Loading…

Increasing the serum persistence of an IgG fragment by random mutagenesis

The major histocompatibility complex (MHC) class l-related receptor FcRn is involved in regulating serum gammaglobulin (IgG) levels in mice. With the aim of increasing the serum half-life of a recombinant murine Fcγ1 fragment, the affinity for binding to FcRn at pH 6,0 has been increased by random m...

Full description

Saved in:

Bibliographic Details
Published in:	Nature biotechnology 1997-07, Vol.15 (7), p.637-640
Main Authors:	Ghetie, Victor, Popov, Serguei, Borvak, Jozef, Radu, Caius, Matesoi, Diana, Medesan, Corneliu, Ober, Raimund J, Ward, E. Sally
Format:	Article
Language:	English
Subjects:	Agriculture Animals Base Sequence Bioinformatics Biological and medical sciences Biomedical and Life Sciences Biomedical Engineering/Biotechnology Biomedicine Biotechnology Fundamental and applied biological sciences. Psychology Half-Life Humans Hydrogen-Ion Concentration Immunoglobulin Fragments - blood Immunoglobulin Fragments - genetics Immunoglobulin G - blood Immunoglobulin G - genetics Life Sciences Methods. Procedures. Technologies Mice Mutagenesis Oligodeoxyribonucleotides - genetics Protein Engineering Receptors, IgG - genetics Receptors, IgG - metabolism research-article
Citations:	Items that this one cites Items that cite this one
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

cited_by	cdi_FETCH-LOGICAL-c510t-5537b8f2586974567dd4a3c3fb4ea5154d37e63014fb58550874ca2f1d8166753
cites	cdi_FETCH-LOGICAL-c510t-5537b8f2586974567dd4a3c3fb4ea5154d37e63014fb58550874ca2f1d8166753
container_end_page	640
container_issue	7
container_start_page	637
container_title	Nature biotechnology
container_volume	15
creator	Ghetie, Victor Popov, Serguei Borvak, Jozef Radu, Caius Matesoi, Diana Medesan, Corneliu Ober, Raimund J Ward, E. Sally
description	The major histocompatibility complex (MHC) class l-related receptor FcRn is involved in regulating serum gammaglobulin (IgG) levels in mice. With the aim of increasing the serum half-life of a recombinant murine Fcγ1 fragment, the affinity for binding to FcRn at pH 6,0 has been increased by random mutagenesis of Thr252, Thr254, and Thr256 followed by selection using bacteriophage display. These residues were chosen as they are in proximity to the FcRn-IgG (Fc) interaction site. Two mutants with higher affinity (due to lower off-rates) than the wild-type Fc have been isolated and analyzed in pharmacokinetic studies in mice. The mutant with the highest affinity has a significantly longer serum half-life than the wild type fragment, despite its lower off-rate from FcRn at pH 7.4. The results provide support for the involvement of FcRn in the home-ostasis of serum IgGs in mice. The indications that a homologous FcRn regulates IgG levels in humans suggest that this approach has implications for increasing the serum persistence of therapeutic antibodies.
