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Increasing the affinity of a human IgG1 for the neonatal Fc receptor: Biological consequences

Increasing the affinity of a human IgG1 for the neonatal Fc receptor: Biological consequences
Increasing the affinity of a human IgG1 for the neonatal Fc receptor: Biological consequences

Many biological functions, including control of the homeostasis and maternofetal transfer of serum γ-globulins, are mediated by the MHC class I-related neonatal FcR (FcRn). A correlation exists in mice between the binding affinity of IgG1/Fc fragments to FcRn at pH 6.0 and their serum t1/2. To expand this observation, phage display of mutagenized Fc fragments derived from a human IgG1 was used to increase their affinity to both murine and human FcRn. Ten variants were identified that have a higher affinity toward murine and human FcRn at pH 6.0, with ΔΔG (ΔGwild type - ΔGmutant) from 1.0 to 2.0 kcal/mol and from 0.6 to 2.4 kcal/mol, respectively. Those variants exhibit a parallel increase in binding at pH 7.4 to murine, but not human, FcRn. Although not degraded in blood in vitro, accumulated in tissues, nor excreted in urine, their serum concentration in mice is decreased. We propose that higher affinity to FcRn at pH 7.4 adversely affects release into the serum and offsets the benefit of the enhanced binding at pH 6.0.

0022-1767
5171-5180
Dall' Acqua, William F.
ecf4a7fd-8c01-486e-886f-c6853b4ad3c7
Woods, Robert M.
7988daac-25d9-4177-9fd5-4c85e009a4bb
Ward, E. Sally
b31c0877-8abe-485f-b800-244a9d3cd6cc
Palaszynski, Susan R.
2731ca65-a3eb-450a-8941-ea1a44008005
Patel, Nita K.
51b89940-9544-434d-b85a-d6fb1fae385a
Brewah, Yambasu A.
084c1386-e030-497f-82bd-4bca9c47b0dc
Wu, Herren
4901bfcc-ea08-4c96-a6f9-7600618738e0
Kiener, Peter A.
79c9b4f3-c2c1-45cf-b223-8a851b21b8c6
Langermann, Solomon
c3f46966-bf92-4113-ad50-ef122ac03151
Dall' Acqua, William F.
ecf4a7fd-8c01-486e-886f-c6853b4ad3c7
Woods, Robert M.
7988daac-25d9-4177-9fd5-4c85e009a4bb
Ward, E. Sally
b31c0877-8abe-485f-b800-244a9d3cd6cc
Palaszynski, Susan R.
2731ca65-a3eb-450a-8941-ea1a44008005
Patel, Nita K.
51b89940-9544-434d-b85a-d6fb1fae385a
Brewah, Yambasu A.
084c1386-e030-497f-82bd-4bca9c47b0dc
Wu, Herren
4901bfcc-ea08-4c96-a6f9-7600618738e0
Kiener, Peter A.
79c9b4f3-c2c1-45cf-b223-8a851b21b8c6
Langermann, Solomon
c3f46966-bf92-4113-ad50-ef122ac03151

Dall' Acqua, William F., Woods, Robert M., Ward, E. Sally, Palaszynski, Susan R., Patel, Nita K., Brewah, Yambasu A., Wu, Herren, Kiener, Peter A. and Langermann, Solomon (2002) Increasing the affinity of a human IgG1 for the neonatal Fc receptor: Biological consequences. Journal of Immunology, 169 (9), 5171-5180.

Record type: Article

Abstract

Many biological functions, including control of the homeostasis and maternofetal transfer of serum γ-globulins, are mediated by the MHC class I-related neonatal FcR (FcRn). A correlation exists in mice between the binding affinity of IgG1/Fc fragments to FcRn at pH 6.0 and their serum t1/2. To expand this observation, phage display of mutagenized Fc fragments derived from a human IgG1 was used to increase their affinity to both murine and human FcRn. Ten variants were identified that have a higher affinity toward murine and human FcRn at pH 6.0, with ΔΔG (ΔGwild type - ΔGmutant) from 1.0 to 2.0 kcal/mol and from 0.6 to 2.4 kcal/mol, respectively. Those variants exhibit a parallel increase in binding at pH 7.4 to murine, but not human, FcRn. Although not degraded in blood in vitro, accumulated in tissues, nor excreted in urine, their serum concentration in mice is decreased. We propose that higher affinity to FcRn at pH 7.4 adversely affects release into the serum and offsets the benefit of the enhanced binding at pH 6.0.

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Published date: 1 November 2002

Identifiers

Local EPrints ID: 425138
URI: http://eprints.soton.ac.uk/id/eprint/425138
ISSN: 0022-1767
PURE UUID: bb1d8f8d-715b-48ec-b9b0-8c6da81deb10
ORCID for E. Sally Ward: ORCID iD orcid.org/0000-0003-3232-7238

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Date deposited: 11 Oct 2018 16:30
Last modified: 07 Oct 2020 02:22

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Contributors

Author: William F. Dall' Acqua
Author: Robert M. Woods
Author: E. Sally Ward ORCID iD
Author: Susan R. Palaszynski
Author: Nita K. Patel
Author: Yambasu A. Brewah
Author: Herren Wu
Author: Peter A. Kiener
Author: Solomon Langermann

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