Roger, Wanjie, Sylvia, Ober, Raimund J. and Ward, E. Sally
(2006)
Divergent activities of an engineered antibody in murine and human systems have implications for therapeutic antibodies.
Proceedings of the National Academy of Sciences of the United States of America, 103 (49), .
(doi:10.1073/pnas.0606304103).
Abstract
The MHC class I-related receptor, neonatal Fc receptor (FcRn), plays a central role in regulating the transport and in vivo persistence of immunoglobulin G (IgG). IgG-FcRn interactions can be targeted for engineering to modulate the in vivo longevity and transport of an antibody, and this has implications for the successful application of therapeutic IgGs. Although mice are widely used to preclinically test antibodies, human and mouse FcRn have significant differences in binding specificity. Here we show that an engineered human IgG1 has disparate properties in murine and human systems. The mutant shows improved transport relative to wild-type human IgG1 in assays of human FcRn function but has short in vivo persistence and competitively inhibits FcRn activity in mice. These studies indicate potential limitations of using mice as preclinical models for the analysis of engineered antibodies. Alternative assays are proposed that serve as indicators of the properties of IgGs in humans.
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e-pub ahead of print date: 20 November 2006
Published date: 5 December 2006
Keywords:
Antibody engineering, Half-life, Human IgG1, Maternofetal transfer, Neonatal Fc receptor
Identifiers
Local EPrints ID: 424100
URI: http://eprints.soton.ac.uk/id/eprint/424100
ISSN: 0027-8424
PURE UUID: 42cdc2c1-9bba-4b30-9593-599d95486705
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Date deposited: 04 Oct 2018 16:30
Last modified: 16 Mar 2024 04:37
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Contributors
Author:
Carlos Vaccaro
Author:
Roger Bawdon
Author:
Sylvia Wanjie
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