doi_str_mv	10.1038/nbt0797-637
format	article
fullrecord	<record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_16032128</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>16032128</sourcerecordid><originalsourceid>FETCH-LOGICAL-c510t-5537b8f2586974567dd4a3c3fb4ea5154d37e63014fb58550874ca2f1d8166753</originalsourceid><addsrcrecordid>eNp1kUFLwzAYhoMoc05PnoUI4kWrSdMk7VGGzsLAi55Lmn6pHWs6k_awf29Gy_DiKR-8D--XPEHompInSlj6bMueyExGgskTNKc8EREVmTgNM0llRCgX5-jC-w0hRCRCzNAsi2kWCz5HeW61A-UbW-P-G7AHN7R4B843vgerAXcGK4vzeoWNU3ULtsflHjtlq67F7dCrGiwE-hKdGbX1cDWdC_T19vq5fI_WH6t8-bKONKekjzhnskxNzFORyYQLWVWJYpqZMgHFw-UrJkEwQhNT8pTz8IJEq9jQKqVCSM4W6H7s3bnuZwDfF23jNWy3ykI3-IIKwmIapwF8GEHtOu8dmGLnmla5fUFJcRBXTOKKIC7QN1PtULZQHdnJVMjvplx5rbbBhdWNP2KxlCylh5rHEfMhsTW4YtMNzgYh_2y9HXGr-sHBse7Pl7JfxXiOJA</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>16032128</pqid></control><display><type>article</type><title>Increasing the serum persistence of an IgG fragment by random mutagenesis</title><source>Springer Nature - Connect here FIRST to enable access</source><creator>Ghetie, Victor ; Popov, Serguei ; Borvak, Jozef ; Radu, Caius ; Matesoi, Diana ; Medesan, Corneliu ; Ober, Raimund J ; Ward, E. Sally</creator><creatorcontrib>Ghetie, Victor ; Popov, Serguei ; Borvak, Jozef ; Radu, Caius ; Matesoi, Diana ; Medesan, Corneliu ; Ober, Raimund J ; Ward, E. Sally</creatorcontrib><description>The major histocompatibility complex (MHC) class l-related receptor FcRn is involved in regulating serum gammaglobulin (IgG) levels in mice. With the aim of increasing the serum half-life of a recombinant murine Fcγ1 fragment, the affinity for binding to FcRn at pH 6,0 has been increased by random mutagenesis of Thr252, Thr254, and Thr256 followed by selection using bacteriophage display. These residues were chosen as they are in proximity to the FcRn-IgG (Fc) interaction site. Two mutants with higher affinity (due to lower off-rates) than the wild-type Fc have been isolated and analyzed in pharmacokinetic studies in mice. The mutant with the highest affinity has a significantly longer serum half-life than the wild type fragment, despite its lower off-rate from FcRn at pH 7.4. The results provide support for the involvement of FcRn in the home-ostasis of serum IgGs in mice. The indications that a homologous FcRn regulates IgG levels in humans suggest that this approach has implications for increasing the serum persistence of therapeutic antibodies.</description><identifier>ISSN: 1087-0156</identifier><identifier>EISSN: 1546-1696</identifier><identifier>DOI: 10.1038/nbt0797-637</identifier><identifier>PMID: 9219265</identifier><identifier>CODEN: NABIF9</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>Agriculture ; Animals ; Base Sequence ; Bioinformatics ; Biological and medical sciences ; Biomedical and Life Sciences ; Biomedical Engineering/Biotechnology ; Biomedicine ; Biotechnology ; Fundamental and applied biological sciences. Psychology ; Half-Life ; Humans ; Hydrogen-Ion Concentration ; Immunoglobulin Fragments - blood ; Immunoglobulin Fragments - genetics ; Immunoglobulin G - blood ; Immunoglobulin G - genetics ; Life Sciences ; Methods. Procedures. Technologies ; Mice ; Mutagenesis ; Oligodeoxyribonucleotides - genetics ; Protein Engineering ; Receptors, IgG - genetics ; Receptors, IgG - metabolism ; research-article</subject><ispartof>Nature biotechnology, 1997-07, Vol.15 (7), p.637-640</ispartof><rights>Nature Publishing Company 1997</rights><rights>1997 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c510t-5537b8f2586974567dd4a3c3fb4ea5154d37e63014fb58550874ca2f1d8166753</citedby><cites>FETCH-LOGICAL-c510t-5537b8f2586974567dd4a3c3fb4ea5154d37e63014fb58550874ca2f1d8166753</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,2727,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2773817$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9219265$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ghetie, Victor</creatorcontrib><creatorcontrib>Popov, Serguei</creatorcontrib><creatorcontrib>Borvak, Jozef</creatorcontrib><creatorcontrib>Radu, Caius</creatorcontrib><creatorcontrib>Matesoi, Diana</creatorcontrib><creatorcontrib>Medesan, Corneliu</creatorcontrib><creatorcontrib>Ober, Raimund J</creatorcontrib><creatorcontrib>Ward, E. Sally</creatorcontrib><title>Increasing the serum persistence of an IgG fragment by random mutagenesis</title><title>Nature biotechnology</title><addtitle>Nat Biotechnol</addtitle><addtitle>Nat Biotechnol</addtitle><description>The major histocompatibility complex (MHC) class l-related receptor FcRn is involved in regulating serum gammaglobulin (IgG) levels in mice. With the aim of increasing the serum half-life of a recombinant murine Fcγ1 fragment, the affinity for binding to FcRn at pH 6,0 has been increased by random mutagenesis of Thr252, Thr254, and Thr256 followed by selection using bacteriophage display. These residues were chosen as they are in proximity to the FcRn-IgG (Fc) interaction site. Two mutants with higher affinity (due to lower off-rates) than the wild-type Fc have been isolated and analyzed in pharmacokinetic studies in mice. The mutant with the highest affinity has a significantly longer serum half-life than the wild type fragment, despite its lower off-rate from FcRn at pH 7.4. The results provide support for the involvement of FcRn in the home-ostasis of serum IgGs in mice. The indications that a homologous FcRn regulates IgG levels in humans suggest that this approach has implications for increasing the serum persistence of therapeutic antibodies.</description><subject>Agriculture</subject><subject>Animals</subject><subject>Base Sequence</subject><subject>Bioinformatics</subject><subject>Biological and medical sciences</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedical Engineering/Biotechnology</subject><subject>Biomedicine</subject><subject>Biotechnology</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Half-Life</subject><subject>Humans</subject><subject>Hydrogen-Ion Concentration</subject><subject>Immunoglobulin Fragments - blood</subject><subject>Immunoglobulin Fragments - genetics</subject><subject>Immunoglobulin G - blood</subject><subject>Immunoglobulin G - genetics</subject><subject>Life Sciences</subject><subject>Methods. Procedures. Technologies</subject><subject>Mice</subject><subject>Mutagenesis</subject><subject>Oligodeoxyribonucleotides - genetics</subject><subject>Protein Engineering</subject><subject>Receptors, IgG - genetics</subject><subject>Receptors, IgG - metabolism</subject><subject>research-article</subject><issn>1087-0156</issn><issn>1546-1696</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1997</creationdate><recordtype>article</recordtype><recordid>eNp1kUFLwzAYhoMoc05PnoUI4kWrSdMk7VGGzsLAi55Lmn6pHWs6k_awf29Gy_DiKR-8D--XPEHompInSlj6bMueyExGgskTNKc8EREVmTgNM0llRCgX5-jC-w0hRCRCzNAsi2kWCz5HeW61A-UbW-P-G7AHN7R4B843vgerAXcGK4vzeoWNU3ULtsflHjtlq67F7dCrGiwE-hKdGbX1cDWdC_T19vq5fI_WH6t8-bKONKekjzhnskxNzFORyYQLWVWJYpqZMgHFw-UrJkEwQhNT8pTz8IJEq9jQKqVCSM4W6H7s3bnuZwDfF23jNWy3ykI3-IIKwmIapwF8GEHtOu8dmGLnmla5fUFJcRBXTOKKIC7QN1PtULZQHdnJVMjvplx5rbbBhdWNP2KxlCylh5rHEfMhsTW4YtMNzgYh_2y9HXGr-sHBse7Pl7JfxXiOJA</recordid><startdate>19970701</startdate><enddate>19970701</enddate><creator>Ghetie, Victor</creator><creator>Popov, Serguei</creator><creator>Borvak, Jozef</creator><creator>Radu, Caius</creator><creator>Matesoi, Diana</creator><creator>Medesan, Corneliu</creator><creator>Ober, Raimund J</creator><creator>Ward, E. Sally</creator><general>Nature Publishing Group US</general><general>Nature</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7T5</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope></search><sort><creationdate>19970701</creationdate><title>Increasing the serum persistence of an IgG fragment by random mutagenesis</title><author>Ghetie, Victor ; Popov, Serguei ; Borvak, Jozef ; Radu, Caius ; Matesoi, Diana ; Medesan, Corneliu ; Ober, Raimund J ; Ward, E. Sally</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c510t-5537b8f2586974567dd4a3c3fb4ea5154d37e63014fb58550874ca2f1d8166753</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1997</creationdate><topic>Agriculture</topic><topic>Animals</topic><topic>Base Sequence</topic><topic>Bioinformatics</topic><topic>Biological and medical sciences</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedical Engineering/Biotechnology</topic><topic>Biomedicine</topic><topic>Biotechnology</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Half-Life</topic><topic>Humans</topic><topic>Hydrogen-Ion Concentration</topic><topic>Immunoglobulin Fragments - blood</topic><topic>Immunoglobulin Fragments - genetics</topic><topic>Immunoglobulin G - blood</topic><topic>Immunoglobulin G - genetics</topic><topic>Life Sciences</topic><topic>Methods. Procedures. Technologies</topic><topic>Mice</topic><topic>Mutagenesis</topic><topic>Oligodeoxyribonucleotides - genetics</topic><topic>Protein Engineering</topic><topic>Receptors, IgG - genetics</topic><topic>Receptors, IgG - metabolism</topic><topic>research-article</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ghetie, Victor</creatorcontrib><creatorcontrib>Popov, Serguei</creatorcontrib><creatorcontrib>Borvak, Jozef</creatorcontrib><creatorcontrib>Radu, Caius</creatorcontrib><creatorcontrib>Matesoi, Diana</creatorcontrib><creatorcontrib>Medesan, Corneliu</creatorcontrib><creatorcontrib>Ober, Raimund J</creatorcontrib><creatorcontrib>Ward, E. Sally</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Nature biotechnology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ghetie, Victor</au><au>Popov, Serguei</au><au>Borvak, Jozef</au><au>Radu, Caius</au><au>Matesoi, Diana</au><au>Medesan, Corneliu</au><au>Ober, Raimund J</au><au>Ward, E. Sally</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Increasing the serum persistence of an IgG fragment by random mutagenesis</atitle><jtitle>Nature biotechnology</jtitle><stitle>Nat Biotechnol</stitle><addtitle>Nat Biotechnol</addtitle><date>1997-07-01</date><risdate>1997</risdate><volume>15</volume><issue>7</issue><spage>637</spage><epage>640</epage><pages>637-640</pages><issn>1087-0156</issn><eissn>1546-1696</eissn><coden>NABIF9</coden><abstract>The major histocompatibility complex (MHC) class l-related receptor FcRn is involved in regulating serum gammaglobulin (IgG) levels in mice. With the aim of increasing the serum half-life of a recombinant murine Fcγ1 fragment, the affinity for binding to FcRn at pH 6,0 has been increased by random mutagenesis of Thr252, Thr254, and Thr256 followed by selection using bacteriophage display. These residues were chosen as they are in proximity to the FcRn-IgG (Fc) interaction site. Two mutants with higher affinity (due to lower off-rates) than the wild-type Fc have been isolated and analyzed in pharmacokinetic studies in mice. The mutant with the highest affinity has a significantly longer serum half-life than the wild type fragment, despite its lower off-rate from FcRn at pH 7.4. The results provide support for the involvement of FcRn in the home-ostasis of serum IgGs in mice. The indications that a homologous FcRn regulates IgG levels in humans suggest that this approach has implications for increasing the serum persistence of therapeutic antibodies.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>9219265</pmid><doi>10.1038/nbt0797-637</doi><tpages>4</tpages></addata></record>
fulltext	fulltext
identifier	ISSN: 1087-0156
ispartof	Nature biotechnology, 1997-07, Vol.15 (7), p.637-640
issn	1087-0156 1546-1696
language	eng
recordid	cdi_proquest_miscellaneous_16032128
source	Springer Nature - Connect here FIRST to enable access
subjects	Agriculture Animals Base Sequence Bioinformatics Biological and medical sciences Biomedical and Life Sciences Biomedical Engineering/Biotechnology Biomedicine Biotechnology Fundamental and applied biological sciences. Psychology Half-Life Humans Hydrogen-Ion Concentration Immunoglobulin Fragments - blood Immunoglobulin Fragments - genetics Immunoglobulin G - blood Immunoglobulin G - genetics Life Sciences Methods. Procedures. Technologies Mice Mutagenesis Oligodeoxyribonucleotides - genetics Protein Engineering Receptors, IgG - genetics Receptors, IgG - metabolism research-article
title	Increasing the serum persistence of an IgG fragment by random mutagenesis
url	http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-01T06%3A37%3A23IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Increasing%20the%20serum%20persistence%20of%20an%20IgG%20fragment%20by%20random%20mutagenesis&rft.jtitle=Nature%20biotechnology&rft.au=Ghetie,%20Victor&rft.date=1997-07-01&rft.volume=15&rft.issue=7&rft.spage=637&rft.epage=640&rft.pages=637-640&rft.issn=1087-0156&rft.eissn=1546-1696&rft.coden=NABIF9&rft_id=info:doi/10.1038/nbt0797-637&rft_dat=%3Cproquest_cross%3E16032128%3C/proquest_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c510t-5537b8f2586974567dd4a3c3fb4ea5154d37e63014fb58550874ca2f1d8166753%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=16032128&rft_id=info:pmid/9219265&rfr_iscdi=